Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contribute to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis (By similarity). a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + ADP + H(+) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + ADP + H(+) ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] Activated by both the alpha and the beta-gamma G proteins following stimulation of G protein-coupled receptors (GPCRs). Activation by GPCRs is assisted by the regulatory subunit PIK3R5 leading to the translocation from the cytosol to the plasma membrane and to kinase activation; the respective activation involving PIK3R6 requires HRAS for membrane recruitment. Wortmannin sensitive in nM range. Inhibited by AS252424. Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis. Heterodimer of a catalytic subunit PIK3CG and a PIK3R5 or PIK3R6 regulatory subunit. Interacts with GRK2 through the PIK helical domain (By similarity). Interaction with GRK2 is required for targeting to agonist-occupied receptor. Interacts with PDE3B; regulates PDE3B activity and thereby cAMP levels in cells (PubMed:15294162). Interacts with TPM2 (By similarity). Interacts with EPHA8; regulates integrin-mediated cell adhesion to substrate. Interacts with HRAS; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6. Phosphorylated at Thr-1024 by PKA. Phosphorylation inhibits lipid kinase activity. Autophosphorylation at Ser-1101 has no effect on the phosphatidylinositol-4,5-bisphosphate 3-kinase activity. Viable and fertile. Display abnormalities when the immune system is stressed. Reduced leukocyte migration in response to chemotactic agents and towards the site of inflammation. Reduced neutrophil oxidative burst in response to chemotactic agents. Reduced thymocyte survival and defective T lymphocyte activation. Protected from leukocyte infiltration of synovia in a model of rheumatoid arthritis. Dendritic cell showed reduced response to chemokines and migration to draining lymph nodes under inflammatory conditions. Platelets have defects in thrombus formation. Increased cardiac contractility. Display myocardial damage after transverse aortic constriction. Belongs to the PI3/PI4-kinase family.