β4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth

Despite being a cell-matrix adhesion molecule, beta 4 integrin can prompt the multiplication of neoplastic cells dislodged from their substrates (anchorage-independent growth). However, the molecular events underlying this atypical behavior remain partly unexplored. We found that activation of the Met receptor for hepatocyte growth factor results in the tyrosine phosphorylation of beta 4, which is instrumental for integrin-mediated recruitment of the tyrosine phosphatase Shp2. Shp2 binding to beta 4 enhances the activation of Src, which, in turn, phosphorylates the multiadaptor Gab1 predominantly on consensus sites for Grb2 association, leading to privileged stimulation of the Ras-extracellular signal-regulated kinase (ERK) cascade. This signaling axis can be inhibited by small interfering RNA-mediated beta 4 depletion, by a beta 4 mutant unable to bind Shp2, and by pharmacological and genetic inhibition of Shp2 or Src. Preservation of the beta 4 docking sites for Shp2 as well as the integrity of Shp2, Src, or ERK activity are required for the beta 4-mediated induction of anchorage-independent growth. These results unravel a novel pathway whereby beta 4 directs tyrosine kinase-based signals toward adhesion-unrelated outcomes.