|Gene:||PIK3R6||Accession Number: HS16294 (MetaCyc)|
Synonyms: phosphoinositide 3-kinase gamma adapter protein of 87 kDa, p87 PI3K adapter protein, phosphoinositide 3-kinase regulatory subunit 6
Species: Homo sapiens
Component of: phosphatidylinositol 3-kinase, class IB, p110γ/p87 (extended summary available)
The regulatory subunits of the PI 3-kinases influence the subcellular location, enzymatic activity, and stability of the associated catalytic subunit. The family of mammalian regulatory subunits of PI 3-kinase has been slowly expanding, and currently includes six members. Three of these bind to class IA catalytic subunits (known as p110α, p110β and p110δ) and are activated by receptor tyrosine kinases. Two others bind to the class IB catalytic unit p110γ, and are activated by G protein-coupled receptors (GPCRs), and one binds to the class III catalytic p100 subunit.
The first member of the group was p85α (PIK3R1), which contains an N-terminal src-homology 3 (SH3) domain and two src-homology 2 (SH2) domains. Other members were discovered based on homology. p85β (PIK3R2) consists of similar structural domains to p85α but its amino acid sequence is only 62% identical. p55γ (PIK3R3) is composed of a unique 30-residue amino terminus followed by a proline-rich motif and two SH2 domains with significant sequence identify to those in p85. It contains no SH3 domain.
Two types of regulatory subunits interact only with the class IB p110γ catalytic subunit. They consist of p101 (encoded by PIK3R5) and p87 (PIK3R6) [Voigt06]. Both of these subunits bind to both p110γ and heterodimeric GTPase βγ subunits and mediate activation of p110γ downstream of G protein-coupled receptors.
About This Protein
p87 appears to bind to p110γ with a slightly higher affinity and to Gβγ with a slightly lower affinity than does p101 [Voigt06]. In contrast to p101, p87 is highly expressed in heart and may therefore be crucial to p110γ" cardiac function. p87 and p101 are both expressed in dendritic cells, macrophages, and neutrophils, raising the possibility of regulatory subunit-dependent differences in PI3Kγ signaling within the same cell type.
p87 physically interacts with phosphodiesterase (PDE) 3B, suggesting that it mediates the interaction between p110γ and PDE3B, known to activate the later [Voigt06].
The cDNA was cloned and expressed in HEK293 cells transfected with p110γ.
|Map Position: [9,797,734 <- 9,862,774]|
Molecular Weight of Polypeptide: 84.258 kD (from nucleotide sequence)
Species: Homo sapiens
Subunit composition of
phosphatidylinositol 3-kinase, class IB, p110γ/p87 = [PIK3R6][PIK3CG]
phosphoinositide 3-kinase regulatory subunit p87 = PIK3R6 (extended summary available)
phosphatidylinositol 3 kinase catalytic subunit p110γ = PIK3CG (summary available)
The Class I PI 3-kinases, which can be subdivided into IA and IB, are known to be activated by receptors. Although they can phosphorylate an L-1-phosphatidyl-inositol, a 1-phosphatidyl-1D-myo-inositol 4-phosphate, and a 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate in vitro, these enzymes utilize mainly a 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate as a substrate in vivo [Stephens91, Hawkins92].
The Class IB PI 3-kinase phosphatidylinositol 3 kinase catalytic subunit p110γ is associated with either a p101 or a p87 regulatory subunits (encoded by PIK3R5 and PIK3R6, respectively), which may link the kinase to serpentine receptors by the βγ subunits of heterotrimeric G-proteins and thus mediate p110γ activation [Stoyanov95].
Most of our knowledge about the physiological role of PI3Kγ is derived from the characterization of p110γ knockout mice, which show defects in chemoattractant-induced neutrophil migration and oxidative burst, thymocyte development [Li00, Hirsch00, Sasaki00, Koyasu03], macrophage and dendritic cell migration [Del04], and the GPCR-dependent autocrine amplification of FceRI-mediated mast cell degranulation [Laffargue02]. In addition, characterization of these knockout mice revealed a role for the enzyme both in the regulation of myocardial contractility and in cardiac remodeling processes [Oudit04, Crackower02].
Enzymatic reaction of: phosphatidylinositol-4,5-bisphosphate 3-kinase (phosphatidylinositol 3-kinase, class IB, p110γ/p87)
EC Number: 18.104.22.168
The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.
The reaction is favored in the direction shown.
In Pathways: 3-phosphoinositide biosynthesis
Crackower02: Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann MP, Backx PH, Penninger JM (2002). "Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways." Cell 110(6);737-49. PMID: 12297047
Del04: Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A, Sozzani S (2004). "Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice." EMBO J 23(17);3505-15. PMID: 15318168
Hawkins92: Hawkins PT, Jackson TR, Stephens LR (1992). "Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase." Nature 358(6382);157-9. PMID: 1319558
Hirsch00: Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000). "Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation." Science 287(5455);1049-53. PMID: 10669418
Laffargue02: Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E, Wymann MP (2002). "Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function." Immunity 16(3);441-51. PMID: 11911828
Oudit04: Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH (2004). "The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease." J Mol Cell Cardiol 37(2);449-71. PMID: 15276015
Rohde02: Rohde G, Wenzel D, Haucke V (2002). "A phosphatidylinositol (4,5)-bisphosphate binding site within mu2-adaptin regulates clathrin-mediated endocytosis." J Cell Biol 158(2);209-14. PMID: 12119359
Sasaki00: Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger JM (2000). "Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration." Science 287(5455);1040-6. PMID: 10669416
Stoyanov95: Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nurnberg B (1995). "Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase." Science 269(5224);690-3. PMID: 7624799
Voigt06: Voigt P, Dorner MB, Schaefer M (2006). "Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B." J Biol Chem 281(15);9977-86. PMID: 16476736
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