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Vol. 16, Issue 12, 5514-5527, December 2005

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Phosphorylation of N-Cadherin-associated Cortactin by Fer Kinase Regulates N-Cadherin Mobility and Intercellular Adhesion Strength

Tarek Y. El Sayegh ^*, Pamela D. Arora ^*, Lingzhi Fan , Carol A. Laschinger ^*, Peter A. Greer , Christopher A. McCulloch ^*, and Andras Kapus 

^* CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario M5S 3E2, Canada; Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario K7L 3N6, Canada; and Department of Surgery, University of Toronto and St. Michael's Hospital Research Institute, Toronto, Ontario M5B 1W8, Canada

Submitted May 10, 2005; Revised August 25, 2005; Accepted September 13, 2005
Monitoring Editor: Richard Assoian

Cortactin regulates the strength of nascent N-cadherin-mediated intercellular adhesions through a tyrosine phosphorylation-dependent mechanism. Currently, the functional significance of cortactin phosphorylation and the kinases responsible for the regulation of adhesion strength are not defined. We show that the nonreceptor tyrosine kinase Fer phosphorylates cadherin-associated cortactin and that this process is involved in mediating intercellular adhesion strength. In wild-type fibroblasts N-cadherin ligation-induced transient phosphorylation of Fer, indicating that junction formation activates Fer kinase. Tyrosine phosphorylation of cortactin after N-cadherin ligation was strongly reduced in fibroblasts expressing only catalytically inactive Fer (D743R), compared with wild-type cells. In wild-type cells, N-cadherin-coated bead pull-off assays induced fourfold greater endogenous N-cadherin association than in D743R cells. Fluorescence recovery after photobleaching showed that GFP-N-cadherin mobility at nascent contacts was 50% faster in wild-type than D743R cells. In shear wash-off assays, nascent intercellular adhesion strength was twofold higher in wild-type than D743R cells. Cortactin recruitment to adhesions was independent of Fer kinase activity, but was impacted by N-cadherin ligation-provoked Rac activation. We conclude that N-cadherin ligation induces Rac-dependent cortactin recruitment and Fer-dependent cortactin phosphorylation, which in turn promotes enhanced mobilization and interaction of surface expressed N-cadherin in contacting cells.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: T. Y. El Sayegh (t.elsayegh{at}utoronto.ca).

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