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Originally published as MBC in Press, 10.1091/mbc.01-10-0477 on March 7, 2002
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Vol. 13, Issue 5, 1449-1461, May 2002

Crk Adapter Proteins Promote an Epithelial-Mesenchymal-like Transition and Are Required for HGF-mediated Cell Spreading and Breakdown of Epithelial Adherens Junctions

Louie Lamorte,* Isabelle Royal,dagger Dagger Monica Naujokas,dagger and Morag Park*dagger §||

Molecular Oncology Group, McGill University Hospital Center, Departments of  *Biochemistry,  dagger Medicine and  §Oncology, McGill University, Montreal, Quebec, Canada H3A 1A1

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.

|| Corresponding author. E-mail address: morag{at}lan1.molonc.mcgill.ca.

Dagger Present address: Ste-Justine Hospital, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.

Molecular Biology of the Cell
Vol. 13, 1449-1461, May 2002
Copyright © 2002 by The American Society for Cell Biology


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