Beta4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth.
Despite being a cell-matrix adhesion molecule, beta4 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 beta4, which is instrumental for integrin-mediated recruitment of the tyrosine phosphatase Shp2. Shp2 binding to beta4 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 beta4 depletion, by a beta4 mutant unable to bind Shp2, and by pharmacological and genetic inhibition of Shp2 or Src. Preservation of the beta4 docking sites for Shp2 as well as the integrity of Shp2, Src, or ERK activity are required for the beta4-mediated induction of anchorage-independent growth. These results unravel a novel pathway whereby beta4 directs tyrosine kinase-based signals toward adhesion-unrelated outcomes.
Bertotti
Andrea
A
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.
Comoglio
Paolo M
PM
Trusolino
Livio
L
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D002448:Cell Adhesion; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; D039663:Integrin beta4; D047908:Intracellular Signaling Peptides and Proteins; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D016392:Proto-Oncogene Proteins pp60(c-src); D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases