P110α

PIK3CA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases PIK3CA, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, p110-alpha, PI3K-alpha, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
External IDs OMIM: 171834 MGI: 1206581 HomoloGene: 21249 GeneCards: PIK3CA
EC number 2.7.11.1
Targeted by Drug
dactolisib, idelalisib, ly-294002[1]
RNA expression pattern
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_006209.2

NP_032865.2

Location (UCSC) Chr 3: 179.15 – 179.24 Mb Chr 3: 32.4 – 32.47 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

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.[4]

Its role was uncovered by molecular pathological epidemiology (MPE).[5]

Function

Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called phosphatidylinositol 3-kinase (P3K)) 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.[6]

The involvement of p110α in human cancer has been hypothesized since 1995. Support for this hypothesis came from genetic and functional studies, including the discovery of common activating PIK3CA missense mutations in common human tumors.[7] It has been found to be oncogenic and is implicated in cervical cancers.[8] PIK3CA mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes. While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis. It is unknown whether the mutation predicts increased sensitivity to agents targeting the P3K pathway.[9]

PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.[10]

Clinical characteristics

Due to the association between p110α and cancer,[11] it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.[12][13] The presence of PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.[14][15]

Somatic activating mutations in PIK3CA are found in Klippel-Trenaunay syndrome.[16][17]

PIK3CA-associated segmental overgrowth includes brain disorders such as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly. It is also associated with congenital, lipomatous overgrowth of vascular malformations, epidermal nevi and skeletal/spinal anomalies (CLOVES syndrome) and fibroadipose hyperplasia (FH). The conditions are caused by heterozygous (usually somatic mosaic) mutations.[18]

See also

Interactions

P110α has been shown to interact with:

References

  1. ↑ "Drugs that physically interact with Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ 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.
  5. ↑ 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
  6. ↑ "Entrez Gene: PIK3CA".
  7. ↑ Samuels, Yardena; Waldman, Todd (2010-01-01). Rommel, Christian; Vanhaesebroeck, Bart; Vogt, Peter K., eds. Oncogenic Mutations of PIK3CA in Human Cancers. Current Topics in Microbiology and Immunology. Springer Berlin Heidelberg. pp. 21–41. doi:10.1007/82_2010_68. ISBN 9783642148156. PMC 3164550Freely accessible. PMID 20535651.
  8. ↑ 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.
  9. ↑ Zardavas, Dimitrios; Phillips, Wayne A; Loi, Sherene (2014-01-23). "PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data". Breast Cancer Research. 16 (1). doi:10.1186/bcr3605. ISSN 1465-542X. PMC 4054885Freely accessible. PMID 25192370.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Mirzaa, Ghayda; Conway, Robert; Graham, John M.; Dobyns, William B. (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora JH; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C., eds. PIK3CA-Related Segmental Overgrowth. Seattle (WA): University of Washington, Seattle. PMID 23946963.
  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 316541Freely accessible. 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 450176Freely accessible. 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 364842Freely accessible. PMID 8246987.

Further reading

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