BBA - Molecular Cell Research (v.1773, #1)

Taking stock: The many surprising lives of p120-catenins by Alpha S. Yap; Juliet M. Daniel (1).

p120-catenin: Past and present by Albert B. Reynolds (2-7).
p120-catenin was first described in 1989 as a Src substrate whose phosphorylation correlated with transformation. It was identified by cDNA cloning in 1992, and shown to interact with cadherins in 1994. Though enigmatic for some time, p120 has emerged as a master regulator of cadherin stability, and an important modulator of RhoGTPase activities. With the discovery of p120 family members and evidence for fundamental roles in cell biology and cancer, the field has expanded dramatically in recent years. As an introduction to this collection of reviews on p120 and its relatives, the editors have requested a personal commentary and historical perspective on the discovery of p120. The anecdotal parts have no particular purpose, but are mostly unpublished and perhaps of interest to some.
Keywords: p120-catenin; Src, RhoGTPases; Cadherin; Cell–cell adhesion; Tumor suppressor; Metastasis; Contact inhibition;

Role of p120-catenin in cadherin trafficking by Kanyan Xiao; Rebecca G. Oas; Christine M. Chiasson; Andrew P. Kowalczyk (8-16).
p120-catenin (p120) has emerged over the past several years as an important regulatory component of the cadherin adhesive complex. A core function of p120 in mammalian cells is to stabilize cadherins at the cell membrane by modulating cadherin membrane trafficking and degradation. In this way, p120 levels act as a set point mechanism that tunes cell–cell adhesive interactions. The primary control point for this regulatory activity appears to be at the level of cadherin internalization from the plasma membrane, although p120 may also impact other aspects of cadherin trafficking and turnover. In the following review, the general mechanisms of cadherin trafficking are discussed, and models for how p120 may influence cadherin membrane dynamics are presented. In one model, p120 may function as a “cap” to bind the cadherin cytoplasmic tail and prevent cadherin interactions with endocytic membrane trafficking machinery. Alternatively, p120 may stabilize cell junctions or regulate membrane trafficking machinery through interactions with small GTPases such as Rho A, Rac and Cdc42. Through these mechanisms p120 exerts influence over a wide range of biological processes that are dependent upon tight regulation of cell surface cadherin levels.
Keywords: p120-catenin; cadherin; endocytosis; Rho; Rac;

Developmental functions of the P120-catenin sub-family by Pierre D. McCrea; Jae-il Park (17-33).
For more than a decade, cell, developmental and cancer investigators have brought about a wide interest in the biology of catenin proteins, an attraction being their varied functions within differing cellular compartments. While the diversity of catenin localizations and roles has been intriguing, it has also posed a challenge to the clear interpretation of loss- or gain-of-function developmental phenotypes. The most deeply studied member of the larger catenin family is beta-catenin, whose contributions span areas including cell adhesion and intracellular signaling/ transcriptional control. More recently, attention has been directed towards p120-catenin, which in conjunction with the p120-catenin sub-family members ARVCF- and delta-catenins, are the subjects of this review. Although the requirement for vertebrate versus invertebrate p120-catenin are at variance, vertebrate p120-catenin sub-family members may each inter-link cadherin, cytoskeletal and gene regulatory functions in embryogenesis and disease.
Keywords: p120-catenin; ARVCF-catenin; Delta-catenin; Development; Vertebrate; Invertebrate; Wnt signaling pathway; Kaiso repressor;

p120 catenin (p120) is the prototypic member of a subfamily of armadillo repeat domain proteins involved in intercellular adhesion. Recent evidence indicates that p120 associates with classical cadherins and regulates their stability. Ectopic p120 expression results in a variety of morphological effects, and promotes cell migration. There is now strong evidence that p120 acts, at least in part, through regulation of Rho GTPases. The data suggest that p120 may act as a signaling nexus, conveying messages from the cellular micro- and macro-environment to the cell's interior. By regulating Rho GTPases in a context-dependent manner p120 can exert profound effects on cellular responses from synaptic plasticity to vesicle trafficking, as well as regulate the motile vs. sessile, and possibly the proliferative vs. quiescent phenotype of epithelial cells. Here, we review the new evidence on the relationship of p120 to Rho GTPases, and discuss potential roles for the p120–Rho connection in normal and malignant cells.
Keywords: p120; RhoA; Rac1; Cadherin; Cell motility; Cell adhesion; Microenvironment; Cognition;

p120 catenin is a scaffold protein that interacts with cadherin cytoplasmic domain and acts as a crucial component of the signalling that regulates the cycle of adherens junction formation and disassembly. Here, we review the nature of stimuli that modulate p120ctn function and are translated as serine/threonine and tyrosine phosphorylation events at this multisite substrate for a variety of protein kinases. We also highlight recent findings that tentatively link phosphorylation of p120ctn to its role as a signal integrator capable to influence the state of the cadherin adhesive bond, the cytoskeleton and cell motility.
Keywords: p120ctn; E-cadherin; Tyrosine kinase; Protein tyrosine phosphatase; PKC; Actin cytoskeleton; Rho GTPases;

The catenin p120 (hereafter p120ctn) was first identified as a Src kinase substrate and subsequently characterized as an Armadillo catenin member of the cell–cell adhesion cadherin–catenin complex. In the past decade, many studies have revealed roles for p120ctn in regulating Rho family GTPase activity and E-cadherin stability and turnover, events that occur predominantly at the plasma membrane or in the cytoplasm. However, the recent discovery of the nuclear BTB/POZ-ZF transcription factor Kaiso as a p120ctn binding partner, coupled with the detection of p120ctn in the nucleus of some cell lines and tumor tissues, suggested that like the classical β-catenin, p120ctn undergoes nucleocytoplasmic trafficking and regulates gene expression. Indeed, p120ctn has a classic nuclear localization signal and does traffic to the nucleus. Moreover, nuclear p120ctn regulates Kaiso DNA-binding and transcriptional activity, similar to β-catenin's modulation of TCF/LEF transcription activity. However unlike β-catenin, p120ctn does not appear to be a transcriptional activator. Hence it remains to be determined whether the sole role of nuclear p120ctn is regulation of Kaiso or whether p120ctn binds and regulates other transcription factors or nuclear proteins.
Keywords: p120ctn; Catenin; Kaiso; POZ-ZF; Transcription; Gene expression;

Plakophilins 1–3 are members of the p120ctn family of armadillo-related proteins. The plakophilins have been characterized as desmosomal proteins, whereas p120ctn and the closely related δ-catenin, ARVCF and p0071 associate with adherens junctions and play essential roles in stabilizing cadherin mediated adhesion. Recent evidence suggests that plakophilins are essential components of the desmosomal plaque where they interact with desmosomal cadherins as well as the cytoskeletal linker protein desmoplakin. Plakophilins stabilize desmosomal proteins at the plasma membrane and therefore may function in a manner similar to p120ctn in the adherens junctions. The three plakophilins reveal distinct expression patterns, and although partially redundant in their function, mediate distinct effects on desmosomal adhesion. Besides a structural role, a function in signaling has been postulated in analogy to other armadillo proteins such as β-catenin. At least plakophilins 1 and 2 are also localized in the nucleus, and all three proteins occur in a cytoplasmic pool. This review aims to summarize the current knowledge of plakophilin function in the context of cell adhesion, signaling and their putative role in diseases.
Keywords: Desmosomes; Cell adhesion; Skin fragility; ARVC;

Diverse functions of p120ctn in tumors by Jolanda van Hengel; Frans van Roy (78-88).
p120ctn is a member of the Armadillo protein family. It stabilizes the cadherin–catenin adhesion complex at the plasma membrane, but also has additional roles in the cytoplasm and nucleus. Extensive alternative mRNA splicing and multiple phosphorylation sites generate additional complexity. Evidence is emerging that complete loss, downregulation or mislocalization of p120ctn correlates with progression of different types of human tumors. It remains to be determined whether a causal relationship exists between specific isoform expression, subcellular localization or selective phosphorylation of p120ctn on the one hand and tumor prognosis on the other.
Keywords: Cancer progression; EMT; Cell–cell adhesion; Armadillo; Catenin; Cadherin; Rho GTPase;