P110α

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Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
PI3kinase.png
PI3 Kinase 110 alpha bound to the inhibitor PIK-93 (yellow).
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PIK3CA ; CLOVE; CWS5; MCAP; MCM; MCMTC; PI3K; p110-alpha
External IDs OMIM171834 MGI1206581 HomoloGene21249 IUPHAR: 2153 ChEMBL: 4005 GeneCards: PIK3CA Gene
EC number 2.7.1.153, 2.7.11.1
RNA expression pattern
PBB GE PIK3CA 204369 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5290 18706
Ensembl ENSG00000121879 ENSMUSG00000027665
UniProt P42336 P42337
RefSeq (mRNA) NM_006218 NM_008839
RefSeq (protein) NP_006209 NP_032865
Location (UCSC) Chr 3:
179.15 – 179.24 Mb
Chr 3:
32.4 – 32.47 Mb
PubMed search [1] [2]

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[edit]

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[edit]

Recent evidence has shown that the PIK3CA gene is mutated in a range of human cancers.[3][4] It has been found to be oncogenic and has been implicated in cervical cancers.[5]

Due to the association between p110α and cancer,[6] it is believed to be a promising drug target. A number of pharmaceutical companies are currently designing and charactering potential p110α isoform specific inhibitors.[7][8] The presence of PIK3CA mutation may predict response to aspirin therapy for colorectal cancer,[9][10] indicating power and promise of "Molecular Pathological Epidemiology (MPE)" approach[11] as well as a complex interaction within the tumor microenvironment in this phenomenon.[12]

Somatic mosaic mutations in PIK3CA have been implicated in several overgrowth conditions: CLOVES syndrome,[13] macrocephaly-capillary malformation syndrome,[14] hemimegalencephaly[15] and overgrowth with fibroadipose hyperplasia.[16] Somatic activating mutations in PIK3CA also cause vascular malformation in lymphatics and veins and are found in Klippel-Trenaunay syndrome.[17][18]

See also[edit]

Interactions[edit]

P110α has been shown to interact with:

References[edit]

  1. ^ Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, et al. (Aug 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. ^ Chiosea SI, Grandis JR, Lui VW, Diergaarde B, Maxwell JH, Ferris RL, Kim SW, Luvison A, Miller M, Nikiforova MN (17 December 2013). "PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma". BMC Cancer 13: 602. doi:10.1186/1471-2407-13-602. PMC 3878565. PMID 24341335. 
  4. ^ Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, et al. (Jun 2015). "Molecular characterization of apocrine salivary duct carcinoma". The American Journal of Surgical Pathology 39 (6): 744–52. doi:10.1097/PAS.0000000000000410. PMID 25723113. 
  5. ^ Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY (May 2000). "PIK3CA as an oncogene in cervical cancer". Oncogene 19 (23): 2739–44. doi:10.1038/sj.onc.1203597. PMID 10851074. 
  6. ^ Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, et al. (Apr 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963. 
  7. ^ Stein RC (Sep 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. 
  8. ^ Marone R, Cmiljanovic V, Giese B, Wymann MP (Jan 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. 
  9. ^ Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, et al. (Oct 2012). "Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival". The New England Journal of Medicine 367 (17): 1596–606. doi:10.1056/nejmoa1207756. PMID 23094721. 
  10. ^ Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, Davidson B, Kerr DJ, et al. (Dec 2013). "Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer". Journal of Clinical Oncology 31 (34): 4297–305. doi:10.1200/jco.2013.50.0322. PMID 24062397. 
  11. ^ 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
  12. ^ Fuchs CS, Ogino S (Dec 2013). "Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex!". Journal of Clinical Oncology 31 (34): 4358–61. doi:10.1200/jco.2013.52.0080. PMID 24166520. 
  13. ^ 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". American Journal of Human Genetics 90 (6): 1108–15. doi:10.1016/j.ajhg.2012.05.006. PMC 3370283. PMID 22658544. 
  14. ^ Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, et al. (Aug 2012). "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes". Nature Genetics 44 (8): 934–40. doi:10.1038/ng.2331. PMC 3408813. PMID 22729224. 
  15. ^ Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, Funari V, Russ C, Gabriel SB, Mathern GW, Gleeson JG (Aug 2012). "De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly". Nature Genetics 44 (8): 941–5. doi:10.1038/ng.2329. PMID 22729223. 
  16. ^ Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, et al. (Aug 2012). "Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA". Nature Genetics 44 (8): 928–33. doi:10.1038/ng.2332. PMC 3461408. PMID 22729222. 
  17. ^ Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, et al. (Dec 2015). "Somatic Activating PIK3CA Mutations Cause Venous Malformation". American Journal of Human Genetics 97 (6): 914–21. doi:10.1016/j.ajhg.2015.11.011. PMID 26637981. 
  18. ^ Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV, Rialon KL, Guevara CJ, et al. (Apr 2015). "Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA". The Journal of Pediatrics 166 (4): 1048–54.e1–5. doi:10.1016/j.jpeds.2014.12.069. PMID 25681199. 
  19. ^ Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB (Aug 2003). "Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement". The Journal of Biological Chemistry 278 (31): 28793–8. doi:10.1074/jbc.M303900200. PMID 12754211. 
  20. ^ Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A (Aug 2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochemical and Biophysical Research Communications 307 (3): 459–65. doi:10.1016/s0006-291x(03)01187-2. PMID 12893243. 
  21. ^ Luo B, Prescott SM, Topham MK (Oct 2003). "Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta". The Journal of Biological Chemistry 278 (41): 39542–7. doi:10.1074/jbc.M307153200. PMID 12890670. 
  22. ^ Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J (Jan 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. 
  23. ^ Li W, Han M, Guan KL (Apr 2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes & Development 14 (8): 895–900. PMC 316541. PMID 10783161. 
  24. ^ Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J (May 1996). "Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation". The EMBO Journal 15 (10): 2442–51. PMC 450176. PMID 8665852. 
  25. ^ Sade H, Krishna S, Sarin A (Jan 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". The Journal of Biological Chemistry 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID 14583609. 
  26. ^ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (Dec 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". Molecular and Cellular Biology 13 (12): 7708–17. doi:10.1128/mcb.13.12.7708. PMC 364842. PMID 8246987. 

Further reading[edit]