Integrins uncouple src-induced morphological and oncogenic transformation

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 alpha v beta 3 strongly supports Src-mediated oncogenic transformation through an interaction at the beta 3 cytoplasmic tail. Our current findings demonstrate that this interaction does not affect Src-mediated morphological alterations, thus separating oncogenic from morphological transformation. Moreover, beta 1 and beta 3 integrins differently affect the various aspects of Src-induced morphological transformation. High levels of beta 3, but not beta 1, 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 beta 3 extracellular domain. Finally, like tumor formation, podosome assembly occurs independent of beta 3 phosphorylation. Instead, phosphorylation of beta 1 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.