Posted on May 10, 2021
Supplementary MaterialsS1 Fig: Effect of p120 de-phosphorylation on tumor cells on cell growth models of cancer progression
Supplementary MaterialsS1 Fig: Effect of p120 de-phosphorylation on tumor cells on cell growth models of cancer progression. increased expression of E-cadherin has been shown to reverse these phenotypes [1C5]. While EMT and Tiliroside decreased E-cadherin levels can explain some cases of cancer progression, there are still instances where cancer cells maintain E-cadherin expression on their cell surface, do not undergo EMT and are still able Tiliroside to facilitate metastatic outgrowth at a distant site [6C8]. It has been shown that E-cadherin expression is maintained in circulating tumor cell clusters and this enhances tumor cell survival and collective migration of tumor cells . E-cadherin missense mutations are observed in patients with hereditary diffuse gastric cancer and these mutations are thought to be causative for cancer development . While most of these mutations result in truncations and loss of E-cadherin mediated cell adhesion, there are still some missense mutations that are expressed on the cell surface and retain cell adhesive function . Therefore, while there is evidence that E-cadherin is still expressed in several types of cancers, it is not fully understood how E-cadherin mediated cell adhesion is regulated and altered as cancer progresses and metastasizes. E-cadherin is bound to -catenin, -catenin, and p120-catenin through its cytoplasmic tail. This cadherin-catenin complex creates a bridge between E-cadherin and the actin cytoskeleton and can mediate both inside-out and Tiliroside outside-in signaling between cells [11, 12]. The binding of p120-catenin to the E-cadherin juxta membrane domain is known to regulate E-cadherin surface levels and control Rabbit Polyclonal to OGFR E-cadherin protein turnover by suppressing endocytosis [13, 14]. p120-catenin is a member of the armadillo-repeat family of proteins and has N-terminal coiled-coil and regulatory domains . Within the p120-catenin regulatory domain lies a phosphorylation domain that harbors eleven serine, threonine and tyrosine phosphorylation sites [16, 17]. Src family kinases, PKC and EGFR have been shown to be important in mediating changes in p120-catenin phosphorylation Tiliroside . Although the phosphorylation state of p120-catenin does not generally influence E-cadherin stability, it can regulate the strength of the E-cadherin homophilic bond and thus regulate E-cadherin mediated cell adhesion and adhesive strength [11, 12]. When p120-catenin is phosphorylated, E-cadherin is in a low adhesion state while dephosphorylation of p120-catenin leads to strong E-cadherin adhesive binding, providing one mechanism for controlling the level of adhesion between cells . p120-catenin has been considered a tumor suppressor as a result of its ability to stabilize E-cadherin at the cell surface. Several studies have shown that p120-catenin mis-localization or loss indeed results in pro-tumorigenic events [20C22]. In an APC Tiliroside min model, it was shown that p120-catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia indicating that p120-catenin expression levels can control tumorigenicity . Recent studies have also shown that signaling events downstream of p120-catenin and cadherins are crucial for tumorigenicity including Src-mediated transformation as a result of p120-catenin phosphorylation [16, 23]. Although evidence suggests a pro-tumorigenic role for p120-catenin phosphorylation, the mechanism underlying this role is largely unknown. The p120-catenin Y228 phosphorylation has been correlated with progression of oral squamous cancer and aggressiveness of glioblastoma [18, 24, 25]. Tyrosine and threonine phosphorylation of p120-catenin in two sites, Y228 and T916, have been observed to be elevated in renal and breast tumor tissue samples . However, a detailed understanding of what p120-catenin does, how its phosphorylation is controlled and what are the implications in cancer progression have not been evaluated. We have shown that multiple Serine/Threonine residues are dephosphorylated when E-cadherin.