MetaCyc Polypeptide: phosphatidylinositol 3-kinase regulatory subunit p55γ

Gene: PIK3R3 Accession Number: HS04135 (MetaCyc)

Synonyms: p55-GAMMA, PtdIns-3-kinase p55-gamma, p55PIK, phosphoinositide-3-kinase, regulatory subunit, polypeptide 3 (p55, gamma), phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 3 (p55, gamma)

Species: Homo sapiens

Component of: phosphatidylinositol 3-kinase class IA p110β/p85γ (extended summary available)

General Background

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.

The last known regulatory subunit is p150, encoded by PIK3R4, which associates only with the class III p100 catalytic subunit.

About This Protein

p55γ was originally identified in mouse [Pons95]. A cDNA was later cloned from rat brain, and wrongly attributed to altenative splicing of the p85α DNA [Inukai96]. A human fetal brain cDNA has been isolated subsequently [Dey98].

p55γ mRNAs are expressed in most human fetal and adult tissues with particularly high abundance in adult testis. The protein interacts strongly with activated insulin-like growth factor-I receptor (IGFIR) and with the insulin receptor (IR). It contains two Src homology 2 (SH2) domains and no SH3 domain [Dey98].

Map Position: [45,462,790 <- 45,555,292]

Molecular Weight of Polypeptide: 54.462 kD (from nucleotide sequence)

Unification Links: ArrayExpress:Q92569 , Entrez-Nucleotide:AF028785 , Entrez-Nucleotide:D88532 , Mint:MINT-1490763 , PhosphoSite:Q92569 , PhylomeDB:Q92569 , Pride:Q92569 , Protein Model Portal:Q92569 , SMR:Q92569 , String:9606.ENSP00000262741 , UniProt:Q92569

Relationship Links: InterPro:IN-FAMILY:IPR000980 , InterPro:IN-FAMILY:IPR001720 , Panther:IN-FAMILY:PTHR10155 , Pfam:IN-FAMILY:PF00017 , Prints:IN-FAMILY:PR00401 , Prints:IN-FAMILY:PR00678 , Prosite:IN-FAMILY:PS50001 , Smart:IN-FAMILY:SM00252

Gene-Reaction Schematic: ?

Gene-Reaction Schematic

Created 14-Oct-2009 by Caspi R , SRI International

Subunit of: phosphatidylinositol 3-kinase class IA p110β/p85γ

Species: Homo sapiens

Subunit composition of phosphatidylinositol 3-kinase class IA p110β/p85γ = [PIK3R3][PIK3CB]
         phosphatidylinositol 3-kinase regulatory subunit p55γ = PIK3R3 (extended summary available)
         phosphatidylinositol 3 kinase catalytic subunit p110β = PIK3CB (summary available)

General Background

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 IA enzymes are heterodimers composed of a catalytic 110 kDa subunit and a regulatory 85 or 55 kDa subunit. Three distinct p110 subunits are associated with p85 regulatory subunits. They are known as p110α, p100β, and p110δ. They are recruited to, and activated by receptors linked to tyrosine kinases through their regulatory subunits. Ligand stimulation of tyrosine kinase receptors results in phosphorylation of tyrosine residues in specific motifs on the receptor, which act as docking sites for the SH2 domains of the regulatory subunit [Otsu91]. Thus the regulatory subunits serve as adaptors and regulators, allowing translocation of the associated catalytic activity to lipid substrates at the membrane. The catalytic subunits can also be directly regulated by Ras [RodriguezVician94].

Created 14-Oct-2009 by Caspi R , SRI International

Enzymatic reaction of: phosphatidylinositol-4,5-bisphosphate 3-kinase (phosphatidylinositol 3-kinase class IA p110β/p85γ)

EC Number:

a 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + ATP <=> 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + ADP + H+

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


Dey98: Dey BR, Furlanetto RW, Nissley SP (1998). "Cloning of human p55 gamma, a regulatory subunit of phosphatidylinositol 3-kinase, by a yeast two-hybrid library screen with the insulin-like growth factor-I receptor." Gene 209(1-2);175-83. PMID: 9524259

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

Hu93: Hu P, Mondino A, Skolnik EY, Schlessinger J (1993). "Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85." Mol Cell Biol 13(12);7677-88. PMID: 8246984

Inukai96: Inukai K, Anai M, Van Breda E, Hosaka T, Katagiri H, Funaki M, Fukushima Y, Ogihara T, Yazaki Y, Kikuchi , Oka Y, Asano T (1996). "A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene." J Biol Chem 271(10);5317-20. PMID: 8621382

Lecompte08: Lecompte O, Poch O, Laporte J (2008). "PtdIns5P regulation through evolution: roles in membrane trafficking?." Trends Biochem Sci 33(10);453-60. PMID: 18774718

Otsu91: Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N (1991). "Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase." Cell 65(1);91-104. PMID: 1707345

Pons95: Pons S, Asano T, Glasheen E, Miralpeix M, Zhang Y, Fisher TL, Myers MG, Sun XJ, White MF (1995). "The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase." Mol Cell Biol 15(8);4453-65. PMID: 7542745

RodriguezVician94: Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994). "Phosphatidylinositol-3-OH kinase as a direct target of Ras." Nature 370(6490);527-32. PMID: 8052307

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

Stephens91: Stephens LR, Hughes KT, Irvine RF (1991). "Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils." Nature 351(6321);33-9. PMID: 1851250

Ueki02: Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC (2002). "Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase." Proc Natl Acad Sci U S A 99(1);419-24. PMID: 11752399

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

Yart02: Yart A, Roche S, Wetzker R, Laffargue M, Tonks N, Mayeux P, Chap H, Raynal P (2002). "A function for phosphoinositide 3-kinase beta lipid products in coupling beta gamma to Ras activation in response to lysophosphatidic acid." J Biol Chem 277(24);21167-78. PMID: 11916960

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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