Abstract
Focal adhesion kinase (FAK) mediates signal transduction in response to multiple extracellular inputs via tyrosine phosphorylation at specific residues. Although several tyrosine phosphorylation events have been linked to FAK activation and downstream signal transduction, the function of FAK phosphorylation at Tyr(407) was previously unknown. Here, we show for the first time that phosphorylation of FAK Tyr(407) increases during serum starvation, contact inhibition, and cell cycle arrest, all conditions under which activating FAK Tyr(397) phosphorylation decreases. Transfection of NIH3T3 cells with a phosphorylation-mimicking FAK 407E mutant decreased autophosphorylation at Tyr(397) and inhibited both FAK kinase activity in vitro and FAK-mediated functions such as cell adhesion, spreading, proliferation, and migration. The opposite effects were observed in cells transfected with nonphosphorylatable mutant FAK 407F. Taken together, these data suggest the novel concept that FAK Tyr(407) phosphorylation negatively regulates the enzymatic and biological activities of FAK.
Highlights
Focal adhesion kinase (FAK)3 is a nonreceptor cytoplasmic tyrosine kinase that modulates various cell functions, including survival, proliferation, and migration [1, 2]
FAK Tyr407 Phosphorylation Appears to Be Inversely Correlated with Cell Proliferation—To investigate the role of phosphorylation at FAK residue Tyr407, we examined this site-specific phosphorylation under various cell conditions (Fig. 1)
Because both cell proliferation and FAK activity are decreased under conditions of serum starvation, contact inhibition, and cell cycle arrest, these results seem to suggest that FAK Tyr407 phosphorylation might decrease the ability of FAK to regulate cell proliferation
Summary
Focal adhesion kinase (FAK) is a nonreceptor cytoplasmic tyrosine kinase that modulates various cell functions, including survival, proliferation, and migration [1, 2]. As an example of FAK signaling, when integrin is activated, FAK is recruited to focal contacts and autophosphorylated at Tyr397 [8]. This creates a high affinity binding site for the SH2 domain of Src family tyrosine kinases and the p85 subunit of phosphoinositide 3-kinase, allowing their recruitment and activation. A recent study showed that exposure of endothelial cells to vascular endothelial growth factor induced Tyr407 phosphorylation, suggesting that Tyr407 phosphorylation may play a role in transducing the vascular endothelial growth factor signals, which trigger assembly of focal adhesions and endothelial cell migration [18]. VOLUME 282 NUMBER 14 APRIL 6, 2007 time that FAK Tyr407 phosphorylation appears to function in the negative regulation of FAK activity and function
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