Type Iγ phosphatidylinositol phosphate kinase is required for EGF-stimulated directional cell migration

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Abstract
Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) modulates a plethora of cytoskeletal interactions that control the dynamics of actin assembly and, ultimately, cell migration. We show that the type Iγ phosphatidylinositol phosphate kinase 661 (PIPKIγ661), an enzyme that generates PI4,5P2, is required for growth factor but not G protein–coupled receptor–stimulated directional migration. By generating PI4,5P2 and regulating talin assembly, PIPKIγ661 modulates nascent adhesion formation at the leading edge to facilitate cell migration. The epidermal growth factor (EGF) receptor directly phosphorylates PIPKIγ661 at tyrosine 634, and this event is required for EGF-induced migration. This phosphorylation regulates the interaction between PIPKIγ661 and phospholipase Cγ1 (PLCγ1, an enzyme previously shown to be involved in the regulation of EGF-stimulated migration). Our results suggest that phosphorylation events regulating specific PIPKIγ661 interactions are required for growth factor–induced migration. These interactions in turn define the spatial and temporal generation of PI4,5P2 and derived messengers required for directional migration.