調節サブユニットと触媒サブユニットからなるヘテロ二量体。
血小板由来増殖因子やインスリンなどの刺激により活性化される。
SH2ドメインを介してチロシンリン酸化部位に結合して活性化される。
ホスファチジルイノシトール4,5-ビスリン酸をリン酸化し、ホスファチジルイノシトール3,4,5-トリスリン酸を生じる。PIP3は細胞増殖や生存などに重要な役割をもつPHドメインをもつAKT1やPDPK1を動員する。
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Short name=PI3-kinase subunit gamma
Short name=PI3K-gamma
Short name=PI3Kgamma
Short name=PtdIns-3-kinase subunit gamma
EC=2.7.1.153
Alternative name(s):
Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma
Short name=PtdIns-3-kinase subunit p110-gamma
Short name=p110gamma
Phosphoinositide-3-kinase catalytic gamma polypeptide
Serine/threonine protein kinase PIK3CG
EC=2.7.11.1
p120-PI3K
- Function
- 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 ADRBK1 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. Ref.1 Ref.9 Ref.11 Ref.13 Ref.18
- Catalytic activity
- ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate.
ATP + a protein = ADP + a phosphoprotein.
- Enzyme regulation
- 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 subunits (PIK3R5 or PIK3R6) leading to the translocation from the cytosol to the plasma membrane and to kinase activation. Inhibited by AS-604850 and AS-605240. Ref.1 Ref.20
- Pathway
- Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.
- Subunit structure
- Heterodimer of a catalytic subunit PIK3CG and a PIK3R5 or PIK3R6 regulatory subunit. Interacts with ADRBK1 through the PIK helical domain. Interaction with ADRBK1 is required for targeting to agonist-occupied receptor. Interacts with PDE3B By similarity. Interacts with TPM2. 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 By similarity. Ref.8 Ref.9 Ref.12 Ref.13
- Subcellular location
- Cytoplasm. Cell membrane Ref.9.
- Tissue specificity
- Pancreas, skeletal muscle, liver and heart. Ref.1
- Miscellaneous
- Candidate target in therapy for inflammatory diseases. Selective inhibitors and protein ablation are anti-inflammatory in multiple disease models such as asthma, rheumatoid arthritis, allergy, systemic lupus erythematosus, airway inflammation, lung injury and pancreatitis (Ref.15).
Sequence similarities
Belongs to the PI3/PI4-kinase family.
Contains 1 C2 PI3K-type domain.
Contains 1 PI3K-ABD domain.
Contains 1 PI3K-RBD domain.
Contains 1 PI3K/PI4K domain.
Contains 1 PIK helical domain.
Phosphatidylinositol 3-kinase regulatory subunit alpha
Short name=PI3-kinase regulatory subunit alpha
Short name=PI3K regulatory subunit alpha
Short name=PtdIns-3-kinase regulatory subunit alpha
Alternative name(s):
Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
Short name=PI3-kinase subunit p85-alpha
Short name=PtdIns-3-kinase regulatory subunit p85-alpha
:Function
Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling. Ref.11 Ref.51 Ref.53
Subunit structure
Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with FER. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTK2/FAK1 By similarity. Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity By similarity. Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV. Interacts with HCV NS5A. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST. Interacts with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts with NTRK1 (phosphorylated upon ligand-binding). Ref.2 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.32 Ref.36 Ref.37 Ref.38 Ref.53
Tissue specificity
Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level). Ref.2
Domain
The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef.
Post-translational modification
Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.
Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear By similarity. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR. Ref.33 Ref.35
Involvement in disease
Agammaglobulinemia 7, autosomal recessive (AGM7) [MIM:615214]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.42
SHORT syndrome (SHORTS) [MIM:269880]: A rare, multisystem disease characterized by short stature, anomalies of the anterior chamber of the eye, characteristic facial features such as triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella, partial lipodystrophy, hernias, hyperextensibility, and delayed dentition. The clinical phenotype can include insulin resistance, nephrocalcinosis, and hearing deficits. Developmental milestones and cognition are normal.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.57 Ref.58
Sequence similarities
Belongs to the PI3K p85 subunit family.
Contains 1 Rho-GAP domain.
Contains 2 SH2 domains.
Contains 1 SH3 domain.
