Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis

Abstract

E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G 1 and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src-and growth factor-induced endocytosis of E-cadherin.

Cell-cycle dependent localization of MELK and its new partner RACK1 in epithelial versus mesenchyme-like cells in Xenopus embryo

“…We show that RACK1 is localized at the cell–cell contacts in Xenopus embryonic mesenchyme-like cells. This result is in agreement with previous reports showing that RACK1 is localized at cell–cell junctions in HT-29 human colon cancer cell line and mink Mv 1 Lu cells (Swaminathan and Cartwright, 2012; Mourton et al, 2001). We also show that in polarized Xenopus embryonic epithelial cells RACK1 co-localizes with ZO-1 at the apical cell–cell junction.…”

Receptor protein tyrosine phosphatase RPTPα controls epithelial adherens junctions, linking E-cadherin engagement to c-Src signaling to cortactin

“…Potentially, by regulating c-Src, RPTPa could control events in the endocytic pathway, given the implication of the former in epithelial E-cadherin endocytosis (Canel et al, 2010;Swaminathan and Cartwright, 2012) and in neuronal neurotransmitter receptor trafficking in neurons (Ohnishi et al, 2011).…”

Biological influence of Hakai in cancer: a 10-year review

“…It was also previously reported that Rack1 acts as a substrate and inhibitor of Src [58–60], regulating cell growth through the inhibition of Src activity at G1 and mitotic cell-cycle checkpoints and cell survival pathways [61–63]. Taken in consideration these premises, in 2011, it was addressed the effect of Rack1 on Src signaling and its function on E-cadherin-mediated cell–cell adhesions [64]. It was shown that Rack1 promotes cell–cell adhesion by stabilizing E-cadherin and catenins at cell–cell junctions and reduces invasive potential of colon carcinoma cells.…”