Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform

Definition:

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, activation, 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. Contributes 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.

References:

[1]. B Stoyanov, et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science. 1995 Aug 4;269(5224):690-3. [Content Brief]

[2]. Marini Thian, et al. Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation. Haematologica. 2020 Oct 1;105(10):e488. [Content Brief]

[3]. Sathyamangla V Naga Prasad, et al. Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005 Aug;7(8):785-96. [Content Brief]

[4]. Andrew J Takeda, et al. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat Commun. 2019 Sep 25;10(1):4364. [Content Brief]

[5]. Adam C Resnick, et al. Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12783-8. [Content Brief]

[6]. Enrico Patrucco, et al. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004 Aug 6;118(3):375-87. [Content Brief]

[7]. Timothy I Meier, et al. Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms. Protein Expr Purif. 2004 Jun;35(2):218-24. [Content Brief]

[8]. S Suer, et al. Human phosphatidylinositol 4-kinase isoform PI4K92. Expression of the recombinant enzyme and determination of multiple phosphorylation sites. Eur J Biochem. 2001 Apr;268(7):2099-106. [Content Brief]

[9]. Sathyamangla V Naga Prasad, et al. Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol. 2002 Aug 5;158(3):563-75. [Content Brief]

[10]. Lindsay S Wilson, et al. A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells. J Biol Chem. 2011 May 6;286(18):16285-96. [Content Brief]

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