P110α

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha

PI3 Kinase 110 alpha bound to the inhibitor PIK-93 (yellow).
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsPIK3CA ; CLOVE; CWS5; MCAP; MCM; MCMTC; PI3K; p110-alpha
External IDsOMIM: 171834 MGI: 1206581 HomoloGene: 21249 IUPHAR: 2153 ChEMBL: 4005 GeneCards: PIK3CA Gene
EC number2.7.1.153, 2.7.11.1
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez529018706
EnsemblENSG00000121879ENSMUSG00000027665
UniProtP42336P42337
RefSeq (mRNA)NM_006218NM_008839
RefSeq (protein)NP_006209NP_032865
Location (UCSC)Chr 3:
178.87 – 178.96 Mb		Chr 3:
32.4 – 32.47 Mb
PubMed search

The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is encoded by the PIK3CA gene.[1]

Function

Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called phosphatidylinositol 3-kinase) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (PtdIns), PtdIns4P and PtdIns(4,5)P2.[2]

Clinical significance

Recent evidence has shown that the PIK3CA gene is mutated in a range of human cancers. It has been found to be oncogenic and has been implicated in cervical cancers.[3]

Due to the association between p110α and cancer,[4] it is believed to be a promising drug target. A number of pharmaceutical companies are currently designing and charactering potential p110α isoform specific inhibitors.[5][6] The presence of PIK3CA mutation may predict response to aspirin therapy for colorectal cancer,[7][8] indicating power and promise of "Molecular Pathological Epidemiology (MPE)" approach[9] as well as a complex interaction within the tumor microenvironment in this phenomenon.[10]

Somatic mosaic mutations in PIK3CA have been implicated in several overgrowth conditions: CLOVES syndrome,[11] macrocephaly-capillary malformation syndrome,[12] hemimegalencephaly[13] and overgrowth with fibroadipose hyperplasia.[14]

See also

Interactions

P110α has been shown to interact with:


References

  1. ↑ Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R et al. (August 1992). "Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit". Cell 70 (3): 419–29. doi:10.1016/0092-8674(92)90166-A. PMID 1322797.
  2. ↑ "Entrez Gene: PIK3CA".
  3. ↑ Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J et al. (May 2000). "PIK3CA as an oncogene in cervical cancer". Oncogene 19 (23): 2739–44. doi:10.1038/sj.onc.1203597. PMID 10851074.
  4. ↑ Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (April 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963.
  5. ↑ Stein RC (September 2001). "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine-related Cancer (Bioscientifica) 8 (3): 237–48. doi:10.1677/erc.0.0080237. PMID 11566615.
  6. ↑ Marone R, Cmiljanovic V, Giese B, Wymann MP (January 2008). "Targeting phosphoinositide 3-kinase: moving towards therapy". Biochimica et Biophysica Acta 1784 (1): 159–85. doi:10.1016/j.bbapap.2007.10.003. PMID 17997386.
  7. ↑ Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M et al. (2012). "Aspirin use, tumor PIK3CA mutation status, and colorectal cancer survival". N Engl J Med 367: 1596–606. doi:10.1056/nejmoa1207756. PMID 23094721.
  8. ↑ Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E et al. (2013). "Evaluation of PIK3CA mutation as a predictor of benefit from NSAID therapy in colorectal cancer". J Clin Oncol 31: 4297–305. doi:10.1200/jco.2013.50.0322. PMID 24062397.
  9. ↑ Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT. "Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene 2013; doi:10.1038/onc.2013.244
  10. ↑ Fuchs CS, Ogino S (2013). "Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex!". J Clin Oncol 31: 4358–61. doi:10.1200/jco.2013.52.0080. PMID 24166520.
  11. ↑ Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, Mulliken JB, Bowen ME et al. (Jun 2012). "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome". Am J Hum Genet 90 (6): 1108–15. doi:10.1016/j.ajhg.2012.05.006. PMC 3370283. PMID 22658544.
  12. ↑ Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA et al. (2012). "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes". Nat Genet 44 (8): 934–40. doi:10.1038/ng.2331. PMC 3408813. PMID 22729224.
  13. ↑ Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V et al. (2012). "De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly". Nat Genet 44 (8): 941–5. doi:10.1038/ng.2329. PMID 22729223.
  14. ↑ Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q et al. (2012). "Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA". Nat Genet 44 (8): 928–33. doi:10.1038/ng.2332. PMC 3461408. PMID 22729222.
  15. ↑ Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB (2003). "Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement". J. Biol. Chem. 278 (31): 28793–8. doi:10.1074/jbc.M303900200. PMID 12754211.
  16. ↑ Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI et al. (2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochem. Biophys. Res. Commun. 307 (3): 459–65. doi:10.1016/s0006-291x(03)01187-2. PMID 12893243.
  17. ↑ Luo B, Prescott SM, Topham MK (2003). "Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta". J. Biol. Chem. 278 (41): 39542–7. doi:10.1074/jbc.M307153200. PMID 12890670.
  18. ↑ Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P et al. (2004). "The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors". Oncogene 23 (2): 559–68. doi:10.1038/sj.onc.1207161. PMID 14724584.
  19. ↑ Li W, Han M, Guan KL (2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes Dev. 14 (8): 895–900. PMC 316541. PMID 10783161.
  20. ↑ Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J (1996). "Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation". EMBO J. 15 (10): 2442–51. PMC 450176. PMID 8665852.
  21. ↑ Sade H, Krishna S, Sarin A (2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". J. Biol. Chem. 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID 14583609.
  22. ↑ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC et al. (1993). "Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase". Mol. Cell. Biol. 13 (12): 7708–17. PMC 364842. PMID 8246987.

Further reading