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Journal Article
Research Support, Non-U.S. Gov't
Phosphorylation of phosphatidylinositol 4-phosphate 5-kinase γ by Akt regulates its interaction with talin and focal adhesion dynamics.
Biochimica et Biophysica Acta 2015 October
The type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family members and their lipid product, phosphatidylinositol 4,5-bisphosphate (PIP2) are important regulators of actin cytoskeleton. PIP5Kγ 90kDa (PIP5Kγ90), an isoform of PIP5K, localizes to focal adhesions (FAs) and is activated via its interaction with the cytoskeletal protein, talin. Currently, regulatory signaling pathways of talin-PIP5Kγ90 interaction related to FA dynamics and cell motility are not well understood. Considering the presence of Akt consensus motifs in PIP5Kγ90, we examined a potential link of Akt activation to talin-PIP5Kγ90 interaction. We found that Akt phosphorylated PIP5Kγ90 specifically at serine 555 (S555) in vitro and in epidermal growth factor (EGF)-treated cells phosphoinositide 3-kinase-dependently. EGF treatment suppressed talin-PIP5Kγ90 interaction and PIP2 levels. Similarly, a phosphomimetic mutant (S555D), but not non-phosphorylatable mutant (S555A), of PIP5Kγ90 had reduced talin binding affinity, lowered PIP2 levels, and was dislocated from FAs. The S555D mutant also caused decreases in actin stress fibers and vinculin-positive FAs. Moreover, assembly and disassembly of FAs were enhanced by S555D expression and EGF-induced cell migration was relatively low in S555A-expressing cells compared to wild-type-expressing cells. PIP5Kγ87, a PIP5Kγ splice variant lacking the talin binding motif, was phosphorylated by Akt, which, however, hardly affected PIP2 levels. Taken together, our results suggested that Akt-mediated PIP5Kγ90 S555 phosphorylation is a novel regulatory point for talin binding to control PIP2 level at the FAs, thereby modulating FA dynamics and cell motility.
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