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J. Biol. Chem., Vol. 277, Issue 40, 37904-37911, October 4, 2002
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From the Departments of Activation of the Met receptor tyrosine kinase
through its ligand, hepatocyte growth factor, stimulates cell
spreading, cell dispersal, and the inherent morphogenic program of
various epithelial cell lines. Although both hepatocyte growth factor
and epidermal growth factor (EGF) can activate downstream signaling
pathways in Madin-Darby canine kidney epithelial cells, EGF fails to
promote the breakdown of cell-cell junctional complexes and initiate an invasive morphogenic program. We have undertaken a strategy to identify
signals that synergize with EGF in this process. We provide evidence
that the overexpression of the CrkII adapter protein complements
EGF-stimulated pathways to induce cell dispersal in two-dimensional
cultures and cell invasion and branching morphogenesis in
three-dimensional collagen gels. This finding correlates with the
ability of CrkII to promote the breakdown of adherens junctions in
stable cell lines and the ability of EGF to stimulate enhanced Rac
activity in cells overexpressing CrkII. We have previously shown that
the Gab1-docking protein is required for branching morphogenesis
downstream of the Met receptor. Consistent with a role for CrkII in
promoting EGF-dependent branching morphogenesis, the
binding of Gab1 to CrkII is required for the branching morphogenic program downstream of Met. Together, our data support a role for the
CrkII adapter protein in epithelial invasion and morphogenesis and
underscores the importance of considering the synergistic actions of
signaling pathways in cancer progression.
Crk Synergizes with Epidermal Growth Factor for Epithelial
Invasion and Morphogenesis and Is Required for the Met Morphogenic
Program*
§,¶,
, and**
Biochemistry,
Medicine, and ** Oncology, Molecular Oncology Group, McGill
University Hospital Center, McGill University,
Montreal, Quebec H3A 1A1, Canada
*
This research was supported by an operating grant from the
Canadian Breast Cancer Research Initiative with money from the Canadian
Cancer Society (to M. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Canadian Institutes of Health Research scientist
award. To whom correspondence should be addressed: Molecular Oncology
Group, McGill University Hospital Centre, Rm. H510, 687 Pine Ave., W.,
Montreal, Quebec H3A 1A1, Canada. Tel.: 514-842-1231, ext. 35834; Fax:
514-843-1478.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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