Biology:P110α

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Short description: Human protein-coding gene

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]

Its role was uncovered by molecular pathological epidemiology (MPE).[2]

Function

Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called phosphatidylinositol 3-kinase (PI3K)) 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.[3]

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.[4] It has been found to be oncogenic and is implicated in cervical cancers.[5] 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 (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date.[6] 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.[7]

PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.[8]

Clinical characteristics

Due to the association between p110α and cancer,[9] it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.[10][11]

The presence of [a] PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.[12][13]

Somatic activating mutations in PIK3CA are found in Klippel–Trénaunay syndrome and venous malformation.[14][15]

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.[16]

Inhibition

All PI 3-kinases are inhibited by the drugs wortmannin and LY294002 but wortmannin shows better efficiency than LY294002 on the hotspot mutation positions.[17][18]

Pharmacology

In September 2017 Copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[19]

See also

Interactions

P110α has been shown to interact with:

References

  1. ↑ "Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit". Cell 70 (3): 419–29. August 1992. doi:10.1016/0092-8674(92)90166-A. PMID 1322797. 
  2. ↑ "Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology". Oncogene 33 (23): 2949–2955. 2013. doi:10.1038/onc.2013.244. PMID 23792451. 
  3. ↑ "Entrez Gene: PIK3CA". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5290. 
  4. ↑ Rommel, Christian, ed (2010-01-01). "Oncogenic mutations of PIK3CA in human cancers". Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology. 347. Springer Berlin Heidelberg. pp. 21–41. doi:10.1007/82_2010_68. ISBN 9783642148156. 
  5. ↑ "PIK3CA as an oncogene in cervical cancer". Oncogene 19 (23): 2739–44. May 2000. doi:10.1038/sj.onc.1203597. PMID 10851074. 
  6. ↑ "Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach". Journal of Biomolecular Structure & Dynamics 35 (12): 2745–2757. September 2016. doi:10.1080/07391102.2016.1231082. PMID 27581627. 
  7. ↑ "PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data". Breast Cancer Research 16 (1): 201. January 2014. doi:10.1186/bcr3605. PMID 25192370. 
  8. ↑ "Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex!". Journal of Clinical Oncology 31 (34): 4358–61. December 2013. doi:10.1200/jco.2013.52.0080. PMID 24166520. 
  9. ↑ "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. April 2004. doi:10.1126/science.1096502. PMID 15016963. 
  10. ↑ "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine-Related Cancer (Bioscientifica) 8 (3): 237–48. September 2001. doi:10.1677/erc.0.0080237. PMID 11566615. 
  11. ↑ "Targeting phosphoinositide 3-kinase: moving towards therapy". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1784 (1): 159–85. January 2008. doi:10.1016/j.bbapap.2007.10.003. PMID 17997386. 
  12. ↑ "Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival". The New England Journal of Medicine 367 (17): 1596–606. October 2012. doi:10.1056/nejmoa1207756. PMID 23094721. 
  13. ↑ "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. December 2013. doi:10.1200/jco.2013.50.0322. PMID 24062397. https://zenodo.org/record/3439753. [yes|permanent dead link|dead link}}]
  14. ↑ "Somatic Activating PIK3CA Mutations Cause Venous Malformation". American Journal of Human Genetics 97 (6): 914–21. December 2015. doi:10.1016/j.ajhg.2015.11.011. PMID 26637981. 
  15. ↑ "Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA". The Journal of Pediatrics 166 (4): 1048–54.e1–5. April 2015. doi:10.1016/j.jpeds.2014.12.069. PMID 25681199. 
  16. ↑ Pagon, Roberta A., ed (1993-01-01). "PIK3CA-Related Overgrowth Spectrum". PIK3CA-Related Segmental Overgrowth. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK153722/. 
  17. ↑ "Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach". Journal of Biomolecular Structure & Dynamics 35 (12): 2745–2757. September 2016. doi:10.1080/07391102.2016.1231082. PMID 27581627. 
  18. ↑ "Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach". Advances in Protein Chemistry and Structural Biology 102: 267–97. 2016-01-01. doi:10.1016/bs.apcsb.2015.09.008. PMID 26827608. 
  19. ↑ "FDA approves new treatment for adults with relapsed follicular lymphoma". US Food and Drug Administration. September 14, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm. 
  20. ↑ "Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement". The Journal of Biological Chemistry 278 (31): 28793–8. August 2003. doi:10.1074/jbc.M303900200. PMID 12754211. 
  21. ↑ "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochemical and Biophysical Research Communications 307 (3): 459–65. August 2003. doi:10.1016/s0006-291x(03)01187-2. PMID 12893243. 
  22. ↑ "Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta". The Journal of Biological Chemistry 278 (41): 39542–7. October 2003. doi:10.1074/jbc.M307153200. PMID 12890670. 
  23. ↑ "The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors". Oncogene 23 (2): 559–68. January 2004. doi:10.1038/sj.onc.1207161. PMID 14724584. 
  24. ↑ "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. April 2000. doi:10.1101/gad.14.8.895. PMID 10783161. 
  25. ↑ "Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation". The EMBO Journal 15 (10): 2442–51. May 1996. doi:10.1002/j.1460-2075.1996.tb00602.x. PMID 8665852. 
  26. ↑ "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. January 2004. doi:10.1074/jbc.M309924200. PMID 14583609. 
  27. ↑ "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. December 1993. doi:10.1128/mcb.13.12.7708. PMID 8246987. 

Further reading



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