Type I PIPK-alpha regulates directed cell migration by modulating Rac1 plasma membrane targeting and activation.
Phosphatidylinositol-4,5-bisphosphate (PI4,5P(2)) is a critical regulator of cell migration, but the roles of the type I phosphatidylinositol-4-phosphate 5-kinases (PIPKIs), which synthesize PI4,5P(2), have yet to be fully defined in this process. In this study, we report that one kinase, PIPKI-alpha, is a novel upstream regulator of Rac1 that links activated integrins to the regulation of cell migration. We show that PIPKI-alpha controls integrin-induced translocation of Rac1 to the plasma membrane and thereby regulates Rac1 activation. Strikingly, this function is not shared with other PIPKI isoforms, is independent of catalytic activity, and requires physical interaction of PIPKI-alpha with the Rac1 polybasic domain. Consistent with its role in Rac1 activation, depletion of PIPKI-alpha causes pronounced defects in membrane ruffling, actin organization, and focal adhesion formation, and ultimately affects the directional persistence of migration. Thus, our study defines the role of PIPKI-alpha in cell migration and describes a new mechanism for the spatial regulation of Rac1 activity that is critical for cell migration.
Chao
Wei-Ting
WT
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Daquinag
Alexes C
AC
Ashcroft
Felicity
F
Kunz
Jeannette
J
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D016023:Integrins; D007527:Isoenzymes; D019269:Phosphatidylinositol 4,5-Diphosphate; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D020830:rac1 GTP-Binding Protein