Genomes and Genes
Gene Symbol: p85
Description: phosphoinositide-3-kinase regulatory subunit 1
Alias: AGM7, GRB1, IMD36, p85, p85-ALPHA, phosphatidylinositol 3-kinase regulatory subunit alpha, PI3-kinase subunit p85-alpha, PI3K regulatory subunit alpha, phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha, phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 1 (p85 alpha), phosphatidylinositol 3-kinase-associated p-85 alpha, phosphoinositide-3-kinase regulatory subunit alpha, phosphoinositide-3-kinase, regulatory subunit 1 (alpha), ptdIns-3-kinase regulatory subunit alpha
- Dikeakos J, Atkins K, Thomas L, Emert Sedlak L, Byeon I, Jung J, et al. Small molecule inhibition of HIV-1-induced MHC-I down-regulation identifies a temporally regulated switch in Nef action. Mol Biol Cell. 2010;21:3279-92 pubmed publisher..Together, these studies resolve the seemingly controversial models that describe Nef-induced MHC-I down-regulation and provide new insights into the mechanism of Nef action. ..
- Rodrigues G, Falasca M, Zhang Z, Ong S, Schlessinger J. A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol Cell Biol. 2000;20:1448-59 pubmed..A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a ..
- Cheung L, Hennessy B, Li J, Yu S, Myers A, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1:170-85 pubmed publisher..PIK3R1 (p85?) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85?), not ..
- Chamberlain M, Berry T, Pastor M, Anderson D. The p85alpha subunit of phosphatidylinositol 3'-kinase binds to and stimulates the GTPase activity of Rab proteins. J Biol Chem. 2004;279:48607-14 pubmed..Cells expressing BH domain mutants of p85 show a reduced rate of PDGFR degradation as compared with wild type p85 expressing cells...
- Blagoveshchenskaya A, Thomas L, Feliciangeli S, Hung C, Thomas G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell. 2002;111:853-66 pubmed..These data provide new insights into the cellular basis of HIV-1 immunoevasion. ..
- Jaiswal B, Janakiraman V, Kljavin N, Chaudhuri S, Stern H, Wang W, et al. Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell. 2009;16:463-74 pubmed publisher..Oncogenic activating mutations in the p110alpha catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers...
- Jucker M, Südel K, Horn S, Sickel M, Wegner W, Fiedler W, et al. Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia. 2002;16:894-901 pubmed..PI3-kinase is a heterodimer consisting of an 85 kDa adapter protein (p85) containing one SH3 domain and two SH2 domains and a 110 kDa catalytic subunit (p110)...
- Simoncini T, Hafezi Moghadam A, Brazil D, Ley K, Chin W, Liao J. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000;407:538-41 pubmed..Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ER alpha with PI(3)K. ..
- Winnay J, Boucher J, Mori M, Ueki K, Kahn C. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat Med. 2010;16:438-45 pubmed publisher..Thus, p85alphaalpha forms a previously unrecognized link between the PI3K pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, a state that when unresolved leads to insulin resistance. ..
- Esposito D, Li Y, Cama A, Quon M. Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells. Endocrinology. 2001;142:2833-40 pubmed..Overexpression of IRS1-Y612 or IRS1-Y632 caused intermediate effects. Thus, both Tyr(612) and Tyr(632) are important for IRS-1 to fully activate PI3K and mediate translocation of GLUT4 in response to insulin. ..
- Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, et al. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 2001;20:6050-9 pubmedThe p85-associated phosphatidylinositol (PI) 3-kinase/Akt pathway mediates the oestradiol-induced S-phase entry and cyclin D1 promoter activity in MCF-7 cells...
- Baynes K, Beeton C, Panayotou G, Stein R, Soos M, Hansen T, et al. Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity. Diabetologia. 2000;43:321-31 pubmed..Phosphoinositide 3-kinase p85 alpha regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand ..
- Luo J, Field S, Lee J, Engelman J, Cantley L. The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J Cell Biol. 2005;170:455-64 pubmed..The p85 regulatory subunit of PI 3-kinase is required to mediate the insulin-dependent recruitment of PI 3-kinase to the ..
- Chugh P, Fan S, Planelles V, Maggirwar S, Dewhurst S, Kim B. Infection of human immunodeficiency virus and intracellular viral Tat protein exert a pro-survival effect in a human microglial cell line. J Mol Biol. 2007;366:67-81 pubmed..We propose that the expression of Tat may enable HIV-1 infected microglia to survive throughout the course of infection, leading to persistent HIV-1 production and infection in the central nervous system. ..
- Rabinovsky R, Pochanard P, McNear C, Brachmann S, Duke Cohan J, Garraway L, et al. p85 Associates with unphosphorylated PTEN and the PTEN-associated complex. Mol Cell Biol. 2009;29:5377-88 pubmed publisher..Here we show that PTEN associates with p85, the regulatory subunit of PI3K...
- Zhou F, Xue M, Qin D, Zhu X, Wang C, Zhu J, et al. HIV-1 Tat promotes Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6-induced angiogenesis and tumorigenesis by regulating PI3K/PTEN/AKT/GSK-3? signaling pathway. PLoS ONE. 2013;8:e53145 pubmed publisher..Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients. ..
- Chudasama K, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, et al. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013;93:150-7 pubmed publisher..A central component in this pathway is the p85? regulatory subunit, encoded by PIK3R1...
- Taniguchi C, Winnay J, Kondo T, Bronson R, Guimaraes A, Aleman J, et al. The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res. 2010;70:5305-15 pubmed publisherPhosphoinositide 3-kinase (PI3K) plays a critical role in tumorigenesis, and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling...
- Mandelker D, Gabelli S, Schmidt Kittler O, Zhu J, Cheong I, Huang C, et al. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009;106:16996-7001 pubmed publisher..These structural and biochemical data suggest a previously undescribed mechanism for mutational activation of a kinase that involves perturbation of its interaction with the cellular membrane. ..
- Chagpar R, Links P, Pastor M, Furber L, Hawrysh A, Chamberlain M, et al. Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 2010;107:5471-6 pubmed publisher..We demonstrate that ectopically expressed FLAG-tagged p85 coimmunoprecipitates endogenous PTEN in an epidermal growth factor dependent manner...
- Chan T, Rodeck U, Chan A, Kimmelman A, Rittenhouse S, Panayotou G, et al. Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell. 2002;1:181-91 pubmedPhosphoinositide 3-kinase (PI3K) type IA is a heterodimer of a catalytic subunit, p110, and a regulatory subunit, p85. Here we show that p85 contains a GTPase-responsive domain and an inhibitory domain, which together form a molecular ..
- Deregibus M, Cantaluppi V, Doublier S, Brizzi M, Deambrosis I, Albini A, et al. HIV-1-Tat protein activates phosphatidylinositol 3-kinase/ AKT-dependent survival pathways in Kaposi's sarcoma cells. J Biol Chem. 2002;277:25195-202 pubmed
- Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, et al. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001;7:1217-24 pubmed..Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis. ..
- Dyment D, Smith A, Alcantara D, Schwartzentruber J, Basel Vanagaite L, Curry C, et al. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013;93:158-66 pubmed publisher..Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway...
- Burke J, Vadas O, Berndt A, Finegan T, Perisic O, Williams R. Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110?. Structure. 2011;19:1127-37 pubmed publisherPhosphoinositide 3-kinase ? is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there is a single universal p85-mediated regulatory mechanism; however, we find isozyme-..
- Neal C, Xu J, Li P, Mori S, Yang J, Neal N, et al. Overexpression of 14-3-3? in cancer cells activates PI3K via binding the p85 regulatory subunit. Oncogene. 2012;31:897-906 pubmed publisher..Mechanistically, 14-3-3? bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane...
- Sjödahl G, Lauss M, Gudjonsson S, Liedberg F, Hallden C, Chebil G, et al. A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS ONE. 2011;6:e18583 pubmed publisher..Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC. ..
- Zhang X, Vadas O, Perisic O, Anderson K, Clark J, Hawkins P, et al. Structure of lipid kinase p110?/p85? elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol Cell. 2011;41:567-78 pubmed publisherPhosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110?/p85? complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit...
- Cizkova M, Vacher S, Meseure D, Trassard M, Susini A, Mlcuchova D, et al. PIK3R1 underexpression is an independent prognostic marker in breast cancer. BMC Cancer. 2013;13:545 pubmed publisher..0013) and in breast cancer subgroups. PIK3CA mutations and PIK3R1 underexpression show opposite effects on patient outcome and could become useful prognostic and predictive factors in breast cancer. ..
- Brachmann S, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A. 2009;106:22299-304 pubmed publisher..Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235. ..
- Rodriguez Viciana P, Warne P, Khwaja A, Marte B, Pappin D, Das P, et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997;89:457-67 pubmed..The ability of activated Ras to stimulate PI 3-kinase in addition to Raf is therefore important in Ras transformation of mammalian cells and essential in Ras-induced cytoskeletal reorganization. ..
- Holgado Madruga M, Moscatello D, Emlet D, Dieterich R, Wong A. Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. Proc Natl Acad Sci U S A. 1997;94:12419-24 pubmed..Hence, Gab1 has a major role in connecting TrkA with PI 3-kinase activation and for the promotion of cell survival by NGF. ..
- Borgatti P, Zauli G, Colamussi M, Gibellini D, Previati M, Cantley L, et al. Extracellular HIV-1 Tat protein activates phosphatidylinositol 3- and Akt/PKB kinases in CD4+ T lymphoblastoid Jurkat cells. Eur J Immunol. 1997;27:2805-11 pubmed..Taken together, these data suggest that the anti-apoptotic activity of low concentrations of Tat protein on Jurkat cells is mediated by a PI 3-kinase/Akt pathway. ..
- Zhang W, Sloan Lancaster J, Kitchen J, Trible R, Samelson L. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998;92:83-92 pubmed..36-38 kDa protein, previously characterized by its association with Grb2, phospholipase C-gamma1, and the p85 subunit of phosphoinositide 3-kinase...
- Ingham R, Holgado Madruga M, Siu C, Wong A, Gold M. The Gab1 protein is a docking site for multiple proteins involved in signaling by the B cell antigen receptor. J Biol Chem. 1998;273:30630-7 pubmed..Far Western analysis showed that the SH2 domains of Shc, SHP-2, and the p85 subunit of phosphatidylinositol 3-kinase could bind directly to tyrosine-phosphorylated Gab1 isolated from ..
- Nishida K, Yoshida Y, Itoh M, Fukada T, Ohtani T, Shirogane T, et al. Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. Blood. 1999;93:1809-16 pubmed..Overexpression of Gab2 enhanced the gp130 or Src-related kinases-mediated ERK2 activation as that of Gab1 did. These data indicate that Gab-family molecules act as adapters for transmitting various signals. ..
- Swann S, Williams M, Story C, Bobbitt K, Fleis R, Collins K. HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway. Virology. 2001;282:267-77 pubmed..We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface. ..
- Laprise P, Viel A, Rivard N. Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. J Biol Chem. 2004;279:10157-66 pubmed..in intestinal cells not only severely alters adherens junction integrity but also prevents the recruitment of p85/PI3K to E-cadherin-mediated cell-cell contact and inhibits sucrase-isomaltase gene expression...
- Sun M, Hillmann P, Hofmann B, Hart J, Vogt P. Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha. Proc Natl Acad Sci U S A. 2010;107:15547-52 pubmed publisher..Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 ..
- Kasper M, Collins K. Nef-mediated disruption of HLA-A2 transport to the cell surface in T cells. J Virol. 2003;77:3041-9 pubmed
- Chen X, Cheng L, Jia X, Zeng Y, Yao S, Lv Z, et al. Human immunodeficiency virus type 1 Tat accelerates Kaposi sarcoma-associated herpesvirus Kaposin A-mediated tumorigenesis of transformed fibroblasts in vitro as well as in nude and immunocompetent mice. Neoplasia. 2009;11:1272-84 pubmed
- Huang C, Mandelker D, Gabelli S, Amzel L. Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle. 2008;7:1151-6 pubmed..that the majority of the oncogenic mutations occur at the interfaces between p110 domains and between p110 and p85 domains...
- Chamberlain M, Chan T, Oberg J, Hawrysh A, James K, Saxena A, et al. Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation. J Biol Chem. 2008;283:15861-8 pubmed publisher..GTPase-activating protein activity toward Rab5 and Rab4, an activity severely reduced by a single point mutation (p85-R274A)...
- Almind K, Delahaye L, Hansen T, Van Obberghen E, Pedersen O, Kahn C. Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. Proc Natl Acad Sci U S A. 2002;99:2124-8 pubmed..Thus, the Met-326Ile variant of p85alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. ..
- Gillham H, Golding M, Pepperkok R, Gullick W. Intracellular movement of green fluorescent protein-tagged phosphatidylinositol 3-kinase in response to growth factor receptor signaling. J Cell Biol. 1999;146:869-80 pubmed..Here we show using a green fluorescent protein-tagged p85 subunit that phosphatidylinositol 3-kinase is distributed throughout the cytoplasm and is localized to focal ..
- Rocchi S, Tartare Deckert S, Murdaca J, Holgado Madruga M, Wong A, Van Obberghen E. Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol Endocrinol. 1998;12:914-23 pubmed..These include the regulatory subunit p85 of phosphatidylinositol 3-kinase and phosphotyrosine phosphatase, SHP-2...
- Hansen T, Andersen C, Echwald S, Urhammer S, Clausen J, Vestergaard H, et al. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes. 1997;46:494-501 pubmed..In itself, the gene variant does not confer an increased risk of diabetes. ..
- Holgado Madruga M, Emlet D, Moscatello D, Godwin A, Wong A. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature. 1996;379:560-4 pubmed..Over-expression of Gab1 enhances cell growth and results in transformation. We conclude that Gab1 is a new protein in EGF and insulin receptor signalling which could integrate signals from different systems. ..
- Backer J, Myers M, Shoelson S, Chin D, Sun X, Miralpeix M, et al. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992;11:3469-79 pubmed..rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated...
- McGlade C, Ellis C, Reedijk M, Anderson D, Mbamalu G, Reith A, et al. SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. Mol Cell Biol. 1992;12:991-7 pubmed..The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-..
- Musacchio A, Cantley L, Harrison S. Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. Proc Natl Acad Sci U S A. 1996;93:14373-8 pubmed..We describe here the crystal structure of the BH domain from the p85 subunit of phosphatidylinositol 3-kinase at 2.0 A resolution...
- Antonetti D, Algenstaedt P, Kahn C. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol Cell Biol. 1996;16:2195-203 pubmed..This form has an estimated molecular mass of approximately 53 kDa and has been termed p85/AS53...
- Nolte R, Eck M, Schlessinger J, Shoelson S, Harrison S. Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Biol. 1996;3:364-74 pubmed..The structures suggest a mechanism for the biological specificity exhibited by PI 3-kinase in its interactions with phosphoprotein partners. ..
- Liu X, Marengere L, Koch C, Pawson T. The v-Src SH3 domain binds phosphatidylinositol 3'-kinase. Mol Cell Biol. 1993;13:5225-32 pubmed..Furthermore, the v-Src SH3 domain bound in vitro to the amino-terminal region of the p85 alpha subunit of PI 3'-kinase...
- Kapeller R, Toker A, Cantley L, Carpenter C. Phosphoinositide 3-kinase binds constitutively to alpha/beta-tubulin and binds to gamma-tubulin in response to insulin. J Biol Chem. 1995;270:25985-91 pubmed..and Corvera, S. (1993) Mol. Cell. Biol. 13, 6052-6063). In complementary experiments we used the recombinant p85 subunit of PI 3-kinase to identify proteins that associate with phosphoinositide 3-kinase and found that ..
- Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994;77:261-71 pubmed..The same bidentate motif is conserved in the evolutionarily related receptors Sea and Ron, suggesting that in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site. ..