Regulation of the interaction between PIPKI-γ and talin by proline-directed protein kinases

The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type Igamma (PIPKIgamma) regulates PI(4,5)P2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (5650) within the talin-binding sequence of human PIPKIgamma blocks this interaction. At synapses, S650 is phosphorylated by p35/Cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation. S650 is also a substrate for cyclin B1/Cdk1 and its phosphorylation in mitosis correlates with focal adhesion disassembly. Phosphorylation by Src of the tyrosine adjacent to 5650 (Y649 in human PIPKIgamma) was shown to enhance PIPKIgamma targeting to focal adhesions (Ling, K., R.L. Doughman, V.V. Iyer, A.J. Firestone, S.F. Bairstow, D.F. Mosher, M.D. Schaller, and R.A. Anderson. 2003. J. Cell Biol. 163:1339-1349). We find that Y649 phosphorylation does not stimulate directly PIPKIgamma binding to talin, but may do so indirectly by inhibiting S650 phosphorylation. Conversely, S650 phosphoryiation inhibits Y649 phosphorylation by Src. The opposite effects of the phosphorylation of Y649 and S650 likely play a critical role in regulating synaptic function as well as the balance between cell adhesion and cell motility.