Assuntos
Antineoplásicos/uso terapêutico , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adulto , Antineoplásicos/sangue , Antipsicóticos/sangue , Bleomicina/sangue , Bleomicina/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Carcinoma/sangue , Carcinoma/complicações , Carcinoma/tratamento farmacológico , Cisplatino/sangue , Cisplatino/uso terapêutico , Clozapina/sangue , Etoposídeo/sangue , Etoposídeo/uso terapêutico , Feminino , Humanos , Neoplasias Intestinais/sangue , Neoplasias Intestinais/complicações , Neoplasias Intestinais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/complicações , Esquizofrenia/sangue , Esquizofrenia/complicações , Seminoma/sangue , Seminoma/complicações , Seminoma/tratamento farmacológico , Neoplasias Testiculares/sangue , Neoplasias Testiculares/complicações , Neoplasias Testiculares/tratamento farmacológicoRESUMO
Phosphoinositide (PI) 3-kinases play an important role in regulating the adhesive function of a variety of cell types through affinity modulation of integrins. Two type I PI 3-kinase isoforms (p110 beta and p110 gamma) have been implicated in G(i)-dependent integrin alpha(IIb)beta(3) regulation in platelets, however, the mechanisms by which they coordinate their signaling function remains unknown. By employing isoform-selective PI 3-kinase inhibitors and knock-out mouse models we have identified a unique mechanism of PI 3-kinase signaling co-operativity in platelets. We demonstrate that p110 beta is primarily responsible for G(i)-dependent phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) production in ADP-stimulated platelets and is linked to the activation of Rap1b and AKT. In contrast, defective integrin alpha(IIb)beta(3) activation in p110 gamma(-/-) platelets was not associated with alterations in the levels of PI(3,4)P(2) or active Rap1b/AKT. Analysis of the effects of active site pharmacological inhibitors confirmed that p110 gamma principally regulated integrin alpha(IIb)beta(3) activation through a non-catalytic signaling mechanism. Inhibition of the kinase function of PI 3-kinases, combined with deletion of p110 gamma, led to a major reduction in integrin alpha(IIb)beta(3) activation, resulting in a profound defect in platelet aggregation, hemostatic plug formation, and arterial thrombosis. These studies demonstrate a kinase-independent signaling function for p110 gamma in platelets. Moreover, they demonstrate that the combined catalytic and non-catalytic signaling function of p110 beta and p110 gamma is critical for P2Y(12)/G(i)-dependent integrin alpha(IIb)beta(3) regulation. These findings have potentially important implications for the rationale design of novel antiplatelet therapies targeting PI 3-kinase signaling pathways.