title: Role for phosphoinositide 3-kinase in Fc gamma RIIA-induced platelet shape change.
abstract: Platelets transform from disks to irregular spheres, grow filopodia, form ruffles, and spread on surfaces coated with anti-Fc gamma RIIA antibody. Fc gamma RIIA cross-linking leads to a tenfold increase in actin filament barbed end exposure and robust actin assembly. Activation of the small GTPases Rac and Cdc42 follows Fc gamma RIIA cross-linking. Shape change, actin filament barbed end exposure, and quantifiable actin assembly require phosphoinositide 3-kinase (PI3-kinase) activity and a rise in intracellular calcium. PI3-kinase inhibition blocks activation of Rac, but not of Cdc42, and diminishes the association of Arp2/3 complex and CapZ with polymerized actin. Furthermore, addition of constitutively active D-3 phosphorylated polyphosphoinositides or recombinant PI3-kinase subunits to octylglucoside-permeabilized platelets elicits actin filament barbed end exposure by releasing gelsolin and CapZ from the cytoskeleton. Our findings place PI3-kinase activity upstream of Rac, gelsolin, and Arp2/3 complex activation induced by Fc gamma RIIA and clearly distinguish the Fc gamma RIIA signaling pathway to actin filament assembly from the thrombin receptor protease-activated receptor (PAR)-1 pathway.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kurt L
authors.initials: KL
authors.lastname: Barkalow
authors.forename: Hervé
authors.initials: H
authors.lastname: Falet
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.forename: Andrew
authors.initials: A
authors.lastname: van Vugt
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Carpenter
authors.forename: Alan D
authors.initials: AD
authors.lastname: Schreiber
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
mesh_terms: D051378:Actin-Related Protein 3; D000199:Actins / Q000097:blood / Q000187:drug effects / Q000502:physiology; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015703:Antigens, CD / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D001798:Blood Proteins; D002118:Calcium / Q000378:metabolism; D051347:CapZ Actin Capping Protein; D048429:Cell Size; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000097:blood; D005960:Glucosides / Q000494:pharmacology; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins / Q000097:blood; D009124:Muscle Proteins / Q000097:blood; D010539:Permeability / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017452:Receptors, IgG; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology
chemical_list: D051378:Actin-Related Protein 3; D000199:Actins; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015703:Antigens, CD; D001798:Blood Proteins; D002118:Calcium; D051347:CapZ Actin Capping Protein; D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins; D005960:Glucosides; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017452:Receptors, IgG; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; C495928:ACTR3 protein, human; C485792:ANGPTL2 protein, human; C080568:Fc gamma receptor IIA; C018619:octyl-beta-D-glucoside