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Papers In Press, published online ahead of print February 11, 2002
J. Biol. Chem, 10.1074/jbc.C100760200
Submitted on December 23, 2001
Revised on January 30, 2002
Accepted on February 11, 2002
1 integrin-containing invadopodia promotes cell invasion
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Corresponding Author: dschlaep{at}scripps.edu
In viral Src (v-Src) transformed cells, focal adhesion kinase (FAK) associates in a stable signaling complex with v-Src that is mediated by combined v-Src SH2 and gain-of-function v-Src SH3 domain binding to FAK. Here, we assess the significance of the Arg-95 to Trp gain-of-function mutation in the v-Src SH3 domain through comparisons of Src-/- fibroblasts transformed with either Prague C v-Src or a point-mutant (v-Src-RT) containing a normal (Arg-95) SH3 domain. Both v-Src isoforms exhibited equivalent kinase activity, enhanced Src-/- cell motility, and stimulated cell growth in both low serum and soft agar. Notably, the stability of a v-Src-FAK signaling complex and FAK phosphorylation at Tyr-861 and Tyr-925 were reduced in v-Src-RT compared to v-Src-transformed cells. Significantly, v-Src but not v-Src-RT promoted Src-/- cell invasion through a reconstituted Matrigel basement membrane barrier and v-Src co-localized with FAK and 
1 integrin at invadopodia. In contrast, v-Src-RT exhibited a partial peri-nuclear and focal contact distribution in Src-/- cells. Adenoviral-mediated FAK overexpression promoted the recruitment of v-Src-RT to invadopodia, facilitated the formation of a v-Src-RT-FAK signaling complex, and reversed the v-Src-RT invasion deficit. Adenoviral-mediated dominant-negative inhibition of FAK blocked v-Src-stimulated cell invasion. These studies establish that gain-of-function v-Src SH3 targeting interactions with FAK at 1 integrin-containing invadopodia act to stabilize a v-Src-FAK signaling complex promoting cell invasion.
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