Abstract
We have shown previously that cell adhesion or platelet-derived growth factor (PDGF) promotes the in vivo association of focal adhesion kinase (FAK) with phosphatidylinositol (PI) 3-kinase. In vitro experiments indicated that this interaction was mediated by the p85 subunit of PI 3-kinase and dependent on the tyrosine phosphorylation of FAK. Here we report data suggesting that the major autophosphorylation site of FAK (Tyr-397) is the binding site for the SH2 domains of p85 in vitro and is also required for the association of FAK with PI 3-kinase in vivo. We also show that Tyr-397 is responsible for the increased FAK:PI 3-kinase association upon PDGF stimulation, implying that no additional site of FAK was involved in its binding to PI 3-kinase after PDGF stimulation. Finally, we present evidence that the interaction of PI 3-kinase with Tyr-397 of FAK stimulates its activity. Together, these results suggest that FAK activation and autophosphorylation at Tyr-397 may lead to its association with PI 3-kinase through the SH2 domains of p85, which can subsequently activate PI 3-kinase during cell adhesion.
Highlights
Focal adhesion kinase (FAK)1 is a cytoplasmic tyrosine kinase involved in integrin-mediated signal transduction pathways [1,2,3,4]
The Y397F mutant bound the SH2 domain of Grb2 and had tyrosine kinase activity comparable to that of wild type FAK, rendering it unlikely that the point mutation of Tyr-397 to Phe caused an overall conformational change leading to the inability of Y397F mutant to interact with p85
This association has been demonstrated to be mediated by binding of autophosphorylated tyrosine residues in the receptor tyrosine kinase to the SH2 domains of p85 subunit of PI 3-kinase (44 – 47)
Summary
Focal adhesion kinase (FAK)1 is a cytoplasmic tyrosine kinase involved in integrin-mediated signal transduction pathways [1,2,3,4].
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