Integrin-regulated FAK–Src signaling in normal and cancer cells

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Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK–Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK–Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK–Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.

Introduction

The integrin family of transmembrane receptors link the extracellular matrix (ECM) to the intracellular actin cytoskeleton at points of cell–substratum interaction termed focal adhesions. In addition to this structural role, integrin clustering can initiate intracellular signaling events that promote cell proliferation, survival and migration in both normal and tumorigenic cell contexts [1]. One type of signaling event stimulated by integrins is the tyrosine phosphorylation of cytoskeletal-adaptor and signaling proteins. As integrins do not possess intrinsic catalytic activity, the signals initiated by ECM–integrin interactions are transduced into cells through the activation of integrin-associated proteins. This can occur through co-clustering with receptor protein-tyrosine kinases (PTKs) [2] and here we will cover the integrin-associated signaling connections of non-receptor PTKs with emphasis on focal adhesion kinase (FAK) and Src-family PTKs (SFKs). Recent reviews on FAK–Src signaling have focused on the mechanisms of FAK [3] or Src regulation [4], the interplay between Src and integrins [5], FAK-associated signaling connections in the control of cell motility and invasion [6, 7••] and the roles of FAK or Src in cancer [8]. Here, we will discuss recent developments with regard to FAK–Src signaling with an emphasis on how an integrin linkage to these PTKs controls important aspects of both normal and tumor cell behavior.

Section snippets

Multiple routes for integrin activation of the FAK–Src complex

FAK is primarily recruited to sites of integrin clustering via interactions between its C-terminal domain and integrin-associated proteins such as talin and paxillin (Figure 1). The cytoplasmic tail of β-integrins (β1, β3 and β5) facilitates FAK activation through undefined mechanism(s), potentially involving FAK clustering, autophosphorylation at Y397 [9] and a mechanical linkage of integrins to the actin cytoskeleton [10]. Although point mutations in the FAK N-terminal FERM domain further

The FAK–Src motility-promoting signaling complex

FAK promotes normal and cancer cell migration by regulating focal adhesion formation and turnover through multiple signaling connections (Figure 2). Although phosphorylation of paxillin has been proposed to function as a linkage regulating cell contractility and adhesion disassembly [23], FAK-null fibroblasts exhibit enhanced paxillin phosphorylation and adhesion formation [14]. However, the tyrosine phosphorylation of the ArfGAP paxillin kinase linker (PKL, also known as G protein-coupled

Integrin connections to FAK in tumorigenesis and cell survival

Whereas mutational inactivation of β1 integrin or FAK expression results in embryonic lethality, conditional inactivation studies are yielding insights into the role of an integrin–FAK signaling linkage in the processes of tumorigenesis [39••, 40••, 41]. In a polyoma middle T (mT) oncogene breast tumor model, loss of β1 integrin expression did not affect mammary gland development, but instead limited the proliferative capacity of mT-transformed tumor cells, with a corresponding decrease in FAK

Uncovering roles for FAK in promoting tumor progression

Several studies have noted that increased FAK expression, enhanced tumor malignancy and poor prognosis correlate with elevated FAK expression [52]. As recently reviewed [53], Src–FAK signaling promotes E-cadherin internalization during cancer progression, thus facilitating an epithelial-to-mesenchymal transition and enhanced tumor cell motility. Recent studies using transformed FAK-null fibroblasts and RNAi to inhibit FAK expression in carcinoma cells are yielding insights into FAK control of

Novel role for FAK in tumor growth and angiogenesis

Several studies have documented a role for FAK–Src signaling in the control of cell cycle progression in both normal and tumor cells and this is one likely route by which FAK may enhance tumor growth [45, 60]. However, FAK does not function as an oncogene and is not essential for cell proliferation, as demonstrated by the normal growth of FAK−/−p53−/− fibroblasts. In tumorigenic 4T1 breast carcinoma cells, blockage of integrin-stimulated FAK activity or RNAi-mediated reduced FAK expression did

Conclusions

Integrin-mediated activation of FAK and Src regulates various aspects of normal cell behavior and contributes to cancer progression in multiple ways (Figure 4). In normal cells, FAK–Src signals can control cell survival, proliferation and cell motility. Several open questions remain regarding how FAK may act to regulate p53 activity and whether the disruption of this linkage may contribute to increased cell apoptosis in the absence of FAK expression. FAK-null fibroblasts proliferate in cell

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was made possible by grants from the NIH (CA75240, CA87038, CA102310). David Schlaepfer is an Established Investigator of the American Heart Association. This is manuscript number 18343-IMM from The Scripps Research Institute.

References (62)

  • S.L. Harris et al.

    The p53 pathway: positive and negative feedback loops

    Oncogene

    (2005)
  • Q. Ding et al.

    p27Kip1 and cyclin D1 are necessary for focal adhesion kinase regulation of cell cycle progression in glioblastoma cells propagated in vitro and in vivo in the scid mouse brain

    J Biol Chem

    (2005)
  • V.M. Golubovskaya et al.

    Direct interaction of the N-terminal domain of focal adhesion kinase with the N-terminal transactivation domain of p53

    J Biol Chem

    (2005)
  • V. Golubovskaya et al.

    Cloning and characterization of the promoter region of human focal adhesion kinase gene: nuclear factor κ B and p53 binding sites

    Biochim Biophys Acta

    (2004)
  • X. Wu et al.

    FAK-Mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

    Dev Cell

    (2005)
  • J.M. Summy et al.

    Treatment for advanced tumors: SRC reclaims center stage

    Clin Cancer Res

    (2006)
  • H.S. Choi et al.

    Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors

    Bioorg Med Chem Lett

    (2006)
  • V. Gabarra-Niecko et al.

    FAK regulates biological processes important for the pathogenesis of cancer

    Cancer Metastasis Rev

    (2003)
  • W. Guo et al.

    Integrin signalling during tumour progression

    Nat Rev Mol Cell Biol

    (2004)
  • L.A. Cohen et al.

    Mechanisms of focal adhesion kinase regulation

    Curr Cancer Drug Targets

    (2005)
  • M.P. Playford et al.

    The interplay between Src and integrins in normal and tumor biology

    Oncogene

    (2004)
  • S.K. Mitra et al.

    Focal adhesion kinase: in command and control of cell motility

    Nat Rev Mol Cell Biol

    (2005)
  • G.W. McLean et al.

    The role of focal-adhesion kinase in cancer — a new therapeutic opportunity

    Nat Rev Cancer

    (2005)
  • M. Toutant et al.

    Alternative splicing controls the mechanisms of FAK autophosphorylation

    Mol Cell Biol

    (2002)
  • Q. Shi et al.

    A novel mode for integrin-mediated signaling: tethering is required for phosphorylation of FAK Y397

    Mol Biol Cell

    (2003)
  • L.A. Cohen et al.

    Residues within the first subdomain of the FERM-like domain in focal adhesion kinase are important in its regulation

    J Biol Chem

    (2005)
  • J. Brabek et al.

    CAS promotes invasiveness of Src-transformed cells

    Oncogene

    (2004)
  • F. Nasertorabi et al.

    Molecular basis for regulation of Src by the docking protein p130Cas

    J Mol Recognit

    (2006)
  • E.G. Arias-Salgado et al.

    Src kinase activation by direct interaction with the integrin β cytoplasmic domain

    Proc Natl Acad Sci USA

    (2003)
  • S.J. Shattil

    Integrins and Src: dynamic duo of adhesion signaling

    Trends Cell Biol

    (2005)
  • S. Kuphal et al.

    Integrin signaling in malignant melanoma

    Cancer Metastasis Rev

    (2005)
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