P110α Explained

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

• Phosphoinositide 3-kinase
• Phosphoinositide 3-kinase inhibitor
• PIK3CA-related overgrowth spectrum

Interactions

P110α has been shown to interact with:

• ARHGEF1,^[20]
• ADAP1,^[21]
• DGKZ,^[22]
• HRAS,^{[23] [24] [25]} and
• Lck.^{[26] [27]}

Further reading

• Foster FM, Traer CJ, Abraham SM, Fry MJ . The phosphoinositide (PI) 3-kinase family . Journal of Cell Science . 116 . Pt 15 . 3037–40 . August 2003 . 12829733 . 10.1242/jcs.00609 . free .
• Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY . Mutations of PIK3CA in gastric adenocarcinoma . BMC Cancer . 5 . 29 . March 2005 . 15784156 . 1079799 . 10.1186/1471-2407-5-29 . free .
• Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM . The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations . Science . 318 . 5857 . 1744–8 . December 2007 . 18079394 . 10.1126/science.1150799 . 2007Sci...318.1744H . 83474940 .
• Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ, Tsui DW, Liu B, Dawson SJ, Abraham J, Northen H, Peden JF, Mukherjee A, Turashvili G, Green AR, McKinney S, Oloumi A, Shah S, Rosenfeld N, Murphy L, Bentley DR, Ellis IO, Purushotham A, Pinder SE, Børresen-Dale AL, Earl HM, Pharoah PD, Ross MT, Aparicio S, Caldas C . The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes . Nature Communications . 7 . 11479 . May 2016 . 27161491 . 4866047 . 10.1038/ncomms11479 . 2016NatCo...711479P .

Notes and References

1. Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, Thompson A, Totty NF . Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit . Cell . 70 . 3 . 419–29 . August 1992 . 1322797 . 10.1016/0092-8674(92)90166-A . free .
2. Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT . 2013 . Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology . Oncogene . 33. 23. 2949–2955. 10.1038/onc.2013.244 . 23792451. 3818472.
3. Web site: Entrez Gene: PIK3CA .
4. Book: Samuels Y, Waldman T . Phosphoinositide 3-kinase in Health and Disease . Oncogenic mutations of PIK3CA in human cancers . 347 . 21–41 . 2010-01-01 . 20535651 . 3164550 . 10.1007/82_2010_68 . Springer Berlin Heidelberg . Vanhaesebroeck . 9783642148156 . Current Topics in Microbiology and Immunology . Christian . Peter K. . Bart . Vogt . Rommel .
5. Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY . PIK3CA as an oncogene in cervical cancer . Oncogene . 19 . 23 . 2739–44 . May 2000 . 10851074 . 10.1038/sj.onc.1203597 . free .
6. Thirumal Kumar D, George Priya Doss C . Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach . Journal of Biomolecular Structure & Dynamics . 12 . 2745–2757 . September 2016 . 35 . 27581627 . 10.1080/07391102.2016.1231082 .
7. Zardavas D, Phillips WA, Loi S . PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data . Breast Cancer Research . 16 . 1 . 201 . January 2014 . 25192370 . 4054885 . 10.1186/bcr3605 . free .
8. Fuchs CS, Ogino S . Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex! . Journal of Clinical Oncology . 31 . 34 . 4358–61 . December 2013 . 24166520 . 10.1200/jco.2013.52.0080 .
9. Alberto Bardelli . . High frequency of mutations of the PIK3CA gene in human cancers . Science . 304 . 5670 . 554 . April 2004 . 15016963 . 10.1126/science.1096502 . 10147415 .
10. Stein RC . Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment . Endocrine-Related Cancer . 8 . 3 . 237–48 . September 2001 . 11566615 . 10.1677/erc.0.0080237 . . 568427 . free .
11. Marone R, Cmiljanovic V, Giese B, Wymann MP . Targeting phosphoinositide 3-kinase: moving towards therapy . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1784 . 1 . 159–85 . January 2008 . 17997386 . 10.1016/j.bbapap.2007.10.003 .
12. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S . Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival . The New England Journal of Medicine . 367 . 17 . 1596–606 . October 2012 . 23094721 . 10.1056/nejmoa1207756 . 3532946.
13. Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, Davidson B, Kerr DJ, Tomlinson IP, Midgley R . 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 . 24062397 . 10.1200/jco.2013.50.0322 . free .
14. Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M . Somatic Activating PIK3CA Mutations Cause Venous Malformation . American Journal of Human Genetics . 97 . 6 . 914–21 . December 2015 . 26637981 . 10.1016/j.ajhg.2015.11.011 . 4678782 .
15. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HP, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns WB, Kurek KC, Warman ML, McCarroll SA, Murillo R . 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 . 25681199 . 10.1016/j.jpeds.2014.12.069 . 4498659 .
16. Book: Mirzaa G, Conway R, Graham JM Jr, Dobyns WB. PIK3CA-Related Segmental Overgrowth . PIK3CA-Related Overgrowth Spectrum . 1993-01-01 . 23946963 . https://www.ncbi.nlm.nih.gov/books/NBK153722/ . Heather C. . Chin-To . Thomas D. . Lora J.H. . Anne . Stephanie E. . Holly H. . Margaret P. . Adam . Ardinger . Wallace . Amemiya . Bean . Bird . Fong . Mefford . Pagon . University of Washington, Seattle . Roberta A. .
17. Thirumal Kumar D, George Priya Doss C . Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach . Journal of Biomolecular Structure & Dynamics . 12 . 2745–2757 . September 2016 . 35 . 27581627 . 10.1080/07391102.2016.1231082 .
18. Kumar DT, Doss CG . 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 . 26827608 . 10.1016/bs.apcsb.2015.09.008 .
19. Web site: FDA approves new treatment for adults with relapsed follicular lymphoma . September 14, 2017 . US Food and Drug Administration.
20. Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB . Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement . The Journal of Biological Chemistry . 278 . 31 . 28793–8 . August 2003 . 12754211 . 10.1074/jbc.M303900200 . free .
21. Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A . 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 . 12893243 . 10.1016/s0006-291x(03)01187-2 .
22. Luo B, Prescott SM, Topham MK . Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta . The Journal of Biological Chemistry . 278 . 41 . 39542–7 . October 2003 . 12890670 . 10.1074/jbc.M307153200 . free .
23. Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J . The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors . Oncogene . 23 . 2 . 559–68 . January 2004 . 14724584 . 10.1038/sj.onc.1207161 . free .
24. Li W, Han M, Guan KL . 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 . 10.1101/gad.14.8.895 . 10783161 . 316541 .
25. Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J . Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation . The EMBO Journal . 15 . 10 . 2442–51 . May 1996 . 8665852 . 450176 . 10.1002/j.1460-2075.1996.tb00602.x.
26. Sade H, Krishna S, Sarin A . 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 . 14583609 . 10.1074/jbc.M309924200 . free .
27. Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE . 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 . 8246987 . 364842 . 10.1128/mcb.13.12.7708 .