Βeta-catenin N-terminal domain: An enigmatic region prone to cancer causing mutations

Abstract

The Wnt/β-catenin is a highly conserved signaling pathway involved in cell fate decisions during various stages of development. Dysregulation of canonical Wnt/β-catenin signaling has been associated with various diseases including cancer. β-Catenin, the central component of canonical Wnt signaling pathway, is a multi-functional protein playing both structural and signaling roles. β-Catenin is composed of three distinct domains: N-terminal domain, C-terminal domain and a central armadillo repeat domain. N-terminal domain of β-catenin harbours almost all of the cancer causing mutations, thus deciphering its critical structural and functional roles offers great potential in cancer detection and therapy. Here, in this review, we have collected information from pharmacological analysis, bio-physical and structural studies, molecular modeling, in-vivo and in-vitro assays, and transgenic animal experiments employing various N-terminal domain variants of β-catenin to discuss the interaction of β-catenin with its binding partners that specifically interact with this domain and the implications of these interactions on signaling, cell fate determination, and in tumorigenesis. A thorough understanding of interactions between β-catenin and its binding partners will enable us to more effectively understand how β-catenin switches between its multiple roles, and will lead to the development of specific assays for the identification of small molecules as chemotherapeutic agents to treat diseases, including cancer and neurological disorders, where Wnt/β-catenin signaling is dysregulated.

Introduction

The Wnt signaling regulates crucial aspects of cell fate decisions during embryonic development and throughout the life span of an organism [1], [2]. The Wnt signaling cascade is critically important in stem cell biology and regulates maintenance, self-renewal and differentiation of the embryonic and adult stem cells [3], [4], [5]. The three best characterized Wnt signaling pathways are: the canonical Wnt pathway, the non-canonical Wnt/calcium pathway, and the non-canonical planar cell polarity pathway. All three pathways are activated by the binding of a Wnt-protein ligand to membrane bound Frizzled receptor and LRP coreceptor complexes which then pass the signal to the disheveled (Dsh) proteins inside the cell. The canonical Wnt pathway leads to regulation of gene expression and dysregulation of this pathway is associated with a wide array of cancers [6]. The non-canonical planar cell polarity pathway regulates cytoskeleton and the non-canonical Wnt/calcium pathway regulates calcium inside the cell [7]. The hallmark of canonical Wnt pathway is that it operates via β-catenin protein while the non-canonical pathways do not require β-catenin protein. There are two pools of β-catenin within the cell, one at the membrane and other in the cytoplasm. These two pools are required for its two principal functions that include cell–cell adhesion and transcriptional regulation (Fig. 1). As a component of cell–cell adhesion junctions, β-catenin binds to transmembrane cadherins and α-catenin and then links these proteins to the actin cytoskeleton [8]. The cytoplasmic pool of β-catenin associates with the destruction complex composed of the scaffold protein Axin, GSK-3β, casein kinase 1α and the tumor suppressor adenomatous polyposis coli (APC) [9], [10]. In this complex, β-catenin is phosphorylated at the N-terminal region resulting in its ubiquitination followed by proteosomal degradation in the absence of Wnt signaling [10], [11], [12]. However, in the presence of Wnt ligand binding to Frizzled receptor and LRP coreceptor complexes Wnt signaling pathway is activated via phosphorylation of Dsh protein [13], [14], [15], [16] leading to the recruitment of destruction complex to the membrane. As a result of these events, destruction complex components axin and GSK-3β are inhibited via active Dsh proteins [17], [18]. This causes an increase in the cytoplasmic levels of hypo-phosphorylated β-catenin which then translocates into the nucleus and binds to TCF/LEF transcription factors in order to activate the transcription of target genes involved in stimulating cell growth and proliferation [19], [20]. Although lot of literature is available to understand the multiple roles of β-catenin, however, several aspects of β-catenin signaling have not been addressed yet. For example, how β-catenin switches between its two independent roles is not fully understood [21], [22], [23]. This β-catenin role switching process has important implications. Whenever there is any change in this balance or when the signaling properties overweigh the adhesive roles β-catenin acts as an oncogene [24], [25]. The oncogenic signaling properties of β-catenin are consequence of hot-spot exon-3 specific missense mutations [26], [27], [28], [29], [30], [31], [32], [33] and N-terminal domain in-frame deletions as seen in many cancers [34], [35], [36]; and cancer cell lines [37], [38], [39]. Moreover, in vivo activities of β-catenin signaling pathway are not fully clear because genetic analysis of Wnt ligands (19 proteins), frizzled receptors (10 proteins) and TCF transcription factors (4 proteins) is not that easy [40], [41]. Here in this review, we discuss the multiple roles played by β-catenin, with a particular emphasis on its N-terminal domain, the most divergent domain involved in cancer development, cell–cell adhesion and transcription.