Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Phosphoinositide 3-Kinase

  • Honyin Chiu
  • Lomon So
  • David A. Fruman
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_93

Synonyms

Historical Background

Phosphoinositide 3-kinase, commonly abbreviated PI3K, is one of the most well-studied enzymes in the field of signal transduction. PI3K refers to a family of enzymes encoded by eight genes in mammals (Vanhaesebroeck et al. 2010). Orthologs of one or more PI3K genes exist in all animals as well as in yeast. These enzymes share the ability to phosphorylate the 3′-hydroxyl of the inositol head group of phosphatidylinositol (PtdIns), generating the lipid PtdIns-3-P (Fig. 1). Some members of the PI3K family can act on phosphoinositides, which are phosphorylated derivatives of PtdIns (such as PtdIns-4,5-P 2). Therefore, the family is properly referred to as phosphoinositide 3-kinases rather than simply phosphatidylinositol 3-kinases. The products of PI3Ks, generally termed 3-phosphorylated inositides (3-PIs), serve as membrane-recruitment signals for...
This is a preview of subscription content, log in to check access.

References

  1. Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407–11.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Backer JM. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem J. 2016;473(15):2251–71. PMID: 27470591.PubMedCrossRefGoogle Scholar
  4. Braccini L, Ciraolo E, Campa CC, Perino A, Longo DL, Tibolla G, Pregnolato M, Cao Y, Tassone B, Damilano F, Laffargue M, Calautti E, Falasca M, Norata GD, Backer JM, Hirsch E. PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat Commun. 2015;6:7400.Google Scholar
  5. Dbouk HA, Vadas O, Shymanets A, Burke JE, Salamon RS, Khalil BD, Barrett MO, Waldo GL, Surve C, Hsueh C, Perisic O, Harteneck C, Shepherd PR, Harden TK, Smrcka AV, Taussig R, Bresnick AR, Nürnberg B, Williams RL, Backer JM. G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness. Sci Signal. 2012;5(253):ra89.PubMedPubMedCentralCrossRefGoogle Scholar
  6. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539(7629):443–7.PMID: 27828943.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Falasca M, Maffucci T. Regulation and cellular functions of class II phosphoinositide 3-kinases. Biochem J. 2012;443(3):587–601.CrossRefPubMedGoogle Scholar
  8. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13(2):140–56.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Hawkins PT, Stephens LR. PI3K signalling in inflammation. Biochim Biophys Acta. 2015;1851(6):882–97.CrossRefPubMedGoogle Scholar
  10. Hawkins PT, Stephens LR. Emerging evidence of signalling roles for PI(3,4)P2 in Class I and II PI3K-regulated pathways. Biochem Soc Trans. 2016;44(1):307–14.PMID: 26862220.PubMedCrossRefGoogle Scholar
  11. Hu H, Juvekar A, Lyssiotis CA, Lien EC, Albeck JG, Oh D, Varma G, Hung YP, Ullas S, Lauring J, Seth P, Lundquist MR, Tolan DR, Grant AK, Needleman DJ, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell. 2016;164(3):433–46.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Kaneda MM, Cappello P, Nguyen AV, Ralainirina N, Hardamon CR, Foubert P, Schmid MC, Sun P, Mose E, Bouvet M, Lowy AM, Valasek MA, Sasik R, Novelli F, Hirsch E, Varner JA. Macrophage pI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 2016a;6(8):870–85.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. Nature. 2016b;539(7629):437–42.PMID: 27642729.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702–14.PMID: 27616589.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10(3):143–53.CrossRefPubMedGoogle Scholar
  17. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, Won H, Wong W, Berger M, de Stanchina E, Barratt DG, Cosulich S, Klinowska T, Rosen N, Shokat KM. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272–6.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13(5):283–96.CrossRefPubMedGoogle Scholar
  19. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7–24.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Toker A, Marmiroli S. Signaling specificity in the Akt pathway in biology and disease. Adv Biol Regul. 2014;55:28–38.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Vadas O, Burke JE, Zhang X, Berndt A, Williams RL. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal. 2011;4(195):re2.CrossRefPubMedGoogle Scholar
  22. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329–41.CrossRefPubMedGoogle Scholar
  23. Vanhaesebroeck B, Whitehead MA, Piñeiro R. Molecules in medicine mini-review: isoforms of PI3K in biology and disease. J Mol Med. 2016;94(1):5–11.CrossRefPubMedGoogle Scholar
  24. Winnay JN, Solheim MH, Dirice E, Sakaguchi M, Noh H-L, Kang HJ, Takahashi H, Chudasama KK, Kim JK, Molven A, Kahn CR, Njølstad PR. PI3-kinase mutation linked to insulin and growth factor resistance in vivo. J Clin Invest. 2016;126(4):1401–12.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Yang Q, Modi P, Newcomb T, Quéva C, Gandhi V. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res. 2015;21(7):1537–42.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular Biology and BiochemistryUniversity of California, IrvineIrvineUSA
  2. 2.Department of ImmunologyUniversity of WashingtonSeattleUSA