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Molecular and Cellular Biology, September 2004, p. 8113-8133, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8113-8133.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Src-Mediated Phosphorylation of Focal Adhesion Kinase Couples Actin and Adhesion Dynamics to Survival Signaling

M. A. Westhoff,1 B. Serrels,1 V. J. Fincham,1 M. C. Frame,2 and N. O. Carragher1*

The Beatson Institute for Cancer Research, Cancer Research UK,1 Institute of Biological and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom2

Received 8 February 2004/ Returned for modification 30 March 2004/ Accepted 10 June 2004

Integrin-associated focal adhesions not only provide adhesive links between cellular actin and extracellular matrix but also are sites of signal transmission into the cell interior. Many cell responses signal through focal adhesion kinase (FAK), often by integrin-induced autophosphorylation of FAK or phosphorylation by Src family kinases. Here, we used an interfering FAK mutant (4-9F-FAK) to show that Src-dependent FAK phosphorylation is required for focal adhesion turnover and cell migration, by controlling assembly of a calpain 2/FAK/Src/p42ERK complex, calpain activation, and proteolysis of FAK. Expression of 4-9F-FAK in FAK-deficient fibroblasts also disrupts F-actin assembly associated with normal adhesion and spreading. In addition, we found that FAK's ability to regulate both assembly and disassembly of the actin and adhesion networks may be linked to regulation of the protease calpain. Surprisingly, we also found that the same interfering 4-9F-FAK mutant protein causes apoptosis of serum-deprived, transformed cells and suppresses anchorage-independent growth. These data show that Src-mediated phosphorylation of FAK acts as a pivotal regulator of both actin and adhesion dynamics and survival signaling, which, in turn, control apparently distinct processes such as cell migration and anchorage-independent growth. This also highlights that dynamic regulation of actin and adhesions (which include the integrin matrix receptors) is critical to signaling output and biological responses.

* Corresponding author. Mailing address: The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, Scotland, United Kingdom. Phone: 44-141-330-3956. Fax: 44-141-942-6521. E-mail: n.carragher{at}beatson.gla.ac.uk.

Molecular and Cellular Biology, September 2004, p. 8113-8133, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8113-8133.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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