title: Integrin adhesion and force coupling are independently regulated by localized PtdIns(4,5)2 synthesis.
abstract: The 90-kDa isoform of the lipid kinase PIP kinase Type I γ (PIPKIγ) localizes to focal adhesions (FAs), where it provides a local source of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Although PtdIns(4,5)P(2) regulates the function of several FA-associated molecules, the role of the FA-specific pool of PtdIns(4,5)P(2) is not known. We report that the genetic ablation of PIPKIγ specifically from FAs results in defective integrin-mediated adhesion and force coupling. Adhesion defects in cells deficient in FAPtdIns(4,5)P(2) synthesis are corrected within minutes while integrin-actin force coupling remains defective over a longer period. Talin and vinculin, but not kindlin, are less efficiently recruited to new adhesions in these cells. These data demonstrate that the specific depletion of PtdIns(4,5)P(2) from FAs temporally separates integrin-ligand binding from integrin-actin force coupling by regulating talin and vinculin recruitment. Furthermore, it suggests that force coupling relies heavily on locally generated PtdIns(4,5)P(2) rather than bulk membrane PtdIns(4,5)P(2).
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Legate
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Navid
authors.initials: N
authors.lastname: Bonakdar
authors.forename: Ben
authors.initials: B
authors.lastname: Fabry
authors.forename: David
authors.initials: D
authors.lastname: Boettiger
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D022001:Focal Adhesions / Q000737:chemistry / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016608:Talin / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016023:Integrins; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D016608:Talin; C534220:kindlin-1 protein, mouse; D016596:Vinculin; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase