P110α

{{Short description|Human protein-coding gene}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Primary sources|date=June 2016}}{{Infobox_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.<ref name="pmid1322797">{{cite journal | vauthors = Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, Thompson A, Totty NF | date = August 1992 | title = Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit | journal = Cell | volume = 70 | issue = 3 | pages = 419–429 | doi = 10.1016/0092-8674(92)90166-A | doi-access = free | pmid = 1322797 }}</ref>

Its role was uncovered by molecular pathological epidemiology (MPE).<ref>{{cite journal | vauthors = Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT | year = 2013 | title = Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology | journal = Oncogene | volume = 33| issue = 23| pages = 2949–2955| doi = 10.1038/onc.2013.244 | pmid=23792451| pmc =3818472}}</ref>

== 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.<ref name="entrez">{{cite web | title = Entrez Gene: PIK3CA | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5290 }}</ref>

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.<ref>{{cite book | vauthors = Samuels Y, Waldman T | date = 2010-01-01 | veditors = Rommel C, Vanhaesebroeck B, Vogt PK | chapter = Oncogenic mutations of PIK3CA in human cancers | title = Phosphoinositide 3-kinase in Health and Disease | publisher = Springer Berlin Heidelberg | volume = 347 | pages = 21–41 | isbn = 978-3-642-14815-6 | doi = 10.1007/82_2010_68 | pmc = 3164550 | pmid = 20535651 | series = Current Topics in Microbiology and Immunology }}</ref> It has been found to be oncogenic and is implicated in cervical cancers.<ref name="pmid10851074">{{cite journal | vauthors = Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY | date = May 2000 | title = PIK3CA as an oncogene in cervical cancer | journal = Oncogene | volume = 19 | issue = 23 | pages = 2739–2744 | doi = 10.1038/sj.onc.1203597 | doi-access = free | pmid = 10851074 }}</ref> ''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.<ref>{{cite journal | vauthors = Thirumal Kumar D, George Priya Doss C | title = Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach | journal = Journal of Biomolecular Structure & Dynamics | issue = 12 | pages = 2745–2757 | date = September 2016 | volume = 35 | pmid = 27581627 | doi = 10.1080/07391102.2016.1231082 }}</ref> 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.<ref>{{cite journal | vauthors = Zardavas D, Phillips WA, Loi S | date = January 2014 | title = PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data | journal = Breast Cancer Research | volume = 16 | issue = 1 | page = 201 | doi = 10.1186/bcr3605 | doi-access = free | pmc = 4054885 | pmid = 25192370 }}</ref>

PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.<ref>{{cite journal | vauthors = Fuchs CS, Ogino S | date = December 2013 | title = Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex! | journal = Journal of Clinical Oncology | volume = 31 | issue = 34 | pages = 4358–4361 | doi = 10.1200/jco.2013.52.0080 | pmid = 24166520 }}</ref>

== Clinical characteristics ==

Due to the association between p110α and cancer,<ref name="pmid15016963">{{cite journal | vauthors = Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE | date = April 2004 | title = High frequency of mutations of the PIK3CA gene in human cancers | journal = Science | volume = 304 | issue = 5670 | page = 554 | doi = 10.1126/science.1096502 | pmid = 15016963 | author3-link = Alberto Bardelli | s2cid = 10147415 }}</ref> it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.<ref name="pmid11566615">{{cite journal | vauthors = Stein RC | date = September 2001 | title = Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment | journal = Endocrine-Related Cancer | publisher = Bioscientifica | volume = 8 | issue = 3 | pages = 237–248 | doi = 10.1677/erc.0.0080237 | doi-access = free | pmid = 11566615 | s2cid = 568427 }}</ref><ref name="pmid17997386">{{cite journal | vauthors = Marone R, Cmiljanovic V, Giese B, Wymann MP | date = January 2008 | title = Targeting phosphoinositide 3-kinase: moving towards therapy | journal = Biochimica et Biophysica Acta | volume = 1784 | issue = 1 | pages = 159–185 | doi = 10.1016/j.bbapap.2007.10.003 | pmid = 17997386 }}</ref>

The presence of [a] PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.<ref>{{cite journal | vauthors = 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 | date = October 2012 | title = Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival | journal = The New England Journal of Medicine | volume = 367 | issue = 17 | pages = 1596–1606 | doi = 10.1056/nejmoa1207756 | pmc = 3532946 | pmid = 23094721 }}</ref><ref>{{cite journal | vauthors = Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, Davidson B, Kerr DJ, Tomlinson IP, Midgley R | date = December 2013 | title = Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer | journal = Journal of Clinical Oncology | volume = 31 | issue = 34 | pages = 4297–4305 | doi = 10.1200/jco.2013.50.0322 | doi-access = free | pmid = 24062397 }}{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

Somatic activating mutations in PIK3CA are found in Klippel–Trénaunay syndrome and venous malformation.<ref>{{cite journal | vauthors = Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M | date = December 2015 | title = Somatic Activating PIK3CA Mutations Cause Venous Malformation | journal = American Journal of Human Genetics | volume = 97 | issue = 6 | pages = 914–921 | doi = 10.1016/j.ajhg.2015.11.011 | pmc = 4678782 | pmid = 26637981 }}</ref><ref>{{cite journal | vauthors = 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 | title = Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA | journal = The Journal of Pediatrics | volume = 166 | issue = 4 | pages = 1048–54.e1–5 | date = April 2015 | pmid = 25681199 | doi = 10.1016/j.jpeds.2014.12.069 | pmc = 4498659 }}</ref>

''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.<ref>{{cite book | vauthors = Mirzaa G, Conway R, Graham JM Jr, Dobyns WB | date = 1993-01-01 | veditors = Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC | chapter = PIK3CA-Related Overgrowth Spectrum | title = PIK3CA-Related Segmental Overgrowth | publisher = University of Washington, Seattle | pmid = 23946963 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK153722/ }}</ref>

== 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.<ref>{{cite journal | vauthors = Thirumal Kumar D, George Priya Doss C | title = Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach | journal = Journal of Biomolecular Structure & Dynamics | issue = 12 | pages = 2745–2757 | date = September 2016 | volume = 35 | pmid = 27581627 | doi = 10.1080/07391102.2016.1231082 }}</ref><ref>{{cite journal | vauthors = Kumar DT, Doss CG | date = 2016-01-01 | title = Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach | journal = Advances in Protein Chemistry and Structural Biology | volume = 102 | pages = 267–297 | doi = 10.1016/bs.apcsb.2015.09.008 | pmid = 26827608 }}</ref>

== 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.<ref name=FDA576129>{{cite web | url = https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm | archive-url = https://web.archive.org/web/20171031182724/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576129.htm | url-status = dead | archive-date = October 31, 2017 | title = FDA approves new treatment for adults with relapsed follicular lymphoma | date = September 14, 2017 | publisher = US Food and Drug Administration}}</ref>

== Interactions ==

P110α has been shown to interact with: {{div col|colwidth=20em}} * ARHGEF1,<ref name = pmid12754211>{{cite journal | vauthors = Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB | date = August 2003 | title = Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28793–28798 | doi = 10.1074/jbc.M303900200 | doi-access = free | pmid = 12754211 }}</ref> * ADAP1,<ref name = pmid12893243>{{cite journal | vauthors = Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A | date = August 2003 | title = Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C | journal = Biochemical and Biophysical Research Communications | volume = 307 | issue = 3 | pages = 459–465 | doi = 10.1016/s0006-291x(03)01187-2 | pmid = 12893243 }}</ref> * DGKZ,<ref name = pmid12890670>{{cite journal | vauthors = Luo B, Prescott SM, Topham MK | date = October 2003 | title = Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39542–39547 | doi = 10.1074/jbc.M307153200 | doi-access = free | pmid = 12890670 }}</ref> * HRAS,<ref name = pmid14724584>{{cite journal | vauthors = Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J | date = January 2004 | title = The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors | journal = Oncogene | volume = 23 | issue = 2 | pages = 559–568 | doi = 10.1038/sj.onc.1207161 | doi-access = free | pmid = 14724584 }}</ref><ref name = pmid10783161>{{cite journal | vauthors = Li W, Han M, Guan KL | title = The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf | journal = Genes & Development | volume = 14 | issue = 8 | pages = 895–900 | date = April 2000 | doi = 10.1101/gad.14.8.895 | pmid = 10783161 | pmc = 316541 }}</ref><ref name = pmid8665852>{{cite journal | vauthors = Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J | date = May 1996 | title = Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation | journal = The EMBO Journal | volume = 15 | issue = 10 | pages = 2442–2451 | doi = 10.1002/j.1460-2075.1996.tb00602.x | pmc = 450176 | pmid = 8665852 }}</ref> and * Lck.<ref name = pmid14583609>{{cite journal | vauthors = Sade H, Krishna S, Sarin A | date = January 2004 | title = The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 4 | pages = 2937–2944 | doi = 10.1074/jbc.M309924200 | doi-access = free | pmid = 14583609 }}</ref><ref name = pmid8246987>{{cite journal | vauthors = Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE | date = December 1993 | title = 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 | journal = Molecular and Cellular Biology | volume = 13 | issue = 12 | pages = 7708–7717 | doi = 10.1128/mcb.13.12.7708 | pmc = 364842 | pmid = 8246987 }}</ref> {{Div col end}} {{Clear}}

== References == {{Reflist|33em}}

== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Foster FM, Traer CJ, Abraham SM, Fry MJ | date = August 2003 | title = The phosphoinositide (PI) 3-kinase family | journal = Journal of Cell Science | volume = 116 | issue = Pt 15 | pages = 3037–3040 | doi = 10.1242/jcs.00609 | doi-access = free | pmid = 12829733 }} * {{cite journal | vauthors = Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY | date = March 2005 | title = Mutations of PIK3CA in gastric adenocarcinoma | journal = BMC Cancer | volume = 5 | page = 29 | doi = 10.1186/1471-2407-5-29 | doi-access = free | pmc = 1079799 | pmid = 15784156 }} * {{cite journal | vauthors = Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM | date = December 2007 | title = The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations | journal = Science | volume = 318 | issue = 5857 | pages = 1744–1748 | doi = 10.1126/science.1150799 | pmid = 18079394 | bibcode = 2007Sci...318.1744H | s2cid = 83474940 }} * {{cite journal | vauthors = 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 | title = The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes | journal = Nature Communications | volume = 7 | article-number = 11479 | date = May 2016 | pmid = 27161491 | pmc = 4866047 | doi = 10.1038/ncomms11479 | bibcode = 2016NatCo...711479P }} {{refend}}

{{DEFAULTSORT:P110}} Category:EC 2.7.1