v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at Beta1 Integrin-containing Invadopodia Promotes Cell Invasion

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2002
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Hsia, Datsun A.
Ilić, Du ko
Schlaepfer, David D.
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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 ß1 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 ß1 integrin-containing invadopodia act to stabilize a v-Src-FAK signaling complex promoting cell invasion.

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ISO 690HAUCK, Christof R., Datsun A. HSIA, Du ko ILIĆ, David D. SCHLAEPFER, 2002. v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at Beta1 Integrin-containing Invadopodia Promotes Cell Invasion. In: Journal of Biological Chemistry. 2002, 277(15), pp. 12487-12490
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@article{Hauck2002SH3en-6655,
  year={2002},
  title={v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at Beta1 Integrin-containing Invadopodia Promotes Cell Invasion},
  number={15},
  volume={277},
  journal={Journal of Biological Chemistry},
  pages={12487--12490},
  author={Hauck, Christof R. and Hsia, Datsun A. and Ilić, Du ko and Schlaepfer, David D.}
}
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