p120-catenin is required for the collective invasion of squamous cell carcinoma cells via a phosphorylation-independent mechanism

Abstract

Loss of E-cadherin-mediated cell-cell junctions has been correlated with cancer cell invasion and poor patient survival. p120-catenin has emerged as a key player in promoting E-cadherin stability and adherens junction integrity and has been proposed as a potential invasion suppressor by preventing release of cells from the constraints imposed by cadherin-mediated cell-cell adhesion. However, it has been proposed that tyrosine phosphorylation of p120 may contribute to cadherindependent junction disassembly during invasion. Here, we use small interfering RNA (siRNA) in A431 cells to show that knockdown of p120 promotes two-dimensional migration of cells. In contrast, p120 knockdown impairs epidermal growth factor-induced A431 invasion into threedimensional matrix gels or in organotypic culture, whereas re-expression of siRNA-resistant p120, or a p120 isoform that cannot be phosphorylated on tyrosine, restores the collective mode of invasion employed by A431 cells in vitro. Thus, p120 promotes A431 cell invasion in a phosphorylation-independent manner. We show that the collective invasion of A431 cells depends on the presence of cadherin-mediated (P-and E-cadherin) cell-cell contacts, which are lost in cells where p120 expression is knocked down. Furthermore, membranous p120 is maintained in invasive squamous cell carcinomas in tumours suggesting that p120 may be important for the collective invasion of tumours cells in vivo.

p120-catenin is essential for terminal end bud function and mammary morphogenesis

“…The explanation is likely to lie in the extraordinary sensitivity of the TEB to p120 loss and the dependence of TEB function on collective migration, a phenomenon based on dynamically regulated cell-cell adhesion. Our work extends previous observations on the role of p120 in collective migration (Hidalgo-Carcedo et al, 2011;Macpherson et al, 2007;Simpson et al, 2008) to a highly relevant in vivo setting and is in line with prior anecdotal evidence that mammary development essentially fails altogether in the absence of p120 . Given the unique morphogenetic status of the TEB, it will be interesting to extend these studies to p120 KO in breast cancer models as well as fully developed mammary epithelium.…”

“…This result highlights the often overlooked fact that p120 stabilizes all classical cadherins, and implies an activity for P-cadherin that might not be shared by E-and/or Ncadherin (at least in MCF10A cells). Similarly, p120 is required for cadherin-dependent collective invasion in an A431 squamous carcinoma cell model (Macpherson et al, 2007). Eric Sahai's group has recently proposed that collective migration is controlled in part by an E-cadherin/DDR1/Par3-Par6 complex that functions to limit actomyosin contractility as needed at adherens junctions through mechanisms involving p190ARhoGAP (Grlf1) and RhoE (Rnd3) (Hidalgo-Carcedo et al, 2011).…”

Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer

“…The most widely held view is that p120 mutations destabilize AJs and disrupt intercellular adhesion, which in turn enhances migratory and invasive features of cancer-poised cells (5,7,8). This notion is consistent with some human cancers in which loss-of-function mutations occur in other AJ components, e.g., epithelial cadherin (Ecadherin) and ␣-catenin, and with the more broadly observed reductions in membrane immunolocalization of AJ components (9,10).…”

p120catenin alteration in cancer and its role in tumour invasion

“…The function of p120catenin in the regulation of cadherin levels suggests that loss of p120catenin may be responsible for E-cadherin downregulation during tumour progression, but direct evidence is still lacking [11]. Conversely, membraneassociated p120catenin restrains the invasion of tumour cell lines derived from breast, kidney and vulva cancers [72,73]. Another scenario is at play in highly lethal forms of breast tumours, in which membrane-associated p120catenin appears to be pro-invasive (figure 3c).…”