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Published online 11 December 2006. doi:10.1083/jcb.200605114
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 6, 993-1003
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Article

ß4 integrin activates a Shp2–Src signaling pathway that sustains HGF-induced anchorage-independent growth



Andrea Bertotti, Paolo M. Comoglio, and Livio Trusolino

Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo (Torino), Italy

Correspondence to Livio Trusolino: livio.trusolino{at}ircc.it

Despite being a cell–matrix adhesion molecule, ß4 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 ß4, which is instrumental for integrin-mediated recruitment of the tyrosine phosphatase Shp2. Shp2 binding to ß4 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 ß4 depletion, by a ß4 mutant unable to bind Shp2, and by pharmacological and genetic inhibition of Shp2 or Src. Preservation of the ß4 docking sites for Shp2 as well as the integrity of Shp2, Src, or ERK activity are required for the ß4-mediated induction of anchorage-independent growth. These results unravel a novel pathway whereby ß4 directs tyrosine kinase–based signals toward adhesion-unrelated outcomes.

Abbreviations used in this paper: ERK, extracellular signal-regulated kinase; HGF, hepatocyte growth factor.


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