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(Received for publication, December 20, 1996, and in revised form, May 16, 1997)
From the Departments of a Medicine, j Oncology, and
h Biochemistry, Molecular Oncology Group, Royal Victoria
Hospital, McGill University, 687 Pine Ave. West, Montreal, Quebec,
Canada H3A 1A1 and the Departments of c Microbiology & Immunology and d Pharmacology, Kimmel Cancer Institute,
Philadelphia, Pennsylvania 19107
Hepatocyte growth factor/scatter factor is a
multifunctional factor that induces mitogenesis, motility, invasion,
and branching tubulogenesis of several epithelial and endothelial cell
lines in culture. The receptor for hepatocyte growth factor has been identified as the Met-tyrosine kinase. Upon stimulation with hepatocyte growth factor, the Met
Volume 272, Number 33,
Issue of August 15, 1997
pp. 20811-20819
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
subunit becomes highly phosphorylated on
tyrosine residues, one of which, tyrosine 1356 within the carboxyl terminus, is crucial for dissociation, motility, and branching tubule
formation in Madin-Darby canine kidney epithelial cells. Tyrosine 1356 forms a multisubstrate binding site for the Grb2 and Shc adaptor
proteins, the p85 subunit of phosphatidylinositol 3
-kinase,
phospholipase C
, and a phosphatase, SHP2. To investigate additional
signaling molecules that are activated by the Met receptor, we have
identified hepatocyte growth factor-induced phosphoproteins in tubular
epithelial cells. We have established that proteins of 100-130 kDa are
highly phosphorylated following stimulation of epithelial cells and
that one of these is the Grb2-associated binding protein Gab1, a
possible insulin receptor substrate-1-like signal transducer. We show
that Gab1 is the major substrate for the Met kinase in
vitro and in vivo. Association of Gab1 with Met
requires a functional Grb2 binding site involving tyrosine 1356 and to
a lesser extent tyrosine 1349. Met receptor mutants that fail to induce
branching tubulogenesis are impaired in their ability to interact with
Gab1, suggesting that Gab1 may play a role in these processes.
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D. M. Kamikura, H. Khoury, C. Maroun, M. A. Naujokas, and M. Park Enhanced Transformation by a Plasma Membrane-Associated Met Oncoprotein: Activation of a Phosphoinositide 3'-Kinase-Dependent Autocrine Loop Involving Hyaluronic Acid and CD44 Mol. Cell. Biol., May 15, 2000; 20(10): 3482 - 3496. [Abstract] [Full Text]
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D. Sakkab, M. Lewitzky, G. Posern, U. Schaeper, M. Sachs, W. Birchmeier, and S. M. Feller Signaling of Hepatocyte Growth Factor/Scatter Factor (HGF) to the Small GTPase Rap1 via the Large Docking Protein Gab1 and the Adapter Protein CRKL J. Biol. Chem., April 6, 2000; 275(15): 10772 - 10778. [Abstract] [Full Text] [PDF]
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