Department of Medicine, Stanford University, Stanford, CA 94305-5187, USA.
Oncogene. 2012 Jan 19;31(3):376-89. doi: 10.1038/onc.2011.242. Epub 2011 Jun 20.
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.
E-钙黏蛋白及其细胞质伴侣连环蛋白介导上皮细胞间的黏附。这种黏附的破坏使癌细胞能够侵袭和转移。Src 酪氨酸激酶的异常激活通过 E-钙黏蛋白/连环蛋白依赖性机制破坏细胞间的接触。先前我们表明，Rack1 通过在 G1 和有丝分裂检查点以及内在凋亡和 Akt 细胞存活途径中抑制Src 活性来调节结肠细胞的生长。在这里，我们表明 Rack1 通过抑制Src 促进细胞-细胞黏附和降低结肠癌细胞的侵袭潜力，从而部分促进细胞-细胞黏附。Rack1 通过抑制 Src 对 E-钙黏蛋白的磷酸化、E3 连接酶 Hakai 对 E-钙黏蛋白的泛素化以及 E-钙黏蛋白的内吞作用来稳定细胞-细胞连接处的 E-钙黏蛋白和连环蛋白。在细胞外钙耗尽和恢复后，Rack1 促进含有 E-钙黏蛋白的细胞-细胞接触的重新组装。Rack1 还阻止 HGF 诱导的 E-钙黏蛋白内化、细胞-细胞接触破坏和细胞分散。我们的结果揭示了 Rack1 通过调节Src 和生长因子诱导的 E-钙黏蛋白内化在维持肠道上皮细胞连接体动态平衡中的新功能。
