A Role for the Cleaved Cytoplasmic Domain of E-cadherin in the Nucleus

Abstract

Cell-cell contacts play a vital role in intracellular signaling, although the molecular mechanisms of these signaling pathways are not fully understood. E-cadherin, an important mediator of cell-cell adhesions, has been shown to be cleaved by ␥-secretase. This cleavage releases a fragment of E-cadherin, E-cadherin C-terminal fragment 2 (E-cad/CTF2), into the cytosol. Here, we study the fate and function of this fragment. First, we show that coexpression of the cadherin-binding protein, p120 catenin (p120), enhances the nuclear translocation of E-cad/CTF2. By knocking down p120 with short interfering RNA, we also demonstrate that p120 is necessary for the nuclear localization of E-cad/CTF2. Furthermore, p120 enhances and is required for the specific binding of E-cad/CTF2 to DNA. Finally, we show that E-cad/CTF2 can regulate the p120-Kaiso-mediated signaling pathway in the nucleus. These data indicate a novel role for cleaved E-cadherin in the nucleus.In multicellular organisms, individual cells are often connected with each other via cell-cell adhesions to form threedimensionally structured tissues or organs. Formation of tight and compact cell-cell adhesions suppresses free cell movement and provides cells with a positional cue for the establishment of cell polarity. In addition to the structural roles, it has been long known that cell-cell contacts play an important role in various signal transduction pathways (1, 2). In other words, through cell-cell contacts, cells can exchange a variety of information with their neighbors to behave properly in their community.Cadherins are a family of transmembrane cell-cell adhesion proteins that can be subdivided into several groups including classical cadherins and protocadherins (3). Classical cadherins, of which E-cadherin is the best characterized, play a crucial role in mediating cell-cell contacts at adherens junctions. The extracellular domains of classical cadherins form homophilic ligations. The cytoplasmic domain of cadherin includes two cadherin homology (CH) 2 domains: CH2 domain (located at the membrane proximal region) and CH3 domain (located at the distal region). These domains are conserved between classical cadherins. The CH2 and CH3 domains of cadherins interact with p120-catenin (p120) and ␤-catenin, respectively (4, 5). Furthermore, the CH2 domain of E-cadherin also interacts with Hakai (6, 7).Cadherins, especially classical cadherins, have been shown to be involved in several signaling pathways regulating cell proliferation, differentiation, and survival (8 -11). However, the molecular mechanisms whereby cadherins regulate varied cellular processes are not fully understood. The cytoplasmic domain of cadherins does not possess any intrinsic enzymatic activity that could directly mediate signaling pathways in the cytosol. However, cadherin-binding proteins, especially ␤-catenin and p120, have been shown to localize in the nucleus and play a key role in signal transduction. The crucial role of ␤-catenin in the canonical Wnt signaling pathway has been well...

p120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide

“…In addition, p120ctn plays important roles in development and gene expression (13,17). Recent work from our laboratory showed that PS1 localizes at the plasma membrane where it forms complexes with the cadherincatenin adherens junctions (1) and promotes the ␥-secretase processing of cadherins, releasing ␣-and ␤-catenins to the cytosol and producing peptides that function in signal transduction (2,9,18). Additional in vitro studies indicated that members of the p120ctn family of proteins, including ␦-catenin and p0071, bind directly to the large loop of PS1/CTF independently of cadherins (10 -12), but the physiological significance of the p120ctn-PS1 binding remained elusive.…”

“…The p120ctn-catenin family contains 10 -12 armadillo repeats (13), and in contrast to ␤-and ␥-catenins that bind the distal sequence of cytosolic cadherins, members of the p120ctn family bind directly to the juxtamembrane sequence of cadherins and regulate their stability (14,15). p120ctn itself regulates the activity of the Rho family of GTPases (16) and promotes gene expression by binding transcription factor Kaiso and regulating its DNA-binding activity (17,18). Interestingly, conditional knock-out of mouse hippocampal p120ctn results in abnormalities in synaptic transmission and spine morphology (19,20).…”

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

“…emboli formation in vivo. Previously it had been reported that E-cad/CTF2 can regulate the p120-Kaiso-mediated signaling pathway in the nucleus (24).…”

EMT, the cytoskeleton, and cancer cell invasion

“…2 b). In the nucleus, CTF2 modulates the interaction between p120-catenin and Kaiso, a transcriptional repressor, thereby affecting for example cell survival [56]. Destabilization of the E-cadherin adhesion complex is also accomplished by receptor tyrosine kinase or Srcmediated phosphorylation of E-cadherin, followed by its ubiquitylation by the E3 ligase Hakai and subsequent degradation [57,58] (Fig.…”