title: Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions.
abstract: The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.
authors.affiliation: Department of Pharmacology, Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison, 1300 University Avenue, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Ling
authors.forename: Renee L
authors.initials: RL
authors.lastname: Doughman
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Firestone
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Bunce
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000737:chemistry / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism
chemical_list: D000199:Actins; D039641:Integrin beta Chains; D007527:Isoenzymes; D019269:Phosphatidylinositol 4,5-Diphosphate; D011993:Recombinant Fusion Proteins; D016608:Talin; D016596:Vinculin; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat