Skip to main content
Erschienen in: Cancer and Metastasis Reviews 1-2/2012

Open Access 01.06.2012 | NON-THEMATIC REVIEW

Biological influence of Hakai in cancer: a 10-year review

verfasst von: Luis A. Aparicio, Manuel Valladares, Moisés Blanco, Guillermo Alonso, Angélica Figueroa

Erschienen in: Cancer and Metastasis Reviews | Ausgabe 1-2/2012

Abstract

In order to metastasize, cancer cells must first detach from the primary tumor, migrate, invade through tissues, and attach to a second site. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells that is characterized as a potent tumor suppressor and is modulated during various processes including epithelial–mesenchymal transition. Recent data have provided evidences for novel biological functional role of Hakai during tumor progression and other diseases. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago and its implication in human cancer disease. We will highlight the different signaling pathways leading to the influence on Hakai and suggest its potential usefulness as therapeutic target for cancer.

1 Introduction

Most of the human common tumors are carcinomas; which arise from epithelial cells. Epithelial cells are connected to each other by cell–cell contacts which determine cell polarity and participate in cell differentiation and in the establishment and maintenance of tissue homeostasis. Cell–cell contacts are regulated in epithelial cells during embryonic development and in disease such as tumor development. For instance, the downregulation of cell–cell adhesion is a hallmark characteristic of epithelia–mesenchymal transitions (EMT), a process by which cells lose their polarized epithelial phenotype and concomitantly acquire a migratory or mesenchymal phenotype [1]. E-cadherin is the best characterized and prototype member of the classical cadherins in epithelial cells and is characterized as a potent tumor suppressor, being considered hallmark of tumor malignancy [2]. Epithelial tumors often lose E-cadherin partially or completely as they progress toward malignancy [3, 4]; and most studies have shown its anti-invasive and antimetastatic roles [5, 6]. Given the huge importance of E-cadherin in cancer field, it has been extensively studied the mechanisms involved on its inactivation in human cancers; up to date, it has been addressed several mechanisms: first, a genetic mechanism, such as inherited or somatic mutations; second, epigenetic mechanism, such as hypermethylation of E-cadherin promoter or transcriptional silencing by different repressor including Twist, Snail, and ZEB family members and their respective miRNA regulators; and third, E-cadherin can also be regulated by posttranslational modifications, such as phosphorylation, glycosylation, and proteolytic processing [7, 8]. In 2002, it was identified the first posttranslational regulator of E-cadherin stability, named Hakai [9]; since then many articles have described the emerging biological functions for Hakai protein pointing out its influence on tumor progression and disease. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago.

2 Hakai role at adherens junctions

In polarized epithelia of vertebrates, adhesion between epithelial cells is mediated by distinct junctional complexes named tight junctions, at the apical site, adherens junctions (AJ) at the subapical site, and desmosomes, at basolateral site [10]; these three types of junctions are linked to the cytoskeletal filaments. Although all types of junctions are functionally important, it has been shown that AJ are crucial for the regulation of the dynamics of epithelial cell sheet and can also transmit intracellular signals to the interior of the cell under response of extracellular stimuli [11]. AJ are adhesive structures that are regulated in a Ca2+-dependent manner. Calcium-dependent junctions are constitute by a group of type-I transmembrane proteins, and its founding member was termed cadherin [12, 13]. Related molecules identified were also called by several names, such as uvomorulin [14], L-CAM [15], and A-CAM [16]. Original cadherins form a superfamily that is now called “classical” cadherins; however, it has been discovered other members (desmocollin, desmoglein, μ-protocadherin, CNR-cadherin, seven transmembrane cadherin, T-cadherin, and FAT-family cadherins) [17]; moreover, other proteins called nectins were later identified as an AJ components, a family of immunoglobulin-like transmembrane proteins that function in a calcium-independent way to promote cell–cell adhesion [18]. The classical cadherins comprises more than 20 members that contain a common organization domain. The members are called E-cadherin (epithelial, Cdh1), N-cadherin (neuronal, Cdh2), P-cadherin (placental, Cdh3), and so on, each of which shows a distinct tissue distribution [19]. The organization domain consists of an extracellular domain and a cytoplasmic domain. The extracellular domain is divided into five repetitive subdomains, also called cadherin repeats, and every subdomain contain calcium-binding sequences [20]. On its association with calcium, the extracellular domain of cadherins of a cell form homophilic interactions with the extracellular domain of the cadherin of neighboring cell (Fig. 1a, epithelial phenotype). The cytoplasmic domain is highly conserved among classical cadherins and interacts with cytosolic proteins called catenins [2123]. p120 and β-catenin (homologous to Drosophila melanogaster Armadillo) bind to the cytoplasmic tail of the cadherins, and β-catenin binds to α-catenin to form the cadherin–catenin complex. It has been shown that the link of cadherin to the actin cytoskeleton is mediated through the constant shuttling of α-catenin between cadherin/β-catenins and actin which may be a key to explain the dynamic aspect of cell–cell adhesion [24, 25]. Cadherin-based cell–cell contacts are not static but are often dynamically modulated during various physiological and pathological processes including mitosis, epithelial–mesenchymal transition during tumor progression and embryonic development. In all these processes, cadherin has been reported to be downregulated by endocytosis. In epithelial cells, activation of tyrosine kinases such as epidermal growth factor receptor (EGFR), the hepatocyte growth factor (HGF) receptor c-Met, the fibroblast growth factor receptor or Src, induces cell scattering and a fibroblast-like morphology [26, 27]. Met and Src, respectively, have an active function in this process, as they phosphorylate tyrosine residues in the cytoplasmic domain of E-cadherin, thereby promoting its internalization by endocytosis. Fujita et al. [9] underlined the molecular mechanism responsible for this internalization. A new protein named Hakai (which means destruction in Japanese) was identified as a responsible for the binding to the tyrosine phosphorylated E-cadherin mediating its internalization and subsequent ubiquitin-dependent degradation thereby altering cell–cell contacts. In the ubiquitination process, ubiquitin moieties itself is involved and three different types of enzymes: the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2), and a variety of ubiquitin ligases (E3). The E3 ubiquititn ligases provides the specificity as they recognize the substrate through highly specific protein–protein interactions [28]. Hakai, also known as CBLL1, functions as an E3 ubiquitin ligase for E-cadherin that binds to its cytoplasmic domain after tyrosin phosphorylation by tyrosine kinase v-Src. The Src family plays a pivotal role in the regulation of several biological functions associated to changes in morphology, including malignant transformation, cell plasticity, and modulation of intercellular adhesion during EMT [29]. Hakai induces E2-dependent ubiquitination of the E-cadherin complex followed by endocytosis, disrupting cell–cell adhesions and facilitating cell motility under physiological conditions. Although the ubiquitination is one of the most general mechanisms to target cytosolic or nuclear proteins for degradation via proteasome, many membrane proteins have triggered degradation into lysosomes. The first work published in Saccharomyces cerevisiae demonstrated that Ste2p, a G protein-coupled cell surface receptor, undergone ligand-dependent ubiquitination, following internalization into vesicle to be finally degraded into lysosomes [30]. In fact, it has been shown that upon activation of Src in Madin-Darby canine kidney (MDCK) cells, intracellular E-cadherin is shuttled to the lysosomes for degradation, instead of following normal route of the non-ubiquitinated E-cadherin that is recycled back to the lateral plasma membrane to reform new cell–cell contacts [3133]. Indeed, the modification of E-cadherin by ubiquitin is essential for its sorting to the lysosomes, which occurs by a process mediated by hepatocyte growth factor receptor substrate and the activation of specific Rab GTPases (Rab5 and Rab7). Rab5-GTP may serve to enhance the rate of E-cadherin transport, and Rab7 activation may serve to shift the balance to endocytic traffic toward the lysosomes. In consequence, cell–cell contacts do not reform and cells remain motile which underlined the first posttranslational mechanism to downregulate E-cadherin during EMT (Fig. 1b, fibroblast-like phenotype) [934].
Hakai protein was identified by using yeast 2-hybrid screen of an E10.5 mouse cDNA library (on which a bait vector containing an activated Met-kinase, trp-Met) fused to the C-terminal sequence E-cadherin. The cytoplasmic domain of the E-cadherin contains two sequences, cadherin homology 2 (CH2) and cadherin homology 3 (CH3) domains, conserved between classical cadherins; respectively [35, 36]. p120 and β-catenin can interact with these two domains, respectively; however, its interaction does not depend on the activation of trp-Met. Instead, Hakai interacts with the all cytoplasmic domain, the CH2 domain contains three closed tyrosine residues (in mouse: 756, 757, and 758), of which the first and second ones are specific for E-cadherin and the third one is also conserved between cadherins, including N and OB cadherins. Hakai was unable to interact with these two cadherins, neither with several tyrosine kinase receptors, suggesting that its binding is specific on phosphorylated E-cadherin. By the identification of the crystal structure of p120-catenin in complex with the fragment of cadherin it was proposed that p120 might influence the stability and function in cell–cell adhesion complexes [37, 38]. p120-catenin can interact to the juxtamembrane domain of E-cadherin (including tyrosine-phosphorylation sites, where Hakai is also able to interact), therefore, it was believed that the binding of p120 to the juxtamembrane domain of cadherin block factors such as the ubiquitin-ligase Hakai and components of the endocytic machinery, which tag and target cadherin for destruction and internalization [9, 3739]. It was proposed that p120 associates with cadherin through both “static” and “dynamic” interactions over an extended stretch of the juxtamembrane domain. The static interactions reflect strong interactions mediated by the highly conserved core of the juxtamembrane domain, and the dynamic interactions, presumably reflect interactions with lower affinity. These motifs in the juxtamembrane domain coincide with those linked to endocytosis by clathrin or Hakai-associated mechanisms [37, 38]. The binding sites for Hakai and p120 are closely apposed in the intracellular juxtamembrane domain of E-cadherin and, accordingly, p120 is displaced by the binding of Hakai to E-cadherin before endocytosis [9]. Moreover, it is well-known that p120 is also phosphorylated by Src kinase and receptor tyrosine kinases [40] and that acidic pH activates c-Src [41]. An acidic extracellular pH is a feature of the tumor microenvironment and has been associated with tumor behavior [42, 43]. Chen et al. showed that acidic extracellular pH induced activation of Src and Fyn and resulting in a tyrosine phosphorylation of E-cadherin and p120 in HepG2 epithelial cells, which was subsequently bound to Hakai and ubiquitin. In consequence, an acidic pH is also weakening the association of E-cadherin and p120 and contributing to the instability of E-cadherin at adherens junctions [41, 44].

3 In vivo studies of Hakai at adherens junctions

The functional role for Hakai in vivo came out in studies carried out in D. melanogaster. Hakai is highly conserved in metazoans, however, in Drosophila, Hakai did not interact directly to the intracellular domain of Drosophila E-cadherin, suggesting not only a different mode of association between these proteins but also that Drosophila Hakai does not play a major and direct role in downregulation of E-cadherin levels [45]. As the structure of Drosophila Hakai protein predicts cytoplasmic localization, its interaction to Drosophila E-cadherin is likely indirect, involving at least components that binds the cytoplasmic Hakai protein and the extracellular or transmembrane domain of E-cadherin. Indeed, Hakai overexpressed was absent from cell–cell interfaces, but it localized with E-cadherin in cytoplasmic vesicles that are different from known endosomal compartments labeled with Rab5, Rab7, or Rab11. These results suggested that Hakai coexist with E-cadherin in an intracellular vesicle compartment that still has not been identified. Only when E-cadherin was coexpressed together with Hakai, they were both found enriched at cell–cell contacts sites. Moreover, by in situ hybridization, Hakai mRNA expression was highly detected in blastoderm stage embryos and transcripts persisted up to stage 14; high levels of Hakai mRNA was also detected in migrating endoderm cells, distributed through membranous structure in the cytoplasm, perinuclear region, and the plasma membrane, suggesting its possible implication in the migration of these cells over the visceral mesoderm. As endoderm epithelia and visceral mesoderm do not express E-cadherin, additional Drosophila Hakai targets need to be identified and its possible implication in cell adhesion and migration in endoderm and visceral development (for human Hakai substrates see below). In addition, a number of proteins that can interact with Drosophila Hakai were identified, underlying the importance of aPKC and TNF-like protein IMD (immune deficiency). In conclusion, that Hakai is essential for early embryonic morphogenesis was demonstrated in Drosophila, and may also be involved in regulating multiple target proteins that can influence epithelial development in Drosophila [45].

4 Hakai molecular structure

E3 ubiquitin ligases contain motifs for recognizing specific substrates proteins and are key control points for protein ubiquitination. Up to now, the majority of the ubiquitin ligases identified can be divided into two categories on specific structural motifs: (A) those containing HECT domain and (B) those containing the RING-finger domain [46, 47]. The Cbl family ubiquitin ligase in mammals contains three members: c-Cbl, Cbl-b, and Cbl-c. These members are a single subunit RING-finger E3 containing several motifs surrounding the RING finger: a highly conserved N-terminal phosphor-Tyr binding (pTyr-B) domain that is composed of a four-helix bundle, a calcium-binding domain known as “EF hand”, and an atypical SH2 (Src homology 2) domain. The pTyr-B domain mediates interactions between CBL proteins and the phosphorylated residues on its CBL substrates. The RING finger and pTyr-B domains are separated by an α-helical linker region, important for the regulation on its E3 ligase function. In the C-terminal region, CBL proteins have proline-rich domains that mediate interactions with SH3-containing proteins, and tyrosine that become phosphorylated and mediate interactions with SH2 proteins [28]. In eukaryotic cells, phosphorylation regulates cell signaling by pTyr-B domains typified by the SH2 and pTyr-B (PTB) domains. By molecular modeling, it was assumed that the pTyr-B domain of Hakai was a derivative SH2 domain [9], (Fig. 2a). Hakai contains three domains: a typical RING finger, a short pTyr-B domain, and a proline-rich domain [9], considering that Hakai was structurally and functionally related to c-Cbl. Hakai contains 491 amino acids, sharing 97% homology between human and mouse sequences. The predicted amino acid sequence at its N-terminal contained a C3HC4-type RING finger domain, also present in many E3 ubiquitin ligases [48, 49], and in the C-terminal region, 35% of the amino acids are proline residues. However, Hakai and c-Cbl are not true homologues. A recent study has deepened into the molecular structure of E3 ubiquitin-ligase Hakai highlighting a novel pTyr-B domain [50]. This domain was named HYB (Hakai pTyr-binding) and consists of a homodimer formed at a structurally novel interface. Each monomer consists of two, a RING finger domain and a short pTyr-B domain that incorporates an atypical and novel zinc-finger coordination motif that incorporate connected configuration (Fig. 2b). Therefore, the HYB is constituted by four zinc-binding domains that participate to bind pTyr residues surrounded by acidic amino acids [50]. The previously described target motif was in Src-phophorylated E-cadherin, where two consecutive tyrosine residues (Y753 and Y754 in humans) were reported to be involved in the interaction with Hakai. They analyzed the contribution of these tyr residues and conclude that the phosphorylation of Y754 of the E-cadherin is the only tyrosine significantly involved in the binding, and also that a cluster of negative charges from acidic amino acids around this Y754 of E-cadherin was also important. Indeed, they have shown an important contribution from aspartic acid (D756) and glutamic acid (E757), and significant contributions from valine (V752) and aspartic acid (D750). By mass spectrometry, they also identified a list of novel Hakai-binding proteins phosphorylated by Src. They showed that like E-cadherin, cortactin and DOK1 interact with Hakai only when phosphorylated by Src. Moreover, they suggested that this novel HYB identified was also present in other proteins such as ZNF645, a testis-specific human E3 ubiquitin ligase [51], and possibly in Ligand-of-Numb protein X1 and 2 (LNX1 and LXN2). Hakai and ZNF645 share significant homology, however ZNF645 bound to v-Src phosphorylated E-cadherin but not to cortactin, indicating that they likely have their own sets of targets due to differences found in their sequences between the key zinc-coordinating residues. By tissue distribution, they also suggest that ZNF645, found only in primates, is most likely a recent copy of Hakai and an intronless, indicating that is a retrotransposed copy of Hakai [50]. In conclusion, by combining biochemical and crystal structural analyses, authors demonstrated important mechanism by which E3 ubiquitin ligase Hakai binds its targets molecules. They identified a novel HYB domain that is present in other E3 ubiquitin ligases proteins, often deregulated in cancer and other disease. Therefore, it is suggested that this HYB domain can represent a specific target for directed therapies in cancer.

5 Hakai in response to oncogenic signaling pathways

Although it was demonstrated that Src expression regulates ubiquitin-dependent E-cadherin lysosomal degradation [33], it was no until 2008 when for the first time Shen et al. reported upstream regulation [52]. It was previously established that Src, and non-receptor kinase, is a central regulator of signaling downstream of EGFR and it was also shown to regulate EMT by disrupting adherens junctions [53, 54]. On the other hand, Rho GTPases, including Cdc42, Rac1, and RhoA, have all been described to regulate adherens junctions [55, 56]. The majority of previously published data showed that the internalized E-cadherin induced by Ca2+ depletion was either recycled back to the plasma membrane or transiently maintained in endosomes of the cells [31, 57]. Given the roles of Cdc42, Src, and EGFR in adherens junction dynamics, it was studied whether they cooperatively contribute to the dissolution of adherens junctions, leading to E-cadherin ubiquitination and degradation. They demonstrated that after Ca2+ depletion Cdc42 was activated and in consequence it was initiated the activation of EGFR and Src. Activated Src, in turn, tyrosine phosphorylate E-cadherin, leading to Hakai-mediated E-cadherin ubiquitination. Furthermore, they reported that Cdc42 binds to E-cadherin in a GTP-dependent manner and that this binding is essential for Cdc42 to induce the dissolution of adherens junctions [52] (Fig. 3a).
On the other hand, the role of Rack1 in integrin-mediated cell adhesion is well established; however, the function in cell–cell adhesion through E-cadherin was not clear. RACK1 is one of a group of PKC-interacting proteins collectively called receptors for activated c-kinases (RACKs). It was also previously reported that Rack1 acts as a substrate and inhibitor of Src [5860], regulating cell growth through the inhibition of Src activity at G1 and mitotic cell-cycle checkpoints and cell survival pathways [6163]. Taken in consideration these premises, in 2011, it was addressed the effect of Rack1 on Src signaling and its function on E-cadherin-mediated cell–cell adhesions [64]. It was shown that Rack1 promotes cell–cell adhesion by stabilizing E-cadherin and catenins at cell–cell junctions and reduces invasive potential of colon carcinoma cells. Rack1 suppresses the tyrosine phosphorylation of E-cadherin and its binding catenins, attenuating the downstream ubiquitination of E-cadherin, by disrupting Src–E-cadherin–Hakai interactions, and endocytosis of E-cadherin. In consequence, it promotes the reassembly of cell–cell contacts. Moreover, it was demonstrated that Rack1 also block HGF-induced cell scattering by inhibiting E-cadherin endocytosis and junctional disassembly. Therefore, Rack1 targets both Src- and growth-factor-dependent pathways of E-cadherin endocytosis to promote cell–cell adhesion [64], (Fig. 3a).
Given the increasing recognized importance of the EMT process during cancer progression (e.g., from benign adenoma to metastasic carcinoma) several groups have also focused in studying the induction of EMT in response to different signaling pathway and its influence on the E-cadherin downregulation through Hakai action. It is well established that tumor growth factor β (TGFβ) signaling plays an important role in EMT [65]. In fact, adding TGFβ to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. In several epithelial models, cooperation of the Raf/ERK/MAPK pathways and TGFβ signaling is required for induction and maintenance of EMT in vitro and in vivo [66, 67]. Janda et al. have demonstrated how MAPK pathway and TGFβ signaling crosstalk to regulate E-cadherin expression at the initial phases of EMT [68]. They have shown that E-cadherin is downregulated at posttranslational level at the onset of the EMT and not at transcriptional level, as it happens to the majority of genes targets regulated through the cooperation between TGFβ and Raf. This is due to an enhanced endocytosis and lysosomal degradation induced by synergistic activation of both pathways. Moreover, they demonstrated that Raf and TGFβ also cooperate in the induction of E-cadherin monoubiquitination; this effect is explained by TGFβ-dependent transcriptional induction of the E3 ubiquitin ligase Hakai and the Raf-dependent tyrosine phosphorylation of E-cadherin. Although Raf cannot directly phosphorylate E-cadherin on tyrosines, an increase in tyrosine phosphorylation upon Raf hyperactivation suggest that Raf/MAPK pathway triggers a multitude of tyrosine kinases, such as Src that may directly phosphorylate E-cadherin (Fig. 3b). However, they suggested that additional mechanism may exist to induce lysosomal degradation and/or proteolytic cleavage of E-cadherin under the cooperative action of Raf and TGFβ as ubiquitin tagging is not sufficient for E-cadherin degradation [68]. Taken all these publications, Hakai seems to be involved downstream of important signaling pathways involved during tumor progression and in consequence more studies are required to elucidate the emerging role for Hakai as a potential therapeutic target.

6 Hakai downstream of Slit-Robo signaling

It is well established that the Slits secreted proteins guide neuronal and leukocyte migration through their Roundabout (Robo) transmembrane receptors [69, 70]. Moreover, it has been reported that Slit proteins secreted by solid tumors binds to Robo1 expressed in vascular and lymphatic endothelial cells to stimulate angiogenesis and lymphangiogenesis [71, 72]. Slit2 mediates directional migration of glioma cells [73] and its expression is elevated in human colorectal carcinoma tissues and cell lines [71] and Robo1 was found upregulated in colorectal carcinoma tissues, suggesting the possibility of an autocrine mechanism through which colorectal carcinoma cells secrete Slit2 for signaling through Robo1 expressed on these same cells. Zhou et al. investigated the molecular mechanism of autocrine Slit-Robo signaling to induce malignant transformation during pathogenesis of colorectal epithelial cell carcinoma [74]. They found that the overexpression of Slit2 and Robo1, and also the treatment with ectopic Slit2 of Robo1-positive cells with recombinant Slit1, induced EMT-like phenotype, while knockdown of Robo1 or blockade of Slit2 binding to Robo1 triggered the mesenchymal–epithelial transition (MET)-like phenotype. Robo1-Slit2 recruited Hakai to E-cadherin promoting its ubiquitination and lysosomal degradation. These experimental finding provide evidence for induction of EMT-like phenotype through Hakai-mediated E-cadherin downregulation during epithelial colorectal cell carcinogenesis by autocrine Slit-Robo signaling (Fig. 3c). However, Slit-Robo signaling did not significantly reduce E-cadherin levels through transcriptional suppression of E-cadherin or its known transcriptional repressors (Twist, Snail, Slug, or Zeb2). In this regard, Slit-Robo may resemble TGFβ, HGF, Wnt/Frizzled, estrogen, bone morphogenetic proteins, and microRNAs for reversible epithelial to mesenchymal-like transition and cell migration. These data were consistent to the clinical analysis of 472 clinical cases, where metastasis human colorectal carcinoma tissues samples showed an increase in pan-Slit, mainly Slit2, and Robo1 expression compared to non-metastasic samples. Therefore, these findings also reinforce the possibility to investigate inhibitors of Hakai and/or Slit-Robo signaling in clinical testing for treating colorectal carcinoma.

7 Hakai functional role independent of E-cadherin

Other functional roles for Hakai have been addressed independently of E-cadherin protein. This idea came from the novel human Hakai substrates identified [45, 50] and also from the observation of two RNA bands of 2.5 and 4.8 Kb detected by northern blot in most mouse tissues (including testis, heart, brain, spleen, lung, liver, skeletal muscle, and kidney); moreover, mRNA Hakai was detected during developmental stages from days 7 to 17 in postnatal mice. Furthermore, Hakai protein is ubiquitously detected even in tissues that do not contain E-cadherin, such as endoderm epithelia or visceral mesoderm in Drosophila, and also in human spleen and skeletal muscle [9, 45]. Indeed, in 2009 Figueroa et al. described polypyrimidine tract-binding protein-associated splicing factor (PSF) as a novel Hakai-interacting protein in cells that do not contain E-cadherin, however they did not obtain evidence showing that Hakai induces ubiquitination of PSF. PSF was firstly identified as an RNA-binding protein, but it was also shown to affect multiple cellular processes, including transcription, pre-mRNA processing, nuclear retention, or DNA relaxation [7577]. By using cDNA arrays, they determined various specific PSF-associated mRNAs encoding proteins that are involved in several cancer-related processes. Hakai affected the ability of PSF to bind these mRNAs [78, 79]. Furthermore, in this study it is shown that Hakai is involved in the regulation of cell proliferation in an E-cadherin downregulation-independent manner. Hakai overexpression promotes proliferation of various cultured cell lines and the knockdown of Hakai significantly suppressed proliferation of transformed epithelial cells. Additionally, the expression of Hakai was correlated to the proliferation rate in hyperproliferative human tissues Hakai such as endometrium and lymph nodes. Two proteins were proposed to influence proliferation through Hakai: PSF and cyclin D1. They suggested that Hakai may regulate cell proliferation by modulating PSF activity. In Hakai-overexpressing epithelial cells, stable knockdown of PSF partially suppressed the proliferative influence of Hakai overexpression. Moreover, expression of a Hakai mutant lacking the RING finger sequence suppressed cell proliferation, suggesting that this region of Hakai is necessary for promoting cell division. This Hakai mutant was able to bind PSF, indicating that Hakai’s interaction with PSF alone did not promote cell proliferation. The physical and functional interactions between PSF and the E3 ubiquitin-ligase activity of Hakai await further analysis. In another hand, PSF co-localizes with Hakai in the nucleus, raising the possibility that Hakai could play a role in the nucleus through its association with PSF [78, 79]. According to the possible role of Hakai in the nucleus, later report shows that Hakai is a corepressor of estrogen receptor alpha (ERα) in breast cancer cells. By transiently transfection of Hakai, it can repress the transactivation of the ERα through the direct binding to the ERα and by the recruitment of coactivators such as SRC-1 and GRIP-1 (also known as SRC-2) [80]. Hakai overexpression in a tetracycline-induced manner decreased proliferation and migration of ERα-dependent breast cancer MCF-7 cells [80]. These results contrast with previously reported [78] on which overexpression of Hakai increased proliferation in stable cell lines epithelial MDCK. Therefore, Hakai may exert positive or negative control of cell proliferation in different physiological or pathological conditions. Like Hakai, some ubiquitin ligases are reported to function as transcriptional regulators such as E2 ubiquitin ligase BRCA1 that modulate ERα transactivation [81], or RING finger LIM domain-interacting protein that enhanced the activation on targets genes mediated by ERα while it inhibits transcriptional activity of LIM-HD [82]. Therefore, Hakai was proposed as corepressor of ERα playing a role in the development and progression of breast cancer cells. It is possible that the proline-rich domain at the C-terminus of Hakai could be the responsible domain for the repression activity, as this domain is commonly contained in repression domains or near to them, as evidenced in p53 [83], Groucho [84], and HNF4 [85]. As it was previously reported for other E3 ubiquitin ligases [86], these findings suggest that Hakai can have ubiquitin-independent functions in the nucleus or in the cytoplasm that may influence the cell phenotype, in addition to its influence on known substrates (like E-cadherin) or other Hakai interacting proteins.

8 Hakai and cancer: clinical applications

There are several lines of evidence that supported a multiple function of Hakai in tumorigenesis. Firstly, it was reported that Hakai induced anchorage-independent cell growth; moreover, Hakai is highly upregulated in human colon and gastric adenocarcinomas compared to normal tissues [78]. New investigations found a low expression of Hakai and E-cadherin or an inverse correlation between both proteins, while comparing several colon adenocarcinomas although the meaning of these results has to be further investigated [87]. Secondly, in epithelial cells expressing E-cadherin shRNA do not extend spiky protrusions that are seen in Hakai-overexpressing cells [88], suggesting that Hakai can also affect cellular phenotypes in an E-cadherin-independent manner. Hakai is localized at the end of the protrusion where FAK, focal adhesion kinase, is also enriched in Hakai-overexpressing MDCK cells, suggesting that Hakai may be involved in regulating the dynamic extension and retraction of these structures and in influencing cell motility [78]. Hakai’s influence on cell attachment to the substrate and invasion capacity of epithelial MDCK cells was addressed [89]. In this system, Hakai overexpression leads to a reduction in cell adhesion to the substrate with impact on decreasing protein levels of Paxillin, a key focal adhesion-associated protein, although its downregulation was controlled by a proteasome-independent mechanism [89]. Nevertheless, further investigations of Hakai in in vitro and in vivo model systems would lead us to validate its role during tumorigenesis.
Taking together the previous published reports of Hakai during tumor progression, it is increasingly apparent that further investigations of its physiological and pathological functional role would lead us to a novel molecular target for cancer treatment. Up to now, there is only one reported publication on which it is studied the molecular mechanism involving Hakai under the action of an agent against cancer metastasis. One emerging approach in cancer management is the use of “nutraceuticals”, which are relatively nontoxic, cost-effective, and physiologically bioavailable component. Silibinin, a flavonoid from milk thistle seed extract, is a widely consumed dietary supplement that shows a strong efficacy both in vitro and in vivo against prostate cancer, establishing also its implication on epithelial–mesenchymal transition [9092]. Despite the previous finding describing the role of silibinin, the main molecular targets responsible for its strong antimigratory and anti-invasive efficacy remained inconclusive. A recent study demonstrated that silibinin inhibits invasive and migratory potential of several highly metastasic cell lines at nontoxic concentrations. Under these conditions, an increased E-cadherin expression at cellular membrane and an inhibition of nuclear β-catenin level was found, accompanied to a decreased level of Hakai, phospho Src (tyr419), Slug Snail, and phosphor-Akt (ser473) levels, proposing these proteins as a molecular targets implicated in the antimigratory and anti-invasive efficacy of silibinin in prostate cancer cells [93]. These findings have an important translational relevance as the concentration of silibinin used in these studies are within the range of free silibinin levels achieved in the plasma of pancreatic cancer patients in a reported phase I clinical trial [94].

9 Other Hakai clinical applications

Apart from the revised functional role of Hakai in cancer, it is also important to mention Hakai importance in other cellular processes and diseases. In a microarray profiling Hakai was found differentially expressed during erythroid differentiation of murine erythroleukemia cells, suggesting the possibility of considering Hakai as a marker for erythropoiesis [95]. Moreover, Hakai was also proposed to be used to evaluate the mechanism of action of immunosuppressive chemicals on which Hakai expression could be novel gene marker for immunosuppression in mouse lymph node assay [96]. More importantly, there are several reported publications that describe Hakai role in infectious disease. The first work describing Hakai in this process was by Krishnan et al. [97]. By using a human genome-wide RNAi screen they identified Hakai as a protein that affect West Nile virus (WNV) infection. WNV is a type of virus known as flavivirus that constitute a significant global human health problem [98]. They identified 20 ubiquitination-related proteins involved and they proposed Hakai to be involved in the cellular internalization of WNV. They demonstrated that Hakai and the proteasome–ubiquitin system are required for the cellular internalization of WNV [97]. This idea was controversial as later report did not support this data suggesting that Hakai is dispensable for cellular internalization during flavivirus entry [99], and that the apparent role of Hakai in WNV infection proposed by Krishnan et al. [97] could reflect an off-target effect produced by the RNA intereference screen used. They rather support a critical role of the ubiquitin/proteasome system during a post-entry step of the WNV life cycle, and that the proteasome activity is required for amplification of several flavivirus genome [99]. Still, the implication of Hakai during WNV infectious needs to be clarified. Other important studies on Hakai in infectious disease were reported in Listeria monocytogenes. Upon infection Listeria leads to a wide range of symptoms associated to listeriosis, such as gastroenteritis, fetoplacental, and central nervous system infections [100]. Internalization of L. monocytogenes with non-phagocytic cells mainly occurs via two bacterial surface proteins: internalin-A (InIA) and internalin-B (InIB) that has E-cadherin and Met as their respective major host-cell surface receptors [101, 102]. InIA interaction with E-cadherin activates β- and α-catenin-mediated signaling pathways involved in the formation of adherens junctions. The initial signals triggered by the interaction of InIA with E-cadherin enhances the internalization of E-cadherin by Src-mediated tyrosine phosphorylation of E-cadherin followed by its ubiquitination by ubiquitin-ligase Hakai [103]. These posttranslational modifications also occur during bacterial infections and are necessary for an efficient InIA-mediated bacterial internalization which it was shown to be dependent on both caveolin and clathrin. All these data document not only how the endocytosis machinery is recruited and involved in the internalization of L. monocytogenes but also suggest a functional link between E-cadherin endocytosis and the formation of adherens junctions in epithelial cells [103].

10 Conclusions

Taking in consideration the last 10 years of knowledge regarding Hakai, the acquired importance of this protein in cancer and other diseases is increasing apparent. All these reports point out the need to further investigate more deeply the molecular mechanism by which Hakai mediates its action on tumor progression, not only by its influence on EMT though E-cadherin downregulation but also by its influence on early stages of tumor formation. Moreover, novel human substrates in the nucleus or in the cytoplasm for Hakai need to be identified to clarify its influence on cell phenotype, including cell-substrate and invasion capability in tumor cells. Also, more investigations need to address the apparent relevance of Hakai ubiquitin-independent functions that may influence on the cell phenotype. Therefore, Hakai can have different functional roles in different physiological or pathological conditions; in consequence, it is also important to highlight the influence of different signaling pathways on Hakai and to investigate its clinical potential usefulness as therapeutic target for cancer.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Grant support

A.F. is supported by Secretaria Xeral I + D + I, Xunta de Galicia, Spain (IPP.08-07). This work is supported by a grant from Conselleria de Sanidade (PS09/24) and from Secretaria Xeral I + D + I, (10CSA916023PR), both from Xunta de Galicia, Spain.

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

e.Med Innere Medizin

Kombi-Abonnement

Mit e.Med Innere Medizin erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Innere Medizin, den Premium-Inhalten der internistischen Fachzeitschriften, inklusive einer gedruckten internistischen Zeitschrift Ihrer Wahl.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

Literatur
1.
Zurück zum Zitat Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7(2), 131–142.PubMedCrossRef Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7(2), 131–142.PubMedCrossRef
2.
3.
Zurück zum Zitat Birchmeier, W., & Behrens, J. (1994). Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochimica et Biophysica Acta, 1198(1), 11–26.PubMed Birchmeier, W., & Behrens, J. (1994). Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochimica et Biophysica Acta, 1198(1), 11–26.PubMed
4.
Zurück zum Zitat Christofori, G., & Semb, H. (1999). The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends in Biochemical Sciences, 24(2), 73–6.PubMedCrossRef Christofori, G., & Semb, H. (1999). The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends in Biochemical Sciences, 24(2), 73–6.PubMedCrossRef
5.
Zurück zum Zitat Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H., & Christofori, G. (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 392(6672), 190–193.PubMedCrossRef Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H., & Christofori, G. (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 392(6672), 190–193.PubMedCrossRef
6.
Zurück zum Zitat Vleminckx, K., Vakaet, L., Mareel, M., Fiers, W., & van Roy, F. (1991). Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell, 66(1), 107–119.PubMedCrossRef Vleminckx, K., Vakaet, L., Mareel, M., Fiers, W., & van Roy, F. (1991). Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell, 66(1), 107–119.PubMedCrossRef
7.
Zurück zum Zitat Berx, G., & Van Roy, F. (2009). Involvement of members of the cadherin superfamily in cancer (pp. 1–27). Cold Spring Harbor: Cold Spring Harb Perspect Biol. Berx, G., & Van Roy, F. (2009). Involvement of members of the cadherin superfamily in cancer (pp. 1–27). Cold Spring Harbor: Cold Spring Harb Perspect Biol.
8.
Zurück zum Zitat van Roy, F., & Berx, G. (2008). The cell–cell adhesion molecule E-cadherin. Cellular and Molecular Life Sciences, 65(23), 3756–3788.PubMedCrossRef van Roy, F., & Berx, G. (2008). The cell–cell adhesion molecule E-cadherin. Cellular and Molecular Life Sciences, 65(23), 3756–3788.PubMedCrossRef
9.
Zurück zum Zitat Fujita, Y., Krause, G., Scheffner, M., Zechner, D., Leddy, H., Behrens, J., et al. (2002). Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature Cell Biology, 4(3), 222–231.PubMedCrossRef Fujita, Y., Krause, G., Scheffner, M., Zechner, D., Leddy, H., Behrens, J., et al. (2002). Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature Cell Biology, 4(3), 222–231.PubMedCrossRef
10.
Zurück zum Zitat Farquhar, M. G., & Palade, G. E. (1963). Junctional complexes in various epithelia. The Journal of Cell Biology, 17, 375–412.PubMedCrossRef Farquhar, M. G., & Palade, G. E. (1963). Junctional complexes in various epithelia. The Journal of Cell Biology, 17, 375–412.PubMedCrossRef
11.
Zurück zum Zitat D'Souza-Schorey, C. (2005). Disassembling adherens junctions: Breaking up is hard to do. Trends in Cell Biology, 15(1), 19–26.PubMedCrossRef D'Souza-Schorey, C. (2005). Disassembling adherens junctions: Breaking up is hard to do. Trends in Cell Biology, 15(1), 19–26.PubMedCrossRef
12.
Zurück zum Zitat Yoshida, C., & Takeichi, M. (1982). Teratocarcinoma cell adhesion: Identification of a cell-surface protein involved in calcium-dependent cell aggregation. Cell, 28(2), 217–224.PubMedCrossRef Yoshida, C., & Takeichi, M. (1982). Teratocarcinoma cell adhesion: Identification of a cell-surface protein involved in calcium-dependent cell aggregation. Cell, 28(2), 217–224.PubMedCrossRef
13.
Zurück zum Zitat Yoshida-Noro, C., Suzuki, N., & Takeichi, M. (1984). Molecular nature of the calcium-dependent cell–cell adhesion system in mouse teratocarcinoma and embryonic cells studied with a monoclonal antibody. Developmental Biology, 101(1), 19–27.PubMedCrossRef Yoshida-Noro, C., Suzuki, N., & Takeichi, M. (1984). Molecular nature of the calcium-dependent cell–cell adhesion system in mouse teratocarcinoma and embryonic cells studied with a monoclonal antibody. Developmental Biology, 101(1), 19–27.PubMedCrossRef
14.
Zurück zum Zitat Peyriéras, N., Hyafil, F., Louvard, D., Ploegh, H. L., & Jacob, F. (1983). Uvomorulin: A nonintegral membrane protein of early mouse embryo. Proceedings of the National Academy of Sciences of the United States of America, 80(20), 6274–6277.PubMedCrossRef Peyriéras, N., Hyafil, F., Louvard, D., Ploegh, H. L., & Jacob, F. (1983). Uvomorulin: A nonintegral membrane protein of early mouse embryo. Proceedings of the National Academy of Sciences of the United States of America, 80(20), 6274–6277.PubMedCrossRef
15.
Zurück zum Zitat Gallin, W. J., Edelman, G. M., & Cunningham, B. A. (1983). Characterization of L-CAM, a major cell adhesion molecule from embryonic liver cells. Proceedings of the National Academy of Sciences of the United States of America, 80(4), 1038–1042.PubMedCrossRef Gallin, W. J., Edelman, G. M., & Cunningham, B. A. (1983). Characterization of L-CAM, a major cell adhesion molecule from embryonic liver cells. Proceedings of the National Academy of Sciences of the United States of America, 80(4), 1038–1042.PubMedCrossRef
16.
Zurück zum Zitat Volk, T., & Geiger, B. (1984). A 135-kd membrane protein of intercellular adherens junctions. EMBO Journal, 3(10), 2249–2260.PubMed Volk, T., & Geiger, B. (1984). A 135-kd membrane protein of intercellular adherens junctions. EMBO Journal, 3(10), 2249–2260.PubMed
17.
Zurück zum Zitat Angst, B. D., Marcozzi, C., & Magee, A. I. (2001). The cadherin superfamily. Journal of Cell Science, 114(Pt 4), 625–626.PubMed Angst, B. D., Marcozzi, C., & Magee, A. I. (2001). The cadherin superfamily. Journal of Cell Science, 114(Pt 4), 625–626.PubMed
18.
Zurück zum Zitat Nakanishi, H., & Takai, Y. (2004). Roles of nectins in cell adhesion, migration and polarization. Biological Chemistry, 385(10), 885–892.PubMedCrossRef Nakanishi, H., & Takai, Y. (2004). Roles of nectins in cell adhesion, migration and polarization. Biological Chemistry, 385(10), 885–892.PubMedCrossRef
19.
Zurück zum Zitat Takeichi, M. (1988). The cadherins: Cell–cell adhesion molecules controlling animal morphogenesis. Development, 102(4), 639–655.PubMed Takeichi, M. (1988). The cadherins: Cell–cell adhesion molecules controlling animal morphogenesis. Development, 102(4), 639–655.PubMed
20.
Zurück zum Zitat Overduin, M., Harvey, T. S., Bagby, S., Tong, K. I., Yau, P., Takeichi, M., et al. (1995). Solution structure of the epithelial cadherin domain responsible for selective cell adhesion. Science, 267(5196), 386–389.PubMedCrossRef Overduin, M., Harvey, T. S., Bagby, S., Tong, K. I., Yau, P., Takeichi, M., et al. (1995). Solution structure of the epithelial cadherin domain responsible for selective cell adhesion. Science, 267(5196), 386–389.PubMedCrossRef
21.
Zurück zum Zitat Nishimura, T., & Takeichi, M. (2009). Remodeling of the adherens junctions during morphogenesis. Current Topics in Developmental Biology, 89, 33–54.PubMedCrossRef Nishimura, T., & Takeichi, M. (2009). Remodeling of the adherens junctions during morphogenesis. Current Topics in Developmental Biology, 89, 33–54.PubMedCrossRef
22.
Zurück zum Zitat Pokutta, S., & Weis, W. I. (2007). Structure and mechanism of cadherins and catenins in cell–cell contacts. Annual Review of Cell and Developmental Biology, 23, 237–261.PubMedCrossRef Pokutta, S., & Weis, W. I. (2007). Structure and mechanism of cadherins and catenins in cell–cell contacts. Annual Review of Cell and Developmental Biology, 23, 237–261.PubMedCrossRef
23.
Zurück zum Zitat Perez-Moreno, M., & Fuchs, E. (2006). Catenins: Keeping cells from getting their signals crossed. Developmental Cell, 11(5), 601–612.PubMedCrossRef Perez-Moreno, M., & Fuchs, E. (2006). Catenins: Keeping cells from getting their signals crossed. Developmental Cell, 11(5), 601–612.PubMedCrossRef
24.
Zurück zum Zitat Drees, F., Pokutta, S., Yamada, S., Nelson, W. J., & Weis, W. I. (2005). Alpha-catenin is a molecular switch that binds E-cadherin–beta-catenin and regulates actin-filament assembly. Cell, 123(5), 903–915.PubMedCrossRef Drees, F., Pokutta, S., Yamada, S., Nelson, W. J., & Weis, W. I. (2005). Alpha-catenin is a molecular switch that binds E-cadherin–beta-catenin and regulates actin-filament assembly. Cell, 123(5), 903–915.PubMedCrossRef
25.
Zurück zum Zitat Yamada, S., Pokutta, S., Drees, F., Weis, W. I., & Nelson, W. J. (2005). Deconstructing the cadherin–catenin–actin complex. Cell, 123(5), 889–901.PubMedCrossRef Yamada, S., Pokutta, S., Drees, F., Weis, W. I., & Nelson, W. J. (2005). Deconstructing the cadherin–catenin–actin complex. Cell, 123(5), 889–901.PubMedCrossRef
26.
Zurück zum Zitat Behrens, J., Vakaet, L., Friis, R., Winterhager, E., Van Roy, F., Mareel, M. M., et al. (1993). Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. The Journal of Cell Biology, 120(3), 757–766.PubMedCrossRef Behrens, J., Vakaet, L., Friis, R., Winterhager, E., Van Roy, F., Mareel, M. M., et al. (1993). Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. The Journal of Cell Biology, 120(3), 757–766.PubMedCrossRef
27.
Zurück zum Zitat Stoker, M., & Gherardi, E. (1991). Regulation of cell movement: The motogenic cytokines. Biochimica et Biophysica Acta, 1072(1), 81–102.PubMed Stoker, M., & Gherardi, E. (1991). Regulation of cell movement: The motogenic cytokines. Biochimica et Biophysica Acta, 1072(1), 81–102.PubMed
28.
Zurück zum Zitat Lipkowitz, S., & Weissman, A. M. (2011). RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nature Reviews. Cancer, 11(9), 629–643.PubMedCrossRef Lipkowitz, S., & Weissman, A. M. (2011). RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nature Reviews. Cancer, 11(9), 629–643.PubMedCrossRef
29.
Zurück zum Zitat Frame, M. C., Fincham, V. J., Carragher, N. O., & Wyke, J. A. (2002). v-Src's hold over actin and cell adhesions. Nature Reviews Molecular Cell Biology, 3(4), 233–245.PubMedCrossRef Frame, M. C., Fincham, V. J., Carragher, N. O., & Wyke, J. A. (2002). v-Src's hold over actin and cell adhesions. Nature Reviews Molecular Cell Biology, 3(4), 233–245.PubMedCrossRef
30.
Zurück zum Zitat Hicke, L., & Riezman, H. (1996). Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell, 84(2), 277–287.PubMedCrossRef Hicke, L., & Riezman, H. (1996). Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell, 84(2), 277–287.PubMedCrossRef
31.
Zurück zum Zitat Le, T. L., Yap, A. S., & Stow, J. L. (1999). Recycling of E-cadherin: A potential mechanism for regulating cadherin dynamics. The Journal of Cell Biology, 146(1), 219–232.PubMedCrossRef Le, T. L., Yap, A. S., & Stow, J. L. (1999). Recycling of E-cadherin: A potential mechanism for regulating cadherin dynamics. The Journal of Cell Biology, 146(1), 219–232.PubMedCrossRef
32.
Zurück zum Zitat Palacios, F., Price, L., Schweitzer, J., Collard, J. G., & D'Souza-Schorey, C. (2001). An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. EMBO Journal, 20(17), 4973–4986.PubMedCrossRef Palacios, F., Price, L., Schweitzer, J., Collard, J. G., & D'Souza-Schorey, C. (2001). An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. EMBO Journal, 20(17), 4973–4986.PubMedCrossRef
33.
Zurück zum Zitat Palacios, F., Tushir, J., Fujita, Y., & D'Souza-Schorey, C. (2005). Lysosomal targeting of E-cadherin: A unique mechanism for the down-regulation of cell–cell adhesion during epithelial to mesenchymal transitions. Molecular and Cellular Biology, 25(1), 389–402.PubMedCrossRef Palacios, F., Tushir, J., Fujita, Y., & D'Souza-Schorey, C. (2005). Lysosomal targeting of E-cadherin: A unique mechanism for the down-regulation of cell–cell adhesion during epithelial to mesenchymal transitions. Molecular and Cellular Biology, 25(1), 389–402.PubMedCrossRef
34.
Zurück zum Zitat Weidner, K. M., Behrens, J., Vandekerckhove, J., & Birchmeier, W. (1990). Scatter factor: Molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol, 5, 2097–2108.CrossRef Weidner, K. M., Behrens, J., Vandekerckhove, J., & Birchmeier, W. (1990). Scatter factor: Molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol, 5, 2097–2108.CrossRef
35.
Zurück zum Zitat Takeichi, M. (1995). Morphogenetic roles of classic cadherins. Current Opinion in Cell Biology, 7(5), 619–627.PubMedCrossRef Takeichi, M. (1995). Morphogenetic roles of classic cadherins. Current Opinion in Cell Biology, 7(5), 619–627.PubMedCrossRef
36.
Zurück zum Zitat Gumbiner, B. M. (2000). Regulation of cadherin adhesive activity. The Journal of Cell Biology, 148(3), 399–404.PubMedCrossRef Gumbiner, B. M. (2000). Regulation of cadherin adhesive activity. The Journal of Cell Biology, 148(3), 399–404.PubMedCrossRef
37.
Zurück zum Zitat Ishiyama, N., Lee, S., Liu, S., Li, G., Smith, M., Reichardt, L., et al. (2010). Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell–cell adhesion. Cell, 141(1), 117–128.PubMedCrossRef Ishiyama, N., Lee, S., Liu, S., Li, G., Smith, M., Reichardt, L., et al. (2010). Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell–cell adhesion. Cell, 141(1), 117–128.PubMedCrossRef
38.
39.
Zurück zum Zitat Potter, M. D., Barbero, S., & Cheresh, D. A. (2005). Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. The Journal of Biological Chemistry, 280(36), 31906–31912.PubMedCrossRef Potter, M. D., Barbero, S., & Cheresh, D. A. (2005). Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. The Journal of Biological Chemistry, 280(36), 31906–31912.PubMedCrossRef
40.
Zurück zum Zitat Reynolds, A. B., & Roczniak-Ferguson, A. (2004). Emerging roles for p120-catenin in cell adhesion and cancer. Oncogene, 23(48), 7947–7956.PubMedCrossRef Reynolds, A. B., & Roczniak-Ferguson, A. (2004). Emerging roles for p120-catenin in cell adhesion and cancer. Oncogene, 23(48), 7947–7956.PubMedCrossRef
41.
Zurück zum Zitat Chen, K. H., Tung, P. Y., Wu, J. C., Chen, Y., Chen, P. C., Huang, S. H., et al. (2008). An acidic extracellular pH induces Src kinase-dependent loss of beta-catenin from the adherens junction. Cancer Letters, 267(1), 37–48.PubMedCrossRef Chen, K. H., Tung, P. Y., Wu, J. C., Chen, Y., Chen, P. C., Huang, S. H., et al. (2008). An acidic extracellular pH induces Src kinase-dependent loss of beta-catenin from the adherens junction. Cancer Letters, 267(1), 37–48.PubMedCrossRef
42.
Zurück zum Zitat Parks, S. K., Chiche, J., & Pouyssegur, J. (2011). pH control mechanisms of tumor survival and growth. Journal of Cellular Physiology, 226(2), 299–308.PubMedCrossRef Parks, S. K., Chiche, J., & Pouyssegur, J. (2011). pH control mechanisms of tumor survival and growth. Journal of Cellular Physiology, 226(2), 299–308.PubMedCrossRef
43.
Zurück zum Zitat Neri, D., & Supuran, C. T. (2011). Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery, 10(10), 767–77.PubMedCrossRef Neri, D., & Supuran, C. T. (2011). Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery, 10(10), 767–77.PubMedCrossRef
44.
Zurück zum Zitat Chen, Y., Chen, C., Tung, P., Huang, S., & Wang, S. (2009). An acidic extracellular pH disrupts adherens junctions in HepG2 cells by Src kinases-dependent modification of E-cadherin. Journal of Cellular Biochemistry, 108(4), 851–859.PubMedCrossRef Chen, Y., Chen, C., Tung, P., Huang, S., & Wang, S. (2009). An acidic extracellular pH disrupts adherens junctions in HepG2 cells by Src kinases-dependent modification of E-cadherin. Journal of Cellular Biochemistry, 108(4), 851–859.PubMedCrossRef
45.
Zurück zum Zitat Kaido, M., Wada, H., Shindo, M., & Hayashi, S. (2009). Essential requirement for RING finger E3 ubiquitin ligase Hakai in early embryonic development of Drosophila. Genes to Cells, 14(9), 1067–1077.PubMedCrossRef Kaido, M., Wada, H., Shindo, M., & Hayashi, S. (2009). Essential requirement for RING finger E3 ubiquitin ligase Hakai in early embryonic development of Drosophila. Genes to Cells, 14(9), 1067–1077.PubMedCrossRef
46.
Zurück zum Zitat Ardley, H. C., & Robinson, P. A. (2005). E3 ubiquitin ligases. Essays in Biochemistry, 41, 15–30.PubMedCrossRef Ardley, H. C., & Robinson, P. A. (2005). E3 ubiquitin ligases. Essays in Biochemistry, 41, 15–30.PubMedCrossRef
47.
Zurück zum Zitat Jackson, P. K., Eldridge, A. G., Freed, E., Furstenthal, L., Hsu, J. Y., Kaiser, B. K., et al. (2000). The lore of the RINGs: Substrate recognition and catalysis by ubiquitin ligases. Trends in Cell Biology, 10(10), 429–439.PubMedCrossRef Jackson, P. K., Eldridge, A. G., Freed, E., Furstenthal, L., Hsu, J. Y., Kaiser, B. K., et al. (2000). The lore of the RINGs: Substrate recognition and catalysis by ubiquitin ligases. Trends in Cell Biology, 10(10), 429–439.PubMedCrossRef
48.
Zurück zum Zitat Joazeiro, C. A., Wing, S. S., Huang, H., Leverson, J. D., Hunter, T., & Liu, Y. C. (1999). The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science, 286(5438), 309–312.PubMedCrossRef Joazeiro, C. A., Wing, S. S., Huang, H., Leverson, J. D., Hunter, T., & Liu, Y. C. (1999). The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science, 286(5438), 309–312.PubMedCrossRef
49.
Zurück zum Zitat Levkowitz, G., Waterman, H., Ettenberg, S. A., Katz, M., Tsygankov, A. Y., Alroy, I., et al. (1999). Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Molecular Cell, 4(6), 1029–1040.PubMedCrossRef Levkowitz, G., Waterman, H., Ettenberg, S. A., Katz, M., Tsygankov, A. Y., Alroy, I., et al. (1999). Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Molecular Cell, 4(6), 1029–1040.PubMedCrossRef
50.
Zurück zum Zitat Mukherjee, M., Chow, S. Y., Yusoff, P., Seetharaman, J., Ng, C., Sinniah, S., et al. (2012). Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO Journal. doi:emboj2011496. Mukherjee, M., Chow, S. Y., Yusoff, P., Seetharaman, J., Ng, C., Sinniah, S., et al. (2012). Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO Journal. doi:emboj2011496.
51.
Zurück zum Zitat Liu, Y., Bai, G., Zhang, H., Su, D., Tao, D., Yang, Y., et al. (2010). Human RING finger protein ZNF645 is a novel testis-specific E3 ubiquitin ligase. Asian Journal of Andrology, 12(5), 658–66.PubMedCrossRef Liu, Y., Bai, G., Zhang, H., Su, D., Tao, D., Yang, Y., et al. (2010). Human RING finger protein ZNF645 is a novel testis-specific E3 ubiquitin ligase. Asian Journal of Andrology, 12(5), 658–66.PubMedCrossRef
52.
Zurück zum Zitat Shen, Y., Hirsch, D. S., Sasiela, C. A., & Wu, W. J. (2008). Cdc42 regulates E-cadherin ubiquitination and degradation through an epidermal growth factor receptor to Src-mediated pathway. Journal of Biological Chemistry, 283(8), 5127–5137.PubMedCrossRef Shen, Y., Hirsch, D. S., Sasiela, C. A., & Wu, W. J. (2008). Cdc42 regulates E-cadherin ubiquitination and degradation through an epidermal growth factor receptor to Src-mediated pathway. Journal of Biological Chemistry, 283(8), 5127–5137.PubMedCrossRef
53.
Zurück zum Zitat Ishizawar, R., & Parsons, S. J. (2004). c-Src and cooperating partners in human cancer. Cancer Cell, 6(3), 209–214.PubMedCrossRef Ishizawar, R., & Parsons, S. J. (2004). c-Src and cooperating partners in human cancer. Cancer Cell, 6(3), 209–214.PubMedCrossRef
54.
Zurück zum Zitat Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2(6), 442–454.PubMedCrossRef Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2(6), 442–454.PubMedCrossRef
55.
Zurück zum Zitat Braga, V. (2000). Epithelial cell shape: Cadherins and small GTPases. Experimental Cell Research, 261(1), 83–90.PubMedCrossRef Braga, V. (2000). Epithelial cell shape: Cadherins and small GTPases. Experimental Cell Research, 261(1), 83–90.PubMedCrossRef
56.
Zurück zum Zitat Sahai, E., & Marshall, C. J. (2002). RHO-GTPases and cancer. Nature Reviews Cancer, 2(2), 133–142.PubMedCrossRef Sahai, E., & Marshall, C. J. (2002). RHO-GTPases and cancer. Nature Reviews Cancer, 2(2), 133–142.PubMedCrossRef
57.
Zurück zum Zitat Bryant, D. M., & Stow, J. L. (2004). The ins and outs of E-cadherin trafficking. Trends in Cell Biology, 14(8), 427–434.PubMedCrossRef Bryant, D. M., & Stow, J. L. (2004). The ins and outs of E-cadherin trafficking. Trends in Cell Biology, 14(8), 427–434.PubMedCrossRef
58.
Zurück zum Zitat Chang, B. Y., Conroy, K. B., Machleder, E. M., & Cartwright, C. A. (1998). RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of src tyrosine kinases and growth of NIH 3T3 cells. Molecular and Cellular Biology, 18(6), 3245–3256.PubMed Chang, B. Y., Conroy, K. B., Machleder, E. M., & Cartwright, C. A. (1998). RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of src tyrosine kinases and growth of NIH 3T3 cells. Molecular and Cellular Biology, 18(6), 3245–3256.PubMed
59.
Zurück zum Zitat Chang, B. Y., Chiang, M., & Cartwright, C. A. (2001). The interaction of Src and RACK1 is enhanced by activation of protein kinase C and tyrosine phosphorylation of RACK1. Journal of Biological Chemistry, 276(23), 20346–20356.PubMedCrossRef Chang, B. Y., Chiang, M., & Cartwright, C. A. (2001). The interaction of Src and RACK1 is enhanced by activation of protein kinase C and tyrosine phosphorylation of RACK1. Journal of Biological Chemistry, 276(23), 20346–20356.PubMedCrossRef
60.
Zurück zum Zitat Chang, B. Y., Harte, R. A., & Cartwright, C. A. (2002). RACK1: A novel substrate for the Src protein-tyrosine kinase. Oncogene, 21(50), 7619–7629.PubMedCrossRef Chang, B. Y., Harte, R. A., & Cartwright, C. A. (2002). RACK1: A novel substrate for the Src protein-tyrosine kinase. Oncogene, 21(50), 7619–7629.PubMedCrossRef
61.
Zurück zum Zitat Mamidipudi, V., Zhang, J., Lee, K. C., & Cartwright, C. A. (2004). RACK1 regulates G1/S progression by suppressing Src kinase activity. Molecular and Cellular Biology, 24(15), 6788–6798.PubMedCrossRef Mamidipudi, V., Zhang, J., Lee, K. C., & Cartwright, C. A. (2004). RACK1 regulates G1/S progression by suppressing Src kinase activity. Molecular and Cellular Biology, 24(15), 6788–6798.PubMedCrossRef
62.
Zurück zum Zitat Mamidipudi, V., & Cartwright, C. A. (2009). A novel pro-apoptotic function of RACK1: Suppression of Src activity in the intrinsic and Akt pathways. Oncogene, 28(50), 4421–4433.PubMedCrossRef Mamidipudi, V., & Cartwright, C. A. (2009). A novel pro-apoptotic function of RACK1: Suppression of Src activity in the intrinsic and Akt pathways. Oncogene, 28(50), 4421–4433.PubMedCrossRef
63.
Zurück zum Zitat Mamidipudi, V., Dhillon, N. K., Parman, T., Miller, L. D., Lee, K. C., & Cartwright, C. A. (2007). RACK1 inhibits colonic cell growth by regulating Src activity at cell cycle checkpoints. Oncogene, 26(20), 2914–2924.PubMedCrossRef Mamidipudi, V., Dhillon, N. K., Parman, T., Miller, L. D., Lee, K. C., & Cartwright, C. A. (2007). RACK1 inhibits colonic cell growth by regulating Src activity at cell cycle checkpoints. Oncogene, 26(20), 2914–2924.PubMedCrossRef
64.
Zurück zum Zitat Swaminathan, G., & Cartwright, C. A. (2011). Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis. Oncogene, 31(3), 376–89.PubMedCrossRef Swaminathan, G., & Cartwright, C. A. (2011). Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis. Oncogene, 31(3), 376–89.PubMedCrossRef
65.
Zurück zum Zitat Xu, J., Lamouille, S., & Derynck, R. (2009). TGF-beta-induced epithelial to mesenchymal transition. Cell Research, 19(2), 156–172.PubMedCrossRef Xu, J., Lamouille, S., & Derynck, R. (2009). TGF-beta-induced epithelial to mesenchymal transition. Cell Research, 19(2), 156–172.PubMedCrossRef
66.
Zurück zum Zitat Lehmann, K., Janda, E., Pierreux, C. E., Rytömaa, M., Schulze, A., McMahon, M., et al. (2000). Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cells. Genes & Development, 14(20), 2610–2622.CrossRef Lehmann, K., Janda, E., Pierreux, C. E., Rytömaa, M., Schulze, A., McMahon, M., et al. (2000). Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cells. Genes & Development, 14(20), 2610–2622.CrossRef
67.
Zurück zum Zitat Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., et al. (2002). Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. The Journal of Cell Biology, 156(2), 299–313.PubMedCrossRef Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., et al. (2002). Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. The Journal of Cell Biology, 156(2), 299–313.PubMedCrossRef
68.
Zurück zum Zitat Janda, E., Nevolo, M., Lehmann, K., Downward, J., Beug, H., & Grieco, M. (2006). Raf plus TGFbeta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene, 54, 7117–7130.CrossRef Janda, E., Nevolo, M., Lehmann, K., Downward, J., Beug, H., & Grieco, M. (2006). Raf plus TGFbeta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene, 54, 7117–7130.CrossRef
69.
Zurück zum Zitat Dickson, B. J., & Gilestro, G. F. (2006). Regulation of commissural axon pathfinding by slit and its Robo receptors. Annual Review of Cell and Developmental Biology, 22, 651–675.PubMedCrossRef Dickson, B. J., & Gilestro, G. F. (2006). Regulation of commissural axon pathfinding by slit and its Robo receptors. Annual Review of Cell and Developmental Biology, 22, 651–675.PubMedCrossRef
70.
Zurück zum Zitat Wu, J. Y., Feng, L., Park, H. T., Havlioglu, N., Wen, L., Tang, H., et al. (2001). The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature, 410(6831), 948–952.PubMedCrossRef Wu, J. Y., Feng, L., Park, H. T., Havlioglu, N., Wen, L., Tang, H., et al. (2001). The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature, 410(6831), 948–952.PubMedCrossRef
71.
Zurück zum Zitat Wang, B., Xiao, Y., Ding, B. B., Zhang, N., Yuan, X., Gui, L., et al. (2003). Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell, 4(1), 19–29.PubMedCrossRef Wang, B., Xiao, Y., Ding, B. B., Zhang, N., Yuan, X., Gui, L., et al. (2003). Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell, 4(1), 19–29.PubMedCrossRef
72.
Zurück zum Zitat Wang, L. J., Zhao, Y., Han, B., Ma, Y. G., Zhang, J., Yang, D. M., et al. (2008). Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis. Cancer Science, 99(3), 510–517.PubMedCrossRef Wang, L. J., Zhao, Y., Han, B., Ma, Y. G., Zhang, J., Yang, D. M., et al. (2008). Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis. Cancer Science, 99(3), 510–517.PubMedCrossRef
73.
Zurück zum Zitat Mertsch, S., Schmitz, N., Jeibmann, A., Geng, J. G., Paulus, W., & Senner, V. (2008). Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. Journal of Neuro-Oncology, 87(1), 1–7.PubMedCrossRef Mertsch, S., Schmitz, N., Jeibmann, A., Geng, J. G., Paulus, W., & Senner, V. (2008). Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. Journal of Neuro-Oncology, 87(1), 1–7.PubMedCrossRef
74.
Zurück zum Zitat Zhou, W. J., Geng, Z. H., Chi, S., Zhang, W., Niu, X. F., Lan, S. J., et al. (2011). Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis. Cell Research, 21(4), 609–626.PubMedCrossRef Zhou, W. J., Geng, Z. H., Chi, S., Zhang, W., Niu, X. F., Lan, S. J., et al. (2011). Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis. Cell Research, 21(4), 609–626.PubMedCrossRef
75.
Zurück zum Zitat Shav-Tal, Y., & Zipori, D. (2002). PSF and p54(nrb)/NonO–multi-functional nuclear proteins. FEBS Letters, 531(2), 109–114.PubMedCrossRef Shav-Tal, Y., & Zipori, D. (2002). PSF and p54(nrb)/NonO–multi-functional nuclear proteins. FEBS Letters, 531(2), 109–114.PubMedCrossRef
76.
Zurück zum Zitat Cobbold, L. C., Spriggs, K. A., Haines, S. J., Dobbyn, H. C., Hayes, C., de Moor, C. H., et al. (2008). Identification of internal ribosome entry segment (IRES)-trans-acting factors for the Myc family of IRESs. Molecular and Cellular Biology, 28(1), 40–49.PubMedCrossRef Cobbold, L. C., Spriggs, K. A., Haines, S. J., Dobbyn, H. C., Hayes, C., de Moor, C. H., et al. (2008). Identification of internal ribosome entry segment (IRES)-trans-acting factors for the Myc family of IRESs. Molecular and Cellular Biology, 28(1), 40–49.PubMedCrossRef
77.
Zurück zum Zitat Kaneko, S., Rozenblatt-Rosen, O., Meyerson, M., & Manley, J. L. (2007). The multifunctional protein p54nrb/PSF recruits the exonuclease XRN2 to facilitate pre-mRNA 3' processing and transcription termination. Genes & Development, 21(14), 1779–1789.CrossRef Kaneko, S., Rozenblatt-Rosen, O., Meyerson, M., & Manley, J. L. (2007). The multifunctional protein p54nrb/PSF recruits the exonuclease XRN2 to facilitate pre-mRNA 3' processing and transcription termination. Genes & Development, 21(14), 1779–1789.CrossRef
78.
Zurück zum Zitat Figueroa, A., Kotani, H., Toda, Y., Mazan-Mamczarz, K., Mueller, E., Otto, A., et al. (2009). Novel roles of hakai in cell proliferation and oncogenesis. Molecular Biology of the Cell, 20(15), 3533–3542.PubMedCrossRef Figueroa, A., Kotani, H., Toda, Y., Mazan-Mamczarz, K., Mueller, E., Otto, A., et al. (2009). Novel roles of hakai in cell proliferation and oncogenesis. Molecular Biology of the Cell, 20(15), 3533–3542.PubMedCrossRef
79.
Zurück zum Zitat Figueroa, A., Fujita, Y., & Gorospe, M. (2009). Hacking RNA: Hakai promotes tumorigenesis by enhancing the RNA-binding function of PSF. Cell Cycle, 8(22), 3648–3651.PubMedCrossRef Figueroa, A., Fujita, Y., & Gorospe, M. (2009). Hacking RNA: Hakai promotes tumorigenesis by enhancing the RNA-binding function of PSF. Cell Cycle, 8(22), 3648–3651.PubMedCrossRef
80.
Zurück zum Zitat Gong, E., Park, E., & Lee, K. (2010). Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells. Cancer Science, 101(9), 2019–2025.PubMedCrossRef Gong, E., Park, E., & Lee, K. (2010). Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells. Cancer Science, 101(9), 2019–2025.PubMedCrossRef
81.
Zurück zum Zitat Fan, S., Ma, Y. X., Wang, C., Yuan, R. Q., Meng, Q., Wang, J. A., et al. (2001). Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene, 20(1), 77–87.PubMedCrossRef Fan, S., Ma, Y. X., Wang, C., Yuan, R. Q., Meng, Q., Wang, J. A., et al. (2001). Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene, 20(1), 77–87.PubMedCrossRef
82.
Zurück zum Zitat Johnsen, S. A., Güngör, C., Prenzel, T., Riethdorf, S., Riethdorf, L., Taniguchi-Ishigaki, N., et al. (2009). Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Research, 69(1), 128–136.PubMedCrossRef Johnsen, S. A., Güngör, C., Prenzel, T., Riethdorf, S., Riethdorf, L., Taniguchi-Ishigaki, N., et al. (2009). Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Research, 69(1), 128–136.PubMedCrossRef
83.
Zurück zum Zitat Zilfou, J. T., Hoffman, W. H., Sank, M., George, D. L., & Murphy, M. (2001). The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. Molecular and Cellular Biology, 21(12), 3974–3985.PubMedCrossRef Zilfou, J. T., Hoffman, W. H., Sank, M., George, D. L., & Murphy, M. (2001). The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. Molecular and Cellular Biology, 21(12), 3974–3985.PubMedCrossRef
84.
Zurück zum Zitat Chen, G., & Courey, A. J. (2000). Groucho/TLE family proteins and transcriptional repression. Gene, 249(1–2), 1–16.PubMedCrossRef Chen, G., & Courey, A. J. (2000). Groucho/TLE family proteins and transcriptional repression. Gene, 249(1–2), 1–16.PubMedCrossRef
85.
Zurück zum Zitat Iyemere, V. P., Davies, N. H., & Brownlee, G. G. (1998). The activation function 2 domain of hepatic nuclear factor 4 is regulated by a short C-terminal proline-rich repressor domain. Nucleic Acids Research, 26(9), 2098–2104.PubMedCrossRef Iyemere, V. P., Davies, N. H., & Brownlee, G. G. (1998). The activation function 2 domain of hepatic nuclear factor 4 is regulated by a short C-terminal proline-rich repressor domain. Nucleic Acids Research, 26(9), 2098–2104.PubMedCrossRef
86.
Zurück zum Zitat Deshaies, R. J., & Joazeiro, C. A. (2009). RING domain E3 ubiquitin ligases. Annual Review of Biochemistry, 78, 399–434.PubMedCrossRef Deshaies, R. J., & Joazeiro, C. A. (2009). RING domain E3 ubiquitin ligases. Annual Review of Biochemistry, 78, 399–434.PubMedCrossRef
87.
Zurück zum Zitat Rodríguez-Rigueiro, T., Valladares-Ayerbes, M., Haz-Conde, M., Blanco, M., Aparicio, G., Fernández-Puente, P., et al. (2011). A novel procedure for protein extraction from formalin-fixed paraffin-embedded tissues. Proteomics, 11(12), 2555–2559.PubMedCrossRef Rodríguez-Rigueiro, T., Valladares-Ayerbes, M., Haz-Conde, M., Blanco, M., Aparicio, G., Fernández-Puente, P., et al. (2011). A novel procedure for protein extraction from formalin-fixed paraffin-embedded tissues. Proteomics, 11(12), 2555–2559.PubMedCrossRef
88.
Zurück zum Zitat Hogan, C., Dupré-Crochet, S., Norman, M., Kajita, M., Zimmermann, C., Pelling, A. E., et al. (2009). Characterization of the interface between normal and transformed epithelial cells. Nature Cell Biology, 11(4), 460–467.PubMedCrossRef Hogan, C., Dupré-Crochet, S., Norman, M., Kajita, M., Zimmermann, C., Pelling, A. E., et al. (2009). Characterization of the interface between normal and transformed epithelial cells. Nature Cell Biology, 11(4), 460–467.PubMedCrossRef
89.
Zurück zum Zitat Rodríguez-Rigueiro, T., Valladares-Ayerbes, M., Haz-Conde, M., Aparicio, L. A., & Figueroa, A. (2011). Hakai reduces cell–substratum adhesion and increases epithelial cell invasion. BMC Cancer, 11, 474. doi:1471-2407-11-474.PubMedCrossRef Rodríguez-Rigueiro, T., Valladares-Ayerbes, M., Haz-Conde, M., Aparicio, L. A., & Figueroa, A. (2011). Hakai reduces cell–substratum adhesion and increases epithelial cell invasion. BMC Cancer, 11, 474. doi:1471-2407-11-474.PubMedCrossRef
90.
Zurück zum Zitat Singh, R. P., Raina, K., Deep, G., Chan, D., & Agarwal, R. (2009). Silibinin suppresses growth of human prostate carcinoma PC-3 orthotopic xenograft via activation of extracellular signal-regulated kinase 1/2 and inhibition of signal transducers and activators of transcription signaling. Clinical Cancer Research, 15(2), 613–621.PubMedCrossRef Singh, R. P., Raina, K., Deep, G., Chan, D., & Agarwal, R. (2009). Silibinin suppresses growth of human prostate carcinoma PC-3 orthotopic xenograft via activation of extracellular signal-regulated kinase 1/2 and inhibition of signal transducers and activators of transcription signaling. Clinical Cancer Research, 15(2), 613–621.PubMedCrossRef
91.
Zurück zum Zitat Raina, K., Rajamanickam, S., Singh, R. P., Deep, G., Chittezhath, M., & Agarwal, R. (2008). Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Research, 68(16), 6822–6830.PubMedCrossRef Raina, K., Rajamanickam, S., Singh, R. P., Deep, G., Chittezhath, M., & Agarwal, R. (2008). Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Research, 68(16), 6822–6830.PubMedCrossRef
92.
Zurück zum Zitat Singh, R. P., Raina, K., Sharma, G., & Agarwal, R. (2008). Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice. Clinical Cancer Research, 14(23), 7773–7780.PubMedCrossRef Singh, R. P., Raina, K., Sharma, G., & Agarwal, R. (2008). Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice. Clinical Cancer Research, 14(23), 7773–7780.PubMedCrossRef
93.
Zurück zum Zitat Deep, G., Gangar, S., Agarwal, C., & Agarwal, R. (2011). Role of E-cadherin in anti-migratory and anti-invasive efficacy of silibinin in prostate cancer cells. Cancer Prevention Research (Philadelphia, Pa.), 4(8), 1222–1232.CrossRef Deep, G., Gangar, S., Agarwal, C., & Agarwal, R. (2011). Role of E-cadherin in anti-migratory and anti-invasive efficacy of silibinin in prostate cancer cells. Cancer Prevention Research (Philadelphia, Pa.), 4(8), 1222–1232.CrossRef
94.
Zurück zum Zitat Flaig, T. W., Gustafson, D. L., Su, L. J., Zirrolli, J. A., Crighton, F., Harrison, G. S., et al. (2007). A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Investigational New Drugs, 25(2), 139–146.PubMedCrossRef Flaig, T. W., Gustafson, D. L., Su, L. J., Zirrolli, J. A., Crighton, F., Harrison, G. S., et al. (2007). A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Investigational New Drugs, 25(2), 139–146.PubMedCrossRef
95.
Zurück zum Zitat Heo, H. S., Kim, J. H., Lee, Y. J., Kim, S. H., Cho, Y. S., & Kim, C. G. (2005). Microarray profiling of genes differentially expressed during erythroid differentiation of murine erythroleukemia cells. Molecules and Cells, 20(1), 57–68.PubMed Heo, H. S., Kim, J. H., Lee, Y. J., Kim, S. H., Cho, Y. S., & Kim, C. G. (2005). Microarray profiling of genes differentially expressed during erythroid differentiation of murine erythroleukemia cells. Molecules and Cells, 20(1), 57–68.PubMed
96.
Zurück zum Zitat Oshida, K., Maeda, A., Kitsukawa, M., Suga, S., Iwano, S., Miyoshi, T., et al. (2011). Novel gene markers of immunosuppressive chemicals in mouse lymph node assay. Toxicology Letters, 205(1), 79–85.PubMedCrossRef Oshida, K., Maeda, A., Kitsukawa, M., Suga, S., Iwano, S., Miyoshi, T., et al. (2011). Novel gene markers of immunosuppressive chemicals in mouse lymph node assay. Toxicology Letters, 205(1), 79–85.PubMedCrossRef
97.
Zurück zum Zitat Krishnan, M., Ng, A., Sukumaran, B., Gilfoy, F., Uchil, P., Sultana, H., et al. (2008). RNA interference screen for human genes associated with West Nile virus infection. Nature, 455(7210), 242–245.PubMedCrossRef Krishnan, M., Ng, A., Sukumaran, B., Gilfoy, F., Uchil, P., Sultana, H., et al. (2008). RNA interference screen for human genes associated with West Nile virus infection. Nature, 455(7210), 242–245.PubMedCrossRef
98.
Zurück zum Zitat Brinton, M. A. (2002). The molecular biology of West Nile Virus: A new invader of the western hemisphere. Annual Review of Microbiology, 56, 371–402.PubMedCrossRef Brinton, M. A. (2002). The molecular biology of West Nile Virus: A new invader of the western hemisphere. Annual Review of Microbiology, 56, 371–402.PubMedCrossRef
99.
Zurück zum Zitat Fernandez-Garcia, M. D., Meertens, L., Bonazzi, M., Cossart, P., Arenzana-Seisdedos, F., & Amara, A. (2011). Appraising the roles of CBLL1 and the ubiquitin/proteasome system for flavivirus entry and replication. Journal of Virology, 85(6), 2980–2989.PubMedCrossRef Fernandez-Garcia, M. D., Meertens, L., Bonazzi, M., Cossart, P., Arenzana-Seisdedos, F., & Amara, A. (2011). Appraising the roles of CBLL1 and the ubiquitin/proteasome system for flavivirus entry and replication. Journal of Virology, 85(6), 2980–2989.PubMedCrossRef
100.
Zurück zum Zitat Lecuit, M. (2005). Understanding how Listeria monocytogenes targets and crosses host barriers. Clinical Microbiology and Infection, 11(6), 430–436.PubMedCrossRef Lecuit, M. (2005). Understanding how Listeria monocytogenes targets and crosses host barriers. Clinical Microbiology and Infection, 11(6), 430–436.PubMedCrossRef
101.
Zurück zum Zitat Mengaud, J., Ohayon, H., Gounon, P., Mege, R. M., & Cossart, P. (1996). E-cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells. Cell, 84(6), 923–932.PubMedCrossRef Mengaud, J., Ohayon, H., Gounon, P., Mege, R. M., & Cossart, P. (1996). E-cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells. Cell, 84(6), 923–932.PubMedCrossRef
102.
Zurück zum Zitat Shen, Y., Naujokas, M., Park, M., & Ireton, K. (2000). InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell, 103(3), 501–510.PubMedCrossRef Shen, Y., Naujokas, M., Park, M., & Ireton, K. (2000). InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell, 103(3), 501–510.PubMedCrossRef
103.
Zurück zum Zitat Bonazzi, M., Veiga, E., Pizarro-Cerdá, J., & Cossart, P. (2008). Successive post-translational modifications of E-cadherin are required for InlA-mediated internalization of Listeria monocytogenes. Cellular Microbiology, 10(11), 2208–2222.PubMedCrossRef Bonazzi, M., Veiga, E., Pizarro-Cerdá, J., & Cossart, P. (2008). Successive post-translational modifications of E-cadherin are required for InlA-mediated internalization of Listeria monocytogenes. Cellular Microbiology, 10(11), 2208–2222.PubMedCrossRef
Metadaten
Titel
Biological influence of Hakai in cancer: a 10-year review
verfasst von
Luis A. Aparicio
Manuel Valladares
Moisés Blanco
Guillermo Alonso
Angélica Figueroa
Publikationsdatum
01.06.2012
Verlag
Springer US
Erschienen in
Cancer and Metastasis Reviews / Ausgabe 1-2/2012
Print ISSN: 0167-7659
Elektronische ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-012-9348-x

Weitere Artikel der Ausgabe 1-2/2012

Cancer and Metastasis Reviews 1-2/2012 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.