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Vol. 17, Issue 3, 1261-1272, March 2006

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Involvement of Src Family Kinases in N-Cadherin Phosphorylation and -Catenin Dissociation during Transendothelial Migration of Melanoma Cells

Jianfei Qi ^* , Junfu Wang ^* , Olena Romanyuk ^*, and Chi-Hung Siu ^* 

^* Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1L6, Canada

Submitted October 7, 2005; Revised November 28, 2005; Accepted December 8, 2005
Monitoring Editor: Jean Schwarzbauer

N-cadherin is recruited to the heterotypic contact during transendothelial migration of melanoma cells in a coculture system with tumor cells seeded on top of a monolayer of endothelial cells. However, -catenin dissociates from N-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription. In this report, we demonstrate that Src becomes activated at the heterotypic contact between the transmigrating melanoma cell and neighboring endothelial cells. Src activation shows close temporal correlation with tyrosine phosphorylation of N-cadherin. Expression of a dominant-negative Src in melanoma cells blocks N-cadherin phosphorylation, -catenin dissociation, and nuclear translocation in transmigrating cells, consistent with the involvement of Src family kinases. In in vitro binding assays, Src-mediated phosphorylation of the N-cadherin cytoplasmic domain results in a significant reduction in -catenin binding. Although five phospho-tyrosine residues can be identified on the N-cadherin cytoplasmic domain by mass spectrometry, site-specific mutagenesis indicates that Tyr-860 is the critical amino acid involved in -catenin binding. Overexpression of N-cadherin carrying the Y860F mutation inhibits the transmigration of transfected cells across the endothelium. Together, the data suggest a novel role for tyrosine phosphorylation of N-cadherin by Src family kinases in the regulation of -catenin association during transendothelial migration of melanoma cells.

Abbreviations used: CAM, cell adhesion molecule; HMVEC, human lung microvascular endothelial cells; MALDI-TOF, matrix-assisted laser desorption ionization/time-of-flight; SFK, Src family kinase; TEM, transendothelial migration.

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

Present address: Shandong Academy of Medical Sciences, Jinan 250062, Shandong Province, People's Republic of China.

Address correspondence to: Chi-Hung Siu (chi.hung.siu{at}utoronto.ca).

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