Huveneers Stephan, Arslan Serdar, van de Water Bob, Sonnenberg Arnoud, Danen Erik H J
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
J Biol Chem. 2008 May 9;283(19):13243-51. doi: 10.1074/jbc.M800927200. Epub 2008 Mar 7.
Expression of activated mutants of c-Src in epithelial cells can induce tumorigenicity. In addition to such oncogenic transformation, the cells undergo a dramatic morphological transformation: cell-cell contacts are disrupted, spreading on extracellular matrix proteins is suppressed, actin stress fibers and focal contacts are lost, and podosomes are formed. We have previously shown that integrin alphavbeta3 strongly supports Src-mediated oncogenic transformation through an interaction at the beta3 cytoplasmic tail. Our current findings demonstrate that this interaction does not affect Src-mediated morphological alterations, thus separating oncogenic from morphological transformation. Moreover, beta1 and beta3 integrins differently affect the various aspects of Src-induced morphological transformation. High levels of beta3, but not beta1, integrins can prevent Src-induced cell rounding although stress fiber disassembly and podosome formation still occur. Studies using chimeric integrin subunits demonstrate that this protection requires the beta3 extracellular domain. Finally, like tumor formation, podosome assembly occurs independent of beta3 phosphorylation. Instead, phosphorylation of beta1 is required to suppress Rho-mediated contractility in order to assemble podosomes. Thus, integrins regulate Src-mediated oncogenic transformation and various aspects of morphological transformation through dissociable pathways.
上皮细胞中c-Src激活突变体的表达可诱导肿瘤发生。除了这种致癌转化外，细胞还经历了显著的形态学转变：细胞间接触被破坏，在细胞外基质蛋白上的铺展受到抑制，肌动蛋白应力纤维和粘着斑丧失，并且形成了足体。我们之前已经表明，整合素αvβ3通过在β3细胞质尾部的相互作用强烈支持Src介导的致癌转化。我们目前的研究结果表明，这种相互作用不会影响Src介导的形态学改变，从而将致癌转化与形态学转化区分开来。此外，β1和β3整合素对Src诱导的形态学转化的各个方面有不同的影响。高水平的β3整合素而非β1整合素可以防止Src诱导的细胞变圆，尽管应力纤维解体和足体形成仍然会发生。使用嵌合整合素亚基的研究表明，这种保护需要β3细胞外结构域。最后，与肿瘤形成一样，足体组装的发生独立于β3磷酸化。相反，需要β1磷酸化来抑制Rho介导的收缩性以组装足体。因此，整合素通过可分离的途径调节Src介导的致癌转化和形态学转化的各个方面。
