Jump to navigation Jump to search
External IDsGeneCards: [1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)n/an/a
PubMed searchn/an/a
View/Edit Human

Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.[1]


Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in three transcript variants encoding different isoforms.[2]

Clinical significance

Mutations in PIK3R1 are implicated in cases of breast cancer .[3]

Mutations in PIK3R1 are associated to SHORT syndrome .[4]


PIK3R1 has been shown to interact with:


  1. Volinia S, Patracchini P, Otsu M, Hiles I, Gout I, Calzolari E, Bernardi F, Rooke L, Waterfield MD (May 1992). "Chromosomal localization of human p85 alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85 beta". Oncogene. 7 (4): 789–93. PMID 1314371.
  2. "Entrez Gene: PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha)".
  3. The Cancer Genome Atlas Network (October 2012). "Comprehensive molecular portraits of human breast tumours". Nature. 490 (7418): 61–70. doi:10.1038/nature11412. PMC 3465532. PMID 23000897.
  4. Bárcena C, Quesada V, De Sandre-Giovannoli A, Puente DA, Fernández-Toral J, Sigaudy S, Baban A, Lévy N, Velasco G, López-Otín C (2014). "Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome". BMC Med. Genet. 15 (1): 51. doi:10.1186/1471-2350-15-51. PMC 4022398. PMID 24886349.
  5. Kang Q, Cao Y, Zolkiewska A (2001). "Direct interaction between the cytoplasmic tail of ADAM 12 and the Src homology 3 domain of p85alpha activates phosphatidylinositol 3-kinase in C2C12 cells". J. Biol. Chem. 276 (27): 24466–72. doi:10.1074/jbc.M101162200. PMID 11313349.
  6. Li E, Stupack DG, Brown SL, Klemke R, Schlaepfer DD, Nemerow GR (2000). "Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry". J. Biol. Chem. 275 (19): 14729–35. doi:10.1074/jbc.275.19.14729. PMID 10799562.
  7. Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O (1998). "The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells". J. Biol. Chem. 273 (24): 14962–7. doi:10.1074/jbc.273.24.14962. PMID 9614102.
  8. Elly C, Witte S, Zhang Z, Rosnet O, Lipkowitz S, Altman A, Liu YC (1999). "Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation". Oncogene. 18 (5): 1147–56. doi:10.1038/sj.onc.1202411. PMID 10022120.
  9. De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R (1999). "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". EMBO J. 18 (4): 904–15. doi:10.1093/emboj/18.4.904. PMC 1171183. PMID 10022833.
  10. van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M (2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood. 96 (10): 3406–13. PMID 11071635.
  11. Serve H, Hsu YC, Besmer P (1994). "Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells". J. Biol. Chem. 269 (8): 6026–30. PMID 7509796.
  12. Pagès F, Ragueneau M, Klasen S, Battifora M, Couez D, Sweet R, Truneh A, Ward SG, Olive D (1996). "Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association". J. Biol. Chem. 271 (16): 9403–9. doi:10.1074/jbc.271.16.9403. PMID 8621607.
  13. Lee DM, Patel DD, Pendergast AM, Haynes BF (1996). "Functional association of CD7 with phosphatidylinositol 3-kinase: interaction via a YEDM motif". Int. Immunol. 8 (8): 1195–203. doi:10.1093/intimm/8.8.1195. PMID 8918688.
  14. Subrahmanyam G, Rudd CE, Schneider H (2003). "Association of T cell antigen CD7 with type II phosphatidylinositol-4 kinase, a key component in pathways of inositol phosphate turnover". Eur. J. Immunol. 33 (1): 46–52. doi:10.1002/immu.200390006. PMID 12594831.
  15. Ye K, Hurt KJ, Wu FY, Fang M, Luo HR, Hong JJ, Blackshaw S, Ferris CD, Snyder SH (2000). "Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N". Cell. 103 (6): 919–30. doi:10.1016/S0092-8674(00)00195-1. PMID 11136977.
  16. Gesbert F, Garbay C, Bertoglio J (1998). "Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells". J. Biol. Chem. 273 (7): 3986–93. doi:10.1074/jbc.273.7.3986. PMID 9461587.
  17. Zhang S, Broxmeyer HE (1999). "p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells". Biochem. Biophys. Res. Commun. 254 (2): 440–5. doi:10.1006/bbrc.1998.9959. PMID 9918857.
  18. Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ (2008). "FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival". Bone. 42 (6): 1032–9. doi:10.1016/j.bone.2008.02.009. PMID 18374639.
  19. Pandey A, Lazar DF, Saltiel AR, Dixit VM (1994). "Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity". J. Biol. Chem. 269 (48): 30154–7. PMID 7982920.
  20. 20.0 20.1 Shigematsu H, Iwasaki H, Otsuka T, Ohno Y, Arima F, Niho Y (1997). "Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity". J. Biol. Chem. 272 (22): 14334–40. doi:10.1074/jbc.272.22.14334. PMID 9162069.
  21. Damen JE, Cutler RL, Jiao H, Yi T, Krystal G (1995). "Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity". J. Biol. Chem. 270 (40): 23402–8. doi:10.1074/jbc.270.40.23402. PMID 7559499.
  22. Hellyer NJ, Kim MS, Koland JG (2001). "Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor". J. Biol. Chem. 276 (45): 42153–61. doi:10.1074/jbc.M102079200. PMID 11546794.
  23. Lin J, Adam RM, Santiestevan E, Freeman MR (1999). "The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells". Cancer Res. 59 (12): 2891–7. PMID 10383151.
  24. Gautreau A, Poullet P, Louvard D, Arpin M (1999). "Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7300–5. doi:10.1073/pnas.96.13.7300. PMC 22080. PMID 10377409.
  25. Chacko GW, Brandt JT, Coggeshall KM, Anderson CL (1996). "Phosphoinositide 3-kinase and p72syk noncovalently associate with the low affinity Fc gamma receptor on human platelets through an immunoreceptor tyrosine-based activation motif. Reconstitution with synthetic phosphopeptides". J. Biol. Chem. 271 (18): 10775–81. doi:10.1074/jbc.271.18.10775. PMID 8631888.
  26. Ibarrola I, Vossebeld PJ, Homburg CH, Thelen M, Roos D, Verhoeven AJ (1997). "Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa". Biochim. Biophys. Acta. 1357 (3): 348–58. doi:10.1016/S0167-4889(97)00034-7. PMID 9268059.
  27. 27.0 27.1 Bertagnolo V, Marchisio M, Volinia S, Caramelli E, Capitani S (1998). "Nuclear association of tyrosine-phosphorylated Vav to phospholipase C-gamma1 and phosphoinositide 3-kinase during granulocytic differentiation of HL-60 cells". FEBS Lett. 441 (3): 480–4. doi:10.1016/S0014-5793(98)01593-2. PMID 9891995.
  28. Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ (1996). "A Grb2-associated docking protein in EGF- and insulin-receptor signalling". Nature. 379 (6565): 560–4. doi:10.1038/379560a0. PMID 8596638.
  29. Rocchi S, Tartare-Deckert S, Murdaca J, Holgado-Madruga M, Wong AJ, Van Obberghen E (1998). "Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules". Mol. Endocrinol. 12 (7): 914–23. doi:10.1210/mend.12.7.0141. PMID 9658397.
  30. Lynch DK, Daly RJ (2002). "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J. 21 (1–2): 72–82. doi:10.1093/emboj/21.1.72. PMC 125816. PMID 11782427.
  31. Crouin C, Arnaud M, Gesbert F, Camonis J, Bertoglio J (2001). "A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partners". FEBS Lett. 495 (3): 148–53. doi:10.1016/S0014-5793(01)02373-0. PMID 11334882.
  32. Saleem A, Kharbanda S, Yuan ZM, Kufe D (1995). "Monocyte colony-stimulating factor stimulates binding of phosphatidylinositol 3-kinase to Grb2.Sos complexes in human monocytes". J. Biol. Chem. 270 (18): 10380–3. doi:10.1074/jbc.270.18.10380. PMID 7737969.
  33. Wang J, Auger KR, Jarvis L, Shi Y, Roberts TM (1995). "Direct association of Grb2 with the p85 subunit of phosphatidylinositol 3-kinase". J. Biol. Chem. 270 (21): 12774–80. doi:10.1074/jbc.270.21.12774. PMID 7759531.
  34. Hanna AN, Chan EY, Xu J, Stone JC, Brindley DN (1999). "A novel pathway for tumor necrosis factor-alpha and ceramide signaling involving sequential activation of tyrosine kinase, p21(ras), and phosphatidylinositol 3-kinase". J. Biol. Chem. 274 (18): 12722–9. doi:10.1074/jbc.274.18.12722. PMID 10212255.
  35. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J (1997). "Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras". Cell. 89 (3): 457–67. doi:10.1016/S0092-8674(00)80226-3. PMID 9150145.
  36. 36.0 36.1 Hamer I, Foti M, Emkey R, Cordier-Bussat M, Philippe J, De Meyts P, Maeder C, Kahn CR, Carpentier JL (2002). "An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events". Diabetologia. 45 (5): 657–67. doi:10.1007/s00125-002-0798-5. PMID 12107746.
  37. Hadari YR, Tzahar E, Nadiv O, Rothenberg P, Roberts CT, LeRoith D, Yarden Y, Zick Y (1992). "Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers". J. Biol. Chem. 267 (25): 17483–6. PMID 1381348.
  38. Morrison KB, Tognon CE, Garnett MJ, Deal C, Sorensen PH (2002). "ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation". Oncogene. 21 (37): 5684–95. doi:10.1038/sj.onc.1205669. PMID 12173038.
  39. Gual P, Gonzalez T, Grémeaux T, Barres R, Le Marchand-Brustel Y, Tanti JF (2003). "Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes". J. Biol. Chem. 278 (29): 26550–7. doi:10.1074/jbc.M212273200. PMID 12730242.
  40. Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter-Su C (1996). "Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling". J. Biol. Chem. 271 (46): 29415–21. doi:10.1074/jbc.271.46.29415. PMID 8910607.
  41. Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P (1997). "Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation". J. Biol. Chem. 272 (42): 26173–8. doi:10.1074/jbc.272.42.26173. PMID 9334184.
  42. Kim B, Cheng HL, Margolis B, Feldman EL (1998). "Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling". J. Biol. Chem. 273 (51): 34543–50. doi:10.1074/jbc.273.51.34543. PMID 9852124.
  43. Reddy SA, Huang JH, Liao WS (1997). "Phosphatidylinositol 3-kinase in interleukin 1 signaling. Physical interaction with the interleukin 1 receptor and requirement in NFkappaB and AP-1 activation". J. Biol. Chem. 272 (46): 29167–73. doi:10.1074/jbc.272.46.29167. PMID 9360994.
  44. Fuhrer DK, Yang YC (1996). "Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11". Biochem. Biophys. Res. Commun. 224 (2): 289–96. doi:10.1006/bbrc.1996.1023. PMID 8702385.
  45. Sánchez-Margalet V, Najib S (2001). "Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling". Mol. Cell. Endocrinol. 183 (1–2): 113–21. doi:10.1016/S0303-7207(01)00587-1. PMID 11604231.
  46. Shen Z, Batzer A, Koehler JA, Polakis P, Schlessinger J, Lydon NB, Moran MF (1999). "Evidence for SH3 domain directed binding and phosphorylation of Sam68 by Src". Oncogene. 18 (33): 4647–53. doi:10.1038/sj.onc.1203079. PMID 10467411.
  47. Kozutsumi H, Toyoshima H, Hagiwara K, Yazaki Y, Hirai H (1994). "Human ltk receptor tyrosine kinase binds to PLC-gamma 1, PI3-K, GAP and Raf-1 in vivo". Oncogene. 9 (10): 2991–8. PMID 8084603.
  48. Ueno H, Honda H, Nakamoto T, Yamagata T, Sasaki K, Miyagawa K, Mitani K, Yazaki Y, Hirai H (1997). "The phosphatidylinositol 3' kinase pathway is required for the survival signal of leukocyte tyrosine kinase". Oncogene. 14 (25): 3067–72. doi:10.1038/sj.onc.1201153. PMID 9223670.
  49. Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A (2001). "Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells". Biochem. J. 356 (Pt 2): 461–71. doi:10.1042/0264-6021:3560461. PMC 1221857. PMID 11368773.
  50. Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR (2004). "Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase". FEBS Lett. 575 (1–3): 35–40. doi:10.1016/j.febslet.2004.07.090. PMID 15388330.
  51. Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD (1997). "P110delta, a novel phosphoinositide 3-kinase in leukocytes". Proc. Natl. Acad. Sci. U.S.A. 94 (9): 4330–5. doi:10.1073/pnas.94.9.4330. PMC 20722. PMID 9113989.
  52. Guinebault C, Payrastre B, Racaud-Sultan C, Mazarguil H, Breton M, Mauco G, Plantavid M, Chap H (1995). "Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85 alpha with actin filaments and focal adhesion kinase". J. Cell Biol. 129 (3): 831–42. doi:10.1083/jcb.129.3.831. PMC 2120444. PMID 7537275.
  53. Karlsson T, Songyang Z, Landgren E, Lavergne C, Di Fiore PP, Anafi M, Pawson T, Cantley LC, Claesson-Welsh L, Welsh M (1995). "Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins". Oncogene. 10 (8): 1475–83. PMID 7537362.
  54. Kapeller R, Toker A, Cantley LC, Carpenter CL (1995). "Phosphoinositide 3-kinase binds constitutively to alpha/beta-tubulin and binds to gamma-tubulin in response to insulin". J. Biol. Chem. 270 (43): 25985–91. doi:10.1074/jbc.270.43.25985. PMID 7592789.
  55. Lan Z, Wu H, Li W, Wu S, Lu L, Xu M, Dai W (2000). "Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway". Blood. 95 (2): 633–8. PMID 10627473.
  56. Banin S, Truong O, Katz DR, Waterfield MD, Brickell PM, Gout I (1996). "Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases". Curr. Biol. 6 (8): 981–8. doi:10.1016/S0960-9822(02)00642-5. PMID 8805332.

Further reading

  • Benito M, Valverde AM, Lorenzo M (1996). "IGF-I: a mitogen also involved in differentiation processes in mammalian cells". Int. J. Biochem. Cell Biol. 28 (5): 499–510. doi:10.1016/1357-2725(95)00168-9. PMID 8697095.
  • Snapper SB, Rosen FS (1999). "The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization". Annu. Rev. Immunol. 17: 905–29. doi:10.1146/annurev.immunol.17.1.905. PMID 10358777.
  • Katada T, Kurosu H, Okada T, Suzuki T, Tsujimoto N, Takasuga S, Kontani K, Hazeki O, Ui M (1999). "Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors". Chem. Phys. Lipids. 98 (1–2): 79–86. doi:10.1016/S0009-3084(99)00020-1. PMID 10358930.
  • Zhang W, Samelson LE (2000). "The role of membrane-associated adaptors in T cell receptor signalling". Semin. Immunol. 12 (1): 35–41. doi:10.1006/smim.2000.0205. PMID 10723796.
  • Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410.
  • Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Curr. Protein Pept. Sci. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.
  • Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.