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Molecular and Cellular Biology, January 2008, p. 642-655, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01024-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

c-Src-Mediated Epithelial Cell Migration and Invasion Regulated by PDZ Binding Site{triangledown} ,{dagger}

Martin Baumgartner,* Gerald Radziwill,{ddagger} Mihaela Lorger,{ddagger},§ Andreas Weiss, and Karin Moelling

Institute of Medical Virology, University of Zürich, Gloriastrasse 30, 8006 Zürich, Switzerland

Received 11 June 2007/ Returned for modification 28 July 2007/ Accepted 1 November 2007

c-Src tyrosine kinase controls proliferation, cell adhesion, and cell migration and is highly regulated. A novel regulatory mechanism to control c-Src function that has recently been identified involves the C-terminal amino acid sequence Gly-Glu-Asn-Leu (GENL) of c-Src as ligand for PDZ domains. Herein, we determined the biological relevance of this c-Src regulation in human breast epithelial cells. The intact GENL sequence maintained c-Src in an inactive state in starved cells and restricted c-Src functions that might lead to metastatic transformation under normal growth conditions. c-Src with a C-terminal Leu/Ala mutation in GENL (Src-A) promoted the activation and translocation of cortactin and focal adhesion kinase and increased the motility and persistence of cell migration on the basement membrane. Src-A promoted increased extracellular proteolytic activity, and in acinar cultures, it led to the escape of cells through the basement membrane into the surrounding matrix. We ascribe the regulatory function of C-terminal Leu to the role of GENL in modulating c-Src activity downstream of cell matrix adhesion. We propose that the C terminus of c-Src via its GENL sequence presents a mechanism that restricts c-Src in epithelia and prevents progression toward an invasive phenotype.

* Corresponding author. Mailing address: Institute of Medical Virology, University of Zürich, Gloriastrasse 30, CH-8006 Zürich, Switzerland. Phone: 41 44 634 44 20. Fax: 41 44 634 49 67. E-mail: Martin.Baumgartner{at}immv.uzh.ch

{triangledown} Published ahead of print on 26 November 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

§ Present address: Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Present address: Unit of Experimental Immunotherapy, Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.

{ddagger} G.R. and M.L. contributed equally to this work.

Molecular and Cellular Biology, January 2008, p. 642-655, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01024-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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