Sridhar S C, Miranti C K
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Oncogene. 2006 Apr 13;25(16):2367-78. doi: 10.1038/sj.onc.1209269.
KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrin-mediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.
KAI1/CD82是一种四跨膜蛋白，最初被鉴定为前列腺癌中的转移抑制因子。CD82表达缺失如何促进癌症转移尚不清楚。将转移性前列腺癌细胞系PC3中的CD82表达恢复到生理水平可抑制整合素介导的细胞迁移和侵袭，但不影响整合素表达。在表达CD82的细胞中，受体激酶c-Met的整合素依赖性激活显著降低，其配体HGF/SF对c-Met的激活作用也显著降低。CD82表达还降低了整合素诱导的细胞质酪氨酸激酶Src及其下游底物p130Cas和FAK Y861的激活和磷酸化。抑制c-Met表达或Src激酶功能对PC3细胞基质胶侵袭的抑制程度与CD82表达相同。这些数据表明，CD82通过调节向c-Met和Src激酶的信号传导来发挥抑制整合素诱导的侵袭的作用，并表明CD82缺失可能通过去除c-Met和Src信号的负调节因子来促进转移。
