Receptor tyrosine kinase Met promotes cell survival via kinase-independent maintenance of integrin alpha 3 beta 1

摘要

Matrix adhesion via integrins is required for cell survival. Adhesion of epithelial cells to laminin via integrin alpha 3 beta 1 was previously shown to activate at least two independent survival pathways. First, integrin alpha 3 beta 1 is required for autophagy-induced cell survival after growth factor deprivation. Second, integrin alpha 3 beta 1 independently activates two receptor tyrosine kinases, EGFR and Met, in the absence of ligands. EGFR signaling to Erk promotes survival independently of autophagy. To determine how Met promotes cell survival, we inhibited Met kinase activity or blocked its expression with RNA interference. Loss of Met expression, but not inhibition of Met kinase activity, induced apoptosis by reducing integrin alpha 3 beta 1 levels, activating anoikis, and blocking autophagy. Met was specifically required for the assembly of autophagosomes downstream of LC3II processing. Reexpression of wild-type Met, kinase-dead Met, or integrin alpha 3 was sufficient to rescue death upon removal of endogenous Met. Integrin alpha 3 beta 1 coprecipitated and colocalized with Met in cells. The extracellular and transmembrane domain of Met was required to fully rescue cell death and restore integrin alpha 3 expression. Thus Met promotes survival of laminin-adherent cells by maintaining integrin alpha 3 beta 1 via a kinase-independent mechanism.