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Vol. 13, Issue 5, 1449-1461, May 2002
and§
Molecular Oncology Group, McGill University Hospital Center,
Departments of *Biochemistry, Activation of the Met receptor tyrosine kinase through its ligand,
hepatocyte growth factor (HGF), promotes an epithelial-mesenchymal transition and cell dispersal. However, little is known about the
HGF-dependent signals that regulate these events. HGF stimulation of
epithelial cell colonies leads to the enhanced recruitment of the CrkII
and CrkL adapter proteins to Met-dependent signaling complexes. We
provide evidence that signals involving CrkII and CrkL are required for
the breakdown of adherens junctions, the spreading of epithelial
colonies, and the formation of lamellipodia in response to HGF. The
overexpression of a CrkI SH3 domain mutant blocks these HGF-dependent
events. In addition, the overexpression of CrkII or CrkL promotes
lamellipodia formation, loss of adherens junctions, cell spreading, and
dispersal of colonies of breast cancer epithelial cells in the absence
of HGF. Stable lines of epithelial cells overexpressing CrkII show
enhanced activation of Rac1 and Rap1. The Crk-dependent breakdown of
adherens junctions and cell spreading is inhibited by the expression of
a dominant negative mutant of Rac1 but not Rap1. These findings provide
evidence that Crk adapter proteins play a critical role in the
breakdown of adherens junctions and the spreading of sheets of
epithelial cells.
Medicine and
§Oncology, McGill University, Montreal, Quebec, Canada H3A
1A1
Corresponding author. E-mail
address: morag{at}lan1.molonc.mcgill.ca.
Present address: Ste-Justine Hospital, Department
of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
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