title: Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases.
abstract: Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P3generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIIIα and PIPKIα, which sequentially generate PtdIns(3,4,5)P3from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P2generated is selectively used by PI(3)K for PtdIns(3,4,5)P3generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI(3)K signalling complex. Blockade of IQGAP1 interaction with PIPKIα or PI(3)K inhibited PtdIns(3,4,5)P3generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy.
authors.affiliation: University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University Avenue, Madison, Wisconsin 53706, USA.
authors.forename: Suyong
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hedman
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Samar
authors.initials: S
authors.lastname: Sayedyahossein
authors.affiliation: University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University Avenue, Madison, Wisconsin 53706, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Thapa
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
authors.affiliation: University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University Avenue, Madison, Wisconsin 53706, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D007328:Insulin; D010455:Peptides; D018129:Phosphatidylinositol Phosphates; D011956:Receptors, Cell Surface; C060974:phosphatidylinositol 3,4,5-triphosphate; D020703:ras GTPase-Activating Proteins; D019869:Phosphatidylinositol 3-Kinases; D019870:1-Phosphatidylinositol 4-Kinase; C000618292:PI4KIIIalpha protein, human; D051057:Proto-Oncogene Proteins c-akt