ID PK3CA_HUMAN Reviewed; 1068 AA. AC P42336; Q14CW1; Q99762; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 20-FEB-2007, sequence version 2. DT 11-NOV-2015, entry version 169. DE RecName: Full=Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; DE Short=PI3-kinase subunit alpha; DE Short=PI3K-alpha; DE Short=PI3Kalpha; DE Short=PtdIns-3-kinase subunit alpha; DE EC=2.7.1.153; DE AltName: Full=Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; DE Short=PtdIns-3-kinase subunit p110-alpha; DE Short=p110alpha; DE AltName: Full=Phosphoinositide-3-kinase catalytic alpha polypeptide; DE AltName: Full=Serine/threonine protein kinase PIK3CA; DE EC=2.7.11.1; GN Name=PIK3CA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-43 AND ARG-332. RX PubMed=7713498; DOI=10.1006/geno.1994.1655; RA Volinia S., Hiles I., Ormondroyd E., Nizetic D., Antonacci R., RA Rocchi M., Waterfield M.; RT "Molecular cloning, cDNA sequence, and chromosomal localization of the RT human phosphatidylinositol 3-kinase p110 alpha (PIK3CA) gene."; RL Genomics 24:472-477(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9043658; DOI=10.1016/S0968-0896(96)00196-4; RA Stirdivant S.M., Ahern J., Conroy R.R., Barnett S.F., Ledder L.M., RA Oliff A., Heimbrook D.C.; RT "Cloning and mutagenesis of the p110 alpha subunit of human RT phosphoinositide 3'-hydroxykinase."; RL Bioorg. Med. Chem. 5:65-74(1997). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP INTERACTION WITH APPL1. RX PubMed=10490823; DOI=10.1038/sj.onc.1203080; RA Mitsuuchi Y., Johnson S.W., Sonoda G., Tanno S., Golemis E.A., RA Testa J.R.; RT "Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an RT adaptor molecule that interacts with the oncoprotein-serine/threonine RT kinase AKT2."; RL Oncogene 18:4891-4898(1999). RN [5] RP FUNCTION IN INVADOPODIA FORMATION, AND CHARACTERIZATION OF VARIANTS RP LYS-545 AND ARG-1047. RX PubMed=21708979; DOI=10.1083/jcb.201009126; RA Yamaguchi H., Yoshida S., Muroi E., Yoshida N., Kawamura M., RA Kouchi Z., Nakamura Y., Sakai R., Fukami K.; RT "Phosphoinositide 3-kinase signaling pathway mediated by p110{alpha} RT regulates invadopodia formation."; RL J. Cell Biol. 193:1275-1288(2011). RN [6] RP INTERACTION WITH FAM83B. RX PubMed=23676467; RA Cipriano R., Miskimen K.L., Bryson B.L., Foy C.R., Bartel C.A., RA Jackson M.W.; RT "FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates RT to promote epithelial cell transformation and resistance to targeted RT therapies."; RL Oncotarget 4:729-738(2013). RN [7] RP REVIEW ON CANCER. RX PubMed=18418043; DOI=10.4161/cc.7.9.5817; RA Huang C.-H., Mandelker D., Gabelli S.B., Amzel L.M.; RT "Insights into the oncogenic effects of PIK3CA mutations from the RT structure of p110alpha/p85alpha."; RL Cell Cycle 7:1151-1156(2008). RN [8] RP REVIEW ON FUNCTION, AND REVIEW ON CANCER. RX PubMed=18794883; DOI=10.1038/onc.2008.244; RA Zhao L., Vogt P.K.; RT "Class I PI3K in oncogenic cellular transformation."; RL Oncogene 27:5486-5496(2008). RN [9] RP REVIEW ON FUNCTION. RX PubMed=19200708; DOI=10.1016/j.ceb.2008.12.007; RA Jia S., Roberts T.M., Zhao J.J.; RT "Should individual PI3 kinase isoforms be targeted in cancer?"; RL Curr. Opin. Cell Biol. 21:199-208(2009). RN [10] RP X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) IN A COMPLEX WITH PIK3R1, AND RP DOMAINS. RX PubMed=18079394; DOI=10.1126/science.1150799; RA Huang C.-H., Mandelker D., Schmidt-Kittler O., Samuels Y., RA Velculescu V.E., Kinzler K.W., Vogelstein B., Gabelli S.B., RA Amzel L.M.; RT "The structure of a human p110alpha/p85alpha complex elucidates the RT effects of oncogenic PI3Kalpha mutations."; RL Science 318:1744-1748(2007). RN [11] RP STRUCTURE BY NMR OF 331-481. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the C2 domain from human PI3-kinase p110 RT subunit alpha."; RL Submitted (APR-2008) to the PDB data bank. RN [12] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF MUTANT HIS-1047 IN COMPLEX RP WITH WORTMANNIN AND PIK3R1, INTERACTION WITH PIK3R1, CHARACTERIZATION RP OF VARIANT ARG-1047, AND DOMAINS. RX PubMed=19805105; DOI=10.1073/pnas.0908444106; RA Mandelker D., Gabelli S.B., Schmidt-Kittler O., Zhu J., Cheong I., RA Huang C.H., Kinzler K.W., Vogelstein B., Amzel L.M.; RT "A frequent kinase domain mutation that changes the interaction RT between PI3Kalpha and the membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 106:16996-17001(2009). RN [13] RP VARIANTS CANCER LYS-542; LYS-545; PRO-546; ASN-1021; ARG-1047; RP LEU-1047 AND TYR-1065. RX PubMed=15289301; DOI=10.1158/0008-5472.CAN-04-1170; RA Broderick D.K., Di C., Parrett T.J., Samuels Y.R., Cummins J.M., RA McLendon R.E., Fults D.W., Velculescu V.E., Bigner D.D., Yan H.; RT "Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade RT astrocytomas, and medulloblastomas."; RL Cancer Res. 64:5048-5050(2004). RN [14] RP VARIANTS CANCER GLY-545; LYS-545; LYS-546; GLU-546; ARG-1047 AND RP LEU-1047. RX PubMed=15520168; DOI=10.1158/0008-5472.CAN-04-2933; RA Campbell I.G., Russell S.E., Choong D.Y.H., Montgomery K.G., RA Ciavarella M.L., Hooi C.S.F., Cristiano B.E., Pearson R.B., RA Phillips W.A.; RT "Mutation of the PIK3CA gene in ovarian and breast cancer."; RL Cancer Res. 64:7678-7681(2004). RN [15] RP VARIANT CANCER ARG-1047. RX PubMed=15016963; DOI=10.1126/science.1096502; RA Samuels Y., Wang Z., Bardelli A., Silliman N., Ptak J., Szabo S., RA Yan H., Gazdar A., Powell S.M., Riggins G.J., Willson J.K.V., RA Markowitz S., Kinzler K.W., Vogelstein B., Velculescu V.E.; RT "High frequency of mutations of the PIK3CA gene in human cancers."; RL Science 304:554-554(2004). RN [16] RP VARIANTS CANCER GLN-88; LYS-542; ALA-545 AND ASN-1025. RX PubMed=15924253; DOI=10.1007/s00401-005-1000-1; RA Hartmann C., Bartels G., Gehlhaar C., Holtkamp N., von Deimling A.; RT "PIK3CA mutations in glioblastoma multiforme."; RL Acta Neuropathol. 109:639-642(2005). RN [17] RP VARIANTS CANCER LYS-542; LYS-545 AND ARG-1047. RX PubMed=15784156; DOI=10.1186/1471-2407-5-29; RA Li V.S.W., Wong C.W., Chan T.L., Chan A.S.W., Zhao W., Chu K.-M., RA So S., Chen X., Yuen S.T., Leung S.Y.; RT "Mutations of PIK3CA in gastric adenocarcinoma."; RL BMC Cancer 5:29-29(2005). RN [18] RP CHARACTERIZATION OF VARIANTS CRC HIS-38; VAL-106; ARG-420; GLN-453; RP LYS-542; LYS-545; ILE-1043 AND ARG-1047. RX PubMed=15930273; DOI=10.1158/0008-5472.CAN-04-4114; RA Ikenoue T., Kanai F., Hikiba Y., Obata T., Tanaka Y., Imamura J., RA Ohta M., Jazag A., Guleng B., Tateishi K., Asaoka Y., Matsumura M., RA Kawabe T., Omata M.; RT "Functional analysis of PIK3CA gene mutations in human colorectal RT cancer."; RL Cancer Res. 65:4562-4567(2005). RN [19] RP VARIANTS CANCER GLN-542; LYS-542; GLY-545; LYS-545; ARG-1007; RP HIS-1021; CYS-1021; VAL-1035; ILE-1043; TYR-1047; ARG-1047; ASP-1050; RP LYS-1052 AND LEU-1065. RX PubMed=16322209; DOI=10.1158/0008-5472.CAN-05-2620; RA Oda K., Stokoe D., Taketani Y., McCormick F.; RT "High frequency of coexistent mutations of PIK3CA and PTEN genes in RT endometrial carcinoma."; RL Cancer Res. 65:10669-10673(2005). RN [20] RP VARIANTS CANCER LYS-542; GLY-545; LYS-545; GLN-1023; ARG-1047 AND RP LEU-1047. RX PubMed=15994075; DOI=10.1016/j.ejca.2005.04.022; RA Velho S., Oliveira C., Ferreira A., Ferreira A.C., Suriano G., RA Schwartz S. Jr., Duval A., Carneiro F., Machado J.C., Hamelin R., RA Seruca R.; RT "The prevalence of PIK3CA mutations in gastric and colon cancer."; RL Eur. J. Cancer 41:1649-1654(2005). RN [21] RP VARIANTS CANCER LYS-545 AND ARG-1047. RX PubMed=15712344; DOI=10.1002/humu.9316; RA Wang Y., Helland A., Holm R., Kristensen G.B., Boerresen-Dale A.-L.; RT "PIK3CA mutations in advanced ovarian carcinomas."; RL Hum. Mutat. 25:322-322(2005). RN [22] RP VARIANT HCC ALA-545. RX PubMed=15608678; DOI=10.1038/sj.onc.1208304; RA Lee J.W., Soung Y.H., Kim S.Y., Lee H.W., Park W.S., Nam S.W., RA Kim S.H., Lee J.Y., Yoo N.J., Lee S.H.; RT "PIK3CA gene is frequently mutated in breast carcinomas and RT hepatocellular carcinomas."; RL Oncogene 24:1477-1480(2005). RN [23] RP VARIANTS CANCER CYS-343; LYS-542; LYS-545 AND ARG-1047, AND VARIANT RP MET-391. RX PubMed=16533766; DOI=10.1158/1078-0432.CCR-05-2173; RA Qiu W., Schoenleben F., Li X., Ho D.J., Close L.G., Manolidis S., RA Bennett B.P., Su G.H.; RT "PIK3CA mutations in head and neck squamous cell carcinoma."; RL Clin. Cancer Res. 12:1441-1446(2006). RN [24] RP VARIANT CANCER ARG-1047. RX PubMed=16114017; DOI=10.1002/ijc.21444; RA Or Y.Y.-Y., Hui A.B.-Y., To K.-F., Lam C.N.-Y., Lo K.-W.; RT "PIK3CA mutations in nasopharyngeal carcinoma."; RL Int. J. Cancer 118:1065-1067(2006). RN [25] RP VARIANTS BC LYS-542; VAL-542; LYS-545; ARG-546; ARG-1047 AND LEU-1047. RX PubMed=16353168; DOI=10.1002/path.1908; RA Buttitta F., Felicioni L., Barassi F., Martella C., Paolizzi D., RA Fresu G., Salvatore S., Cuccurullo F., Mezzetti A., Campani D., RA Marchetti A.; RT "PIK3CA mutation and histological type in breast carcinoma: high RT frequency of mutations in lobular carcinoma."; RL J. Pathol. 208:350-355(2006). RN [26] RP CHARACTERIZATION OF VARIANTS CANCER LYS-542; LYS-545 AND ARG-1047. RX PubMed=16432179; DOI=10.1073/pnas.0510857103; RA Bader A.G., Kang S., Vogt P.K.; RT "Cancer-specific mutations in PIK3CA are oncogenic in vivo."; RL Proc. Natl. Acad. Sci. U.S.A. 103:1475-1479(2006). RN [27] RP VARIANTS KERSEB LYS-542; LYS-545; GLY-545 AND ARG-1047. RX PubMed=17673550; DOI=10.1073/pnas.0705218104; RA Hafner C., Lopez-Knowles E., Luis N.M., Toll A., Baselga E., RA Fernandez-Casado A., Hernandez S., Ribe A., Mentzel T., Stoehr R., RA Hofstaedter F., Landthaler M., Vogt T., Pujol R.M., Hartmann A., RA Real F.X.; RT "Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic RT keratoses with a characteristic mutation pattern."; RL Proc. Natl. Acad. Sci. U.S.A. 104:13450-13454(2007). RN [28] RP VARIANTS CLOVE ARG-420; LYS-542 AND ARG-1047. RX PubMed=22658544; DOI=10.1016/j.ajhg.2012.05.006; RA Kurek K.C., Luks V.L., Ayturk U.M., Alomari A.I., Fishman S.J., RA Spencer S.A., Mulliken J.B., Bowen M.E., Yamamoto G.L., RA Kozakewich H.P., Warman M.L.; RT "Somatic mosaic activating mutations in PIK3CA cause CLOVES RT syndrome."; RL Am. J. Hum. Genet. 90:1108-1115(2012). RN [29] RP VARIANTS MCAP LYS-81; GLN-88; ARG-364; LYS-365; TYR-378; GLU-453 DEL; RP LYS-545; LYS-726; ARG-914; CYS-1021; ALA-1025; VAL-1035; ILE-1043; RP TYR-1047 AND SER-1049. RX PubMed=22729224; DOI=10.1038/ng.2331; RA Riviere J.B., Mirzaa G.M., O'Roak B.J., Beddaoui M., Alcantara D., RA Conway R.L., St-Onge J., Schwartzentruber J.A., Gripp K.W., RA Nikkel S.M., Worthylake T., Sullivan C.T., Ward T.R., Butler H.E., RA Kramer N.A., Albrecht B., Armour C.M., Armstrong L., Caluseriu O., RA Cytrynbaum C., Drolet B.A., Innes A.M., Lauzon J.L., Lin A.E., RA Mancini G.M., Meschino W.S., Reggin J.D., Saggar A.K., RA Lerman-Sagie T., Uyanik G., Weksberg R., Zirn B., Beaulieu C.L., RA Majewski J., Bulman D.E., O'Driscoll M., Shendure J., Graham J.M. Jr., RA Boycott K.M., Dobyns W.B.; RT "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA RT cause a spectrum of related megalencephaly syndromes."; RL Nat. Genet. 44:934-940(2012). RN [30] RP VARIANTS CWS5 ASP-118; LYS-135; LYS-218; ILE-356; LYS-382 AND ALA-545. RX PubMed=23246288; DOI=10.1016/j.ajhg.2012.10.021; RA Orloff M.S., He X., Peterson C., Chen F., Chen J.L., Mester J.L., RA Eng C.; RT "Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like RT syndromes."; RL Am. J. Hum. Genet. 92:76-80(2013). CC -!- FUNCTION: Phosphoinositide-3-kinase (PI3K) that phosphorylates CC PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- CC phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- CC bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate CC (PIP3). PIP3 plays a key role by recruiting PH domain-containing CC proteins to the membrane, including AKT1 and PDPK1, activating CC signaling cascades involved in cell growth, survival, CC proliferation, motility and morphology. Participates in cellular CC signaling in response to various growth factors. Involved in the CC activation of AKT1 upon stimulation by receptor tyrosine kinases CC ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in CC signaling via insulin-receptor substrate (IRS) proteins. Essential CC in endothelial cell migration during vascular development through CC VEGFA signaling, possibly by regulating RhoA activity. Required CC for lymphatic vasculature development, possibly by binding to RAS CC and by activation by EGF and FGF2, but not by PDGF. Regulates CC invadopodia formation in breast cancer cells through the PDPK1- CC AKT1 pathway. Participates in cardiomyogenesis in embryonic stem CC cells through a AKT1 pathway. Participates in vasculogenesis in CC embryonic stem cells through PDK1 and protein kinase C pathway. CC Has also serine-protein kinase activity: phosphorylates PIK3R1 CC (p85alpha regulatory subunit), EIF4EBP1 and HRAS. CC {ECO:0000269|PubMed:21708979}. CC -!- CATALYTIC ACTIVITY: ATP + 1-phosphatidyl-1D-myo-inositol 4,5- CC bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5- CC trisphosphate. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- SUBUNIT: Heterodimer of a catalytic subunit PIK3CA and a p85 CC regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with IRS1 CC in nuclear extracts. Interacts with RUFY3 (By similarity). CC Interacts with RASD2 (By similarity). Interacts with APPL1. CC Interacts with HRAS and KRAS (By similarity). Interaction with CC HRAS/KRAS is required for PI3K pathway signaling and cell CC proliferation stimulated by EGF and FGF2 (By similarity). CC Interacts with FAM83B; activates the PI3K/AKT signaling cascade CC (PubMed:23676467). {ECO:0000250, ECO:0000269|PubMed:23676467}. CC -!- INTERACTION: CC P21860:ERBB3; NbExp=3; IntAct=EBI-2116585, EBI-720706; CC P35568:IRS1; NbExp=20; IntAct=EBI-2116585, EBI-517592; CC P27986:PIK3R1; NbExp=13; IntAct=EBI-2116585, EBI-79464; CC Q92569:PIK3R3; NbExp=3; IntAct=EBI-2116585, EBI-79893; CC -!- DOMAIN: The PI3K-ABD domain and the PI3K-RBD domain interact with CC the PI3K/PI4K kinase domain. The C2 PI3K-type domain may CC facilitate the recruitment to the plasma membrane. The inhibitory CC interactions with PIK3R1 are mediated by the PI3K-ABD domain and CC the C2 PI3K-type domain with the iSH2 (inter-SH2) region of CC PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and CC the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region CC of PIK3R1. {ECO:0000269|PubMed:18079394, CC ECO:0000269|PubMed:19805105}. CC -!- DISEASE: Note=PIK3CA mutations are involved in various type of CC cancer. Most of the cancer-associated mutations are missense CC mutations and map to one of the three hotspots: Glu-542; Glu-545 CC and His-1047. Mutated isoforms participate in cellular CC transformation and tumorigenesis induced by oncogenic receptor CC tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS CC is required for Ras-driven tumor formation. Mutations increasing CC the lipid kinase activity are required for oncogenic signaling. CC The protein kinase activity may not be required for tumorigenesis. CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease CC characterized by malignant lesions arising from the inner wall of CC the large intestine (the colon) and the rectum. Genetic CC alterations are often associated with progression from CC premalignant lesion (adenoma) to invasive adenocarcinoma. Risk CC factors for cancer of the colon and rectum include colon polyps, CC long-standing ulcerative colitis, and genetic family history. CC Note=The gene represented in this entry may be involved in disease CC pathogenesis. CC -!- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy CC originating from breast epithelial tissue. Breast neoplasms can be CC distinguished by their histologic pattern. Invasive ductal CC carcinoma is by far the most common type. Breast cancer is CC etiologically and genetically heterogeneous. Important genetic CC factors have been indicated by familial occurrence and bilateral CC involvement. Mutations at more than one locus can be involved in CC different families or even in the same case. CC {ECO:0000269|PubMed:16353168}. Note=Disease susceptibility is CC associated with variations affecting the gene represented in this CC entry. CC -!- DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer CC defines malignancies originating from ovarian tissue. Although CC many histologic types of ovarian tumors have been described, CC epithelial ovarian carcinoma is the most common form. Ovarian CC cancers are often asymptomatic and the recognized signs and CC symptoms, even of late-stage disease, are vague. Consequently, CC most patients are diagnosed with advanced disease. Note=Disease CC susceptibility is associated with variations affecting the gene CC represented in this entry. CC -!- DISEASE: Hepatocellular carcinoma (HCC) [MIM:114550]: A primary CC malignant neoplasm of epithelial liver cells. The major risk CC factors for HCC are chronic hepatitis B virus (HBV) infection, CC chronic hepatitis C virus (HCV) infection, prolonged dietary CC aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to CC other causes. {ECO:0000269|PubMed:15608678}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC -!- DISEASE: Keratosis, seborrheic (KERSEB) [MIM:182000]: A common CC benign skin tumor. Seborrheic keratoses usually begin with the CC appearance of one or more sharply defined, light brown, flat CC macules. The lesions may be sparse or numerous. As they initially CC grow, they develop a velvety to finely verrucous surface, followed CC by an uneven warty surface with multiple plugged follicles and a CC dull or lackluster appearance. {ECO:0000269|PubMed:17673550}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- DISEASE: Megalencephaly-capillary malformation-polymicrogyria CC syndrome (MCAP) [MIM:602501]: A syndrome characterized by a CC spectrum of anomalies including primary megalencephaly, prenatal CC overgrowth, brain and body asymmetry, cutaneous vascular CC malformations, digital anomalies consisting of syndactyly with or CC without postaxial polydactyly, connective tissue dysplasia CC involving the skin, subcutaneous tissue, and joints, and cortical CC brain malformations, most distinctively polymicrogyria. CC {ECO:0000269|PubMed:22729224}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Congenital lipomatous overgrowth, vascular malformations, CC and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, CC non-hereditary disorder characterized by asymmetric somatic CC hypertrophy and anomalies in multiple organs. It is defined by CC four main clinical findings: congenital lipomatous overgrowth, CC vascular malformations, epidermal nevi, and skeletal/spinal CC abnormalities. The presence of truncal overgrowth and CC characteristic patterned macrodactyly at birth differentiates CC CLOVE from other syndromic forms of overgrowth. CC {ECO:0000269|PubMed:22658544}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden CC syndrome, a hamartomatous polyposis syndrome with age-related CC penetrance. Cowden syndrome is characterized by hamartomatous CC lesions affecting derivatives of ectodermal, mesodermal and CC endodermal layers, macrocephaly, facial trichilemmomas (benign CC tumors of the hair follicle infundibulum), acral keratoses, CC papillomatous papules, and elevated risk for development of CC several types of malignancy, particularly breast carcinoma in CC women and thyroid carcinoma in both men and women. Colon cancer CC and renal cell carcinoma have also been reported. Hamartomas can CC be found in virtually every organ, but most commonly in the skin, CC gastrointestinal tract, breast and thyroid. CC {ECO:0000269|PubMed:23246288}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- MISCELLANEOUS: The avian sarcoma virus 16 genome encodes an CC oncogene derived from PIK3CA. {ECO:0000305|PubMed:18418043}. CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. CC {ECO:0000255|PROSITE-ProRule:PRU00877, ECO:0000255|PROSITE- CC ProRule:PRU00879, ECO:0000255|PROSITE-ProRule:PRU00880}. CC -!- SIMILARITY: Contains 1 C2 PI3K-type domain. {ECO:0000255|PROSITE- CC ProRule:PRU00880}. CC -!- SIMILARITY: Contains 1 PI3K-ABD domain. {ECO:0000255|PROSITE- CC ProRule:PRU00877}. CC -!- SIMILARITY: Contains 1 PI3K-RBD domain. {ECO:0000255|PROSITE- CC ProRule:PRU00879}. CC -!- SIMILARITY: Contains 1 PI3K/PI4K domain. {ECO:0000255|PROSITE- CC ProRule:PRU00269}. CC -!- SIMILARITY: Contains 1 PIK helical domain. {ECO:0000255|PROSITE- CC ProRule:PRU00878}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/PIK3CAID415ch3q26.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z29090; CAA82333.1; -; mRNA. DR EMBL; U79143; AAB39753.1; -; mRNA. DR EMBL; BC113601; AAI13602.1; -; mRNA. DR EMBL; BC113603; AAI13604.1; -; mRNA. DR CCDS; CCDS43171.1; -. DR PIR; I38110; I38110. DR RefSeq; NP_006209.2; NM_006218.2. DR RefSeq; XP_006713721.1; XM_006713658.2. DR RefSeq; XP_011511196.1; XM_011512894.1. DR UniGene; Hs.553498; -. DR UniGene; Hs.715194; -. DR PDB; 2ENQ; NMR; -; A=331-481. DR PDB; 2RD0; X-ray; 3.05 A; A=1-1068. DR PDB; 3HHM; X-ray; 2.80 A; A=1-1068. DR PDB; 3HIZ; X-ray; 3.30 A; A=1-1068. DR PDB; 3ZIM; X-ray; 2.85 A; A=107-1046. DR PDB; 4JPS; X-ray; 2.20 A; A=1-1068. DR PDB; 4L1B; X-ray; 2.59 A; A=1-1068. DR PDB; 4L23; X-ray; 2.50 A; A=1-1068. DR PDB; 4L2Y; X-ray; 2.80 A; A=1-1068. DR PDB; 4OVU; X-ray; 2.96 A; A=1-1068. DR PDB; 4OVV; X-ray; 3.50 A; A=1-1068. DR PDB; 4TUU; X-ray; 2.64 A; A=105-1048. DR PDB; 4TV3; X-ray; 2.85 A; A=105-1048. DR PDB; 4WAF; X-ray; 2.39 A; A=2-1068. DR PDB; 4YKN; X-ray; 2.90 A; A=2-1068. DR PDBsum; 2ENQ; -. DR PDBsum; 2RD0; -. DR PDBsum; 3HHM; -. DR PDBsum; 3HIZ; -. DR PDBsum; 3ZIM; -. DR PDBsum; 4JPS; -. DR PDBsum; 4L1B; -. DR PDBsum; 4L23; -. DR PDBsum; 4L2Y; -. DR PDBsum; 4OVU; -. DR PDBsum; 4OVV; -. DR PDBsum; 4TUU; -. DR PDBsum; 4TV3; -. DR PDBsum; 4WAF; -. DR PDBsum; 4YKN; -. DR ProteinModelPortal; P42336; -. DR SMR; P42336; 16-105, 107-1046. DR BioGrid; 111308; 61. DR DIP; DIP-42728N; -. DR IntAct; P42336; 41. DR MINT; MINT-1367228; -. DR STRING; 9606.ENSP00000263967; -. DR BindingDB; P42336; -. DR ChEMBL; CHEMBL2111367; -. DR DrugBank; DB00201; Caffeine. DR GuidetoPHARMACOLOGY; 2153; -. DR PhosphoSite; P42336; -. DR BioMuta; PI3KCA; -. DR DMDM; 126302584; -. DR MaxQB; P42336; -. DR PaxDb; P42336; -. DR PRIDE; P42336; -. DR DNASU; 5290; -. DR Ensembl; ENST00000263967; ENSP00000263967; ENSG00000121879. DR GeneID; 5290; -. DR KEGG; hsa:5290; -. DR UCSC; uc003fjk.3; human. DR CTD; 5290; -. DR GeneCards; PIK3CA; -. DR GeneReviews; PIK3CA; -. DR HGNC; HGNC:8975; PIK3CA. DR HPA; CAB017804; -. DR HPA; HPA009985; -. DR MIM; 114480; phenotype. DR MIM; 114500; phenotype. DR MIM; 114550; phenotype. DR MIM; 167000; phenotype. DR MIM; 171834; gene. DR MIM; 182000; phenotype. DR MIM; 602501; phenotype. DR MIM; 612918; phenotype. DR MIM; 615108; phenotype. DR neXtProt; NX_P42336; -. DR Orphanet; 140944; CLOVE syndrome. DR Orphanet; 201; Cowden syndrome. DR Orphanet; 276280; Hemihyperplasia-multiple lipomatosis syndrome. DR Orphanet; 99802; Hemimegalencephaly. DR Orphanet; 144; Hereditary nonpolyposis colon cancer. DR Orphanet; 295239; Macrodactyly of fingers, unilateral. DR Orphanet; 295243; Macrodactyly of toes, unilateral. DR Orphanet; 60040; Megalencephaly-capillary malformation-polymicrogyria syndrome. DR Orphanet; 314662; Segmental progressive overgrowth syndrome with fibroadipose hyperplasia. DR PharmGKB; PA33308; -. DR eggNOG; KOG0904; Eukaryota. DR eggNOG; COG5032; LUCA. DR GeneTree; ENSGT00760000119110; -. DR HOVERGEN; HBG052721; -. DR InParanoid; P42336; -. DR KO; K00922; -. DR OMA; AFAVRCL; -. DR OrthoDB; EOG70CR65; -. DR PhylomeDB; P42336; -. DR TreeFam; TF102031; -. DR BioCyc; MetaCyc:HS04527-MONOMER; -. DR BRENDA; 2.7.1.137; 2681. DR BRENDA; 2.7.1.153; 2681. DR Reactome; R-HSA-109704; PI3K Cascade. DR Reactome; R-HSA-114604; GPVI-mediated activation cascade. DR Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants. DR Reactome; R-HSA-1250342; PI3K events in ERBB4 signaling. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-1433557; Signaling by SCF-KIT. DR Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane. DR Reactome; R-HSA-180292; GAB1 signalosome. DR Reactome; R-HSA-1839117; Signaling by FGFR1 fusion mutants. DR Reactome; R-HSA-186763; Downstream signal transduction. DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling. DR Reactome; R-HSA-198203; PI3K/AKT activation. DR Reactome; R-HSA-202424; Downstream TCR signaling. DR Reactome; R-HSA-2029485; Role of phospholipids in phagocytosis. DR Reactome; R-HSA-210993; Tie2 Signaling. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-2424491; DAP12 signaling. DR Reactome; R-HSA-2730905; Role of LAT2/NTAL/LAB on calcium mobilization. DR Reactome; R-HSA-373753; Nephrin interactions. DR Reactome; R-HSA-388841; Costimulation by the CD28 family. DR Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling. DR Reactome; R-HSA-392451; G beta:gamma signalling through PI3Kgamma. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR Reactome; R-HSA-416482; G alpha (12/13) signalling events. DR Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway. DR Reactome; R-HSA-512988; Interleukin-3, 5 and GM-CSF signaling. DR Reactome; R-HSA-5637810; Constitutive Signaling by EGFRvIII. DR Reactome; R-HSA-5654689; PI-3K cascade:FGFR1. DR Reactome; R-HSA-5654695; PI-3K cascade:FGFR2. DR Reactome; R-HSA-5654710; PI-3K cascade:FGFR3. DR Reactome; R-HSA-5654720; PI-3K cascade:FGFR4. DR Reactome; R-HSA-5655253; Signaling by FGFR2 in disease. DR Reactome; R-HSA-5655291; Signaling by FGFR4 in disease. DR Reactome; R-HSA-5655302; Signaling by FGFR1 in disease. DR Reactome; R-HSA-5655332; Signaling by FGFR3 in disease. DR Reactome; R-HSA-912526; Interleukin receptor SHC signaling. DR Reactome; R-HSA-912631; Regulation of signaling by CBL. DR SignaLink; P42336; -. DR ChiTaRS; PIK3CA; human. DR EvolutionaryTrace; P42336; -. DR GeneWiki; P110%CE%B1; -. DR GenomeRNAi; 5290; -. DR NextBio; 20442; -. DR PRO; PR:P42336; -. DR Proteomes; UP000005640; Chromosome 3. DR Bgee; P42336; -. DR CleanEx; HS_PIK3CA; -. DR ExpressionAtlas; P42336; baseline and differential. DR Genevisible; P42336; HS. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030027; C:lamellipodium; IEA:Ensembl. DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; ISS:BHF-UCL. DR GO; GO:0005943; C:phosphatidylinositol 3-kinase complex, class IA; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; IDA:UniProtKB. DR GO; GO:0035005; F:1-phosphatidylinositol-4-phosphate 3-kinase activity; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016301; F:kinase activity; TAS:Reactome. DR GO; GO:0035004; F:phosphatidylinositol 3-kinase activity; TAS:UniProtKB. DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; TAS:Reactome. DR GO; GO:0030295; F:protein kinase activator activity; IEA:Ensembl. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW. DR GO; GO:0002250; P:adaptive immune response; IBA:GO_Central. DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0007596; P:blood coagulation; TAS:Reactome. DR GO; GO:0060048; P:cardiac muscle contraction; TAS:UniProtKB. DR GO; GO:0060326; P:cell chemotaxis; IBA:GO_Central. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0043542; P:endothelial cell migration; TAS:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl. DR GO; GO:0044029; P:hypomethylation of CpG island; IEA:Ensembl. DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central. DR GO; GO:0045087; P:innate immune response; IBA:GO_Central. DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome. DR GO; GO:0038028; P:insulin receptor signaling pathway via phosphatidylinositol 3-kinase; TAS:UniProtKB. DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome. DR GO; GO:0001889; P:liver development; IEA:Ensembl. DR GO; GO:0098779; P:mitophagy in response to mitochondrial depolarization; IGI:ParkinsonsUK-UCL. DR GO; GO:2000811; P:negative regulation of anoikis; IMP:UniProtKB. DR GO; GO:2000270; P:negative regulation of fibroblast apoptotic process; IEA:Ensembl. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IBA:GO_Central. DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome. DR GO; GO:0046854; P:phosphatidylinositol phosphorylation; ISS:BHF-UCL. DR GO; GO:0036092; P:phosphatidylinositol-3-phosphate biosynthetic process; IBA:GO_Central. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0006644; P:phospholipid metabolic process; TAS:Reactome. DR GO; GO:0030168; P:platelet activation; TAS:UniProtKB. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IEA:Ensembl. DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central. DR GO; GO:0043457; P:regulation of cellular respiration; IEA:Ensembl. DR GO; GO:2000653; P:regulation of genetic imprinting; IEA:Ensembl. DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome. DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome. DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0001944; P:vasculature development; TAS:UniProtKB. DR Gene3D; 1.10.1070.11; -; 1. DR Gene3D; 1.25.40.70; -; 1. DR Gene3D; 2.60.40.150; -; 1. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000403; PI3/4_kinase_cat_dom. DR InterPro; IPR018936; PI3/4_kinase_CS. DR InterPro; IPR003113; PI3K_adapt-bd_dom. DR InterPro; IPR002420; PI3K_C2_dom. DR InterPro; IPR000341; PI3K_Ras-bd_dom. DR InterPro; IPR015433; PI_Kinase. DR InterPro; IPR001263; PInositide-3_kin_accessory_dom. DR InterPro; IPR029071; Ubiquitin-rel_dom. DR PANTHER; PTHR10048; PTHR10048; 1. DR Pfam; PF00454; PI3_PI4_kinase; 1. DR Pfam; PF00792; PI3K_C2; 1. DR Pfam; PF02192; PI3K_p85B; 1. DR Pfam; PF00794; PI3K_rbd; 1. DR Pfam; PF00613; PI3Ka; 1. DR SMART; SM00239; C2; 1. DR SMART; SM00142; PI3K_C2; 1. DR SMART; SM00143; PI3K_p85B; 1. DR SMART; SM00144; PI3K_rbd; 1. DR SMART; SM00145; PI3Ka; 1. DR SMART; SM00146; PI3Kc; 1. DR SUPFAM; SSF48371; SSF48371; 1. DR SUPFAM; SSF49562; SSF49562; 1. DR SUPFAM; SSF54236; SSF54236; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00915; PI3_4_KINASE_1; 1. DR PROSITE; PS00916; PI3_4_KINASE_2; 1. DR PROSITE; PS50290; PI3_4_KINASE_3; 1. DR PROSITE; PS51544; PI3K_ABD; 1. DR PROSITE; PS51547; PI3K_C2; 1. DR PROSITE; PS51546; PI3K_RBD; 1. DR PROSITE; PS51545; PIK_HELICAL; 1. PE 1: Evidence at protein level; KW 3D-structure; Angiogenesis; ATP-binding; Complete proteome; KW Disease mutation; Kinase; Nucleotide-binding; Polymorphism; KW Proto-oncogene; Reference proteome; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1 1068 Phosphatidylinositol 4,5-bisphosphate 3- FT kinase catalytic subunit alpha isoform. FT /FTId=PRO_0000088785. FT DOMAIN 16 105 PI3K-ABD. {ECO:0000255|PROSITE- FT ProRule:PRU00877}. FT DOMAIN 187 289 PI3K-RBD. {ECO:0000255|PROSITE- FT ProRule:PRU00879}. FT DOMAIN 330 487 C2 PI3K-type. {ECO:0000255|PROSITE- FT ProRule:PRU00880}. FT DOMAIN 517 694 PIK helical. {ECO:0000255|PROSITE- FT ProRule:PRU00878}. FT DOMAIN 797 1068 PI3K/PI4K. {ECO:0000255|PROSITE- FT ProRule:PRU00269}. FT VARIANT 38 38 R -> H (in CRC; likely involved in FT disease pathogenesis; shows an increase FT in lipid kinase activity; may disrupt the FT interaction between the PI3K-ABD domain FT and the N-terminal lobe of PI3K/PI4K FT kinase domain possibly affecting the FT conformation of the kinase domain). FT {ECO:0000269|PubMed:15930273}. FT /FTId=VAR_026166. FT VARIANT 43 43 I -> V (in dbSNP:rs1051399). FT {ECO:0000269|PubMed:7713498}. FT /FTId=VAR_042942. FT VARIANT 81 81 E -> K (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069251. FT VARIANT 88 88 R -> Q (in MCAP; also found in a FT glioblastoma multiforme sample; may FT disrupt the interaction between the PI3K- FT ABD domain and the N-terminal lobe of FT PI3K/PI4K kinase domain possibly FT affecting the conformation of the kinase FT domain). {ECO:0000269|PubMed:15924253, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026167. FT VARIANT 106 106 G -> V (in CRC; likely involved in FT disease pathogenesis; shows an increase FT in lipid kinase activity). FT {ECO:0000269|PubMed:15930273}. FT /FTId=VAR_026168. FT VARIANT 118 118 G -> D (in CWS5). FT {ECO:0000269|PubMed:23246288}. FT /FTId=VAR_069786. FT VARIANT 135 135 E -> K (in CWS5). FT {ECO:0000269|PubMed:23246288}. FT /FTId=VAR_069787. FT VARIANT 218 218 E -> K (in CWS5). FT {ECO:0000269|PubMed:23246288}. FT /FTId=VAR_069788. FT VARIANT 332 332 S -> R (in dbSNP:rs1051407). FT {ECO:0000269|PubMed:7713498}. FT /FTId=VAR_042943. FT VARIANT 343 343 Y -> C (found in a cancer sample; unknown FT pathological significance). FT {ECO:0000269|PubMed:16533766}. FT /FTId=VAR_026169. FT VARIANT 356 356 V -> I (in CWS5). FT {ECO:0000269|PubMed:23246288}. FT /FTId=VAR_069789. FT VARIANT 364 364 G -> R (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069252. FT VARIANT 365 365 E -> K (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069253. FT VARIANT 378 378 C -> Y (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069254. FT VARIANT 382 382 R -> K (in CWS5). FT {ECO:0000269|PubMed:23246288}. FT /FTId=VAR_069790. FT VARIANT 391 391 I -> M (in dbSNP:rs3729680). FT {ECO:0000269|PubMed:16533766}. FT /FTId=VAR_026170. FT VARIANT 420 420 C -> R (in CLOVE and CRC; shows an FT increase in lipid kinase activity; may FT increase the affinity for lipid FT membranes). {ECO:0000269|PubMed:15930273, FT ECO:0000269|PubMed:22658544}. FT /FTId=VAR_026171. FT VARIANT 453 453 E -> Q (in CRC; likely involved in FT disease pathogenesis; shows an increase FT in lipid kinase activity; may disrupt the FT interaction of the C2 PI3K-type domain FT with the iSH2 region of the p85 FT regulatory subunit). FT {ECO:0000269|PubMed:15930273}. FT /FTId=VAR_026172. FT VARIANT 453 453 Missing (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069255. FT VARIANT 542 542 E -> K (in CLOVE, KERSEB, CRC and BC; FT also found in glioblastoma multiforme and FT endometrial carcinoma; shows an increase FT in lipid kinase activity; oncogenic in FT vivo; occurs in the interface between the FT PI3K helical domain and the nSH2 (N- FT terminal SH2) region of the p85 FT regulatory subunit and may reduce the FT inhibitory effect of p85; requires FT interaction with RAS to induce cellular FT transformation). FT {ECO:0000269|PubMed:15289301, FT ECO:0000269|PubMed:15784156, FT ECO:0000269|PubMed:15924253, FT ECO:0000269|PubMed:15930273, FT ECO:0000269|PubMed:15994075, FT ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:16353168, FT ECO:0000269|PubMed:16432179, FT ECO:0000269|PubMed:16533766, FT ECO:0000269|PubMed:17673550, FT ECO:0000269|PubMed:22658544}. FT /FTId=VAR_026173. FT VARIANT 542 542 E -> Q (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026174. FT VARIANT 542 542 E -> V (in BC; unknown pathological FT significance). FT {ECO:0000269|PubMed:16353168}. FT /FTId=VAR_026175. FT VARIANT 545 545 E -> A (in CWS5 and HCC; also found in a FT glioblastoma multiforme sample). FT {ECO:0000269|PubMed:15608678, FT ECO:0000269|PubMed:15924253, FT ECO:0000269|PubMed:23246288}. FT /FTId=VAR_026176. FT VARIANT 545 545 E -> G (in KERSEB; also found in an FT endometrial carcinoma sample). FT {ECO:0000269|PubMed:15520168, FT ECO:0000269|PubMed:15994075, FT ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:17673550}. FT /FTId=VAR_026177. FT VARIANT 545 545 E -> K (in MCAP, KERSEB, CRC and BC; FT shows an increase in lipid kinase FT activity; oncogenic in vivo; occurs in FT the interface between the PI3K helical FT domain and the nSH2 (N-terminal SH2) FT region of the p85 regulatory subunit and FT may reduce the inhibitory effect of p85; FT requires interaction with RAS to induce FT cellular transformation; enhances FT invadopodia-mediated extracellular matrix FT degradation and invasion in breast cancer FT cells). {ECO:0000269|PubMed:15289301, FT ECO:0000269|PubMed:15520168, FT ECO:0000269|PubMed:15712344, FT ECO:0000269|PubMed:15784156, FT ECO:0000269|PubMed:15930273, FT ECO:0000269|PubMed:15994075, FT ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:16353168, FT ECO:0000269|PubMed:16432179, FT ECO:0000269|PubMed:16533766, FT ECO:0000269|PubMed:17673550, FT ECO:0000269|PubMed:21708979, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026178. FT VARIANT 546 546 Q -> E (in BC; unknown pathological FT significance). FT {ECO:0000269|PubMed:15520168}. FT /FTId=VAR_026179. FT VARIANT 546 546 Q -> K (in OC; unknown pathological FT significance). FT {ECO:0000269|PubMed:15520168}. FT /FTId=VAR_026180. FT VARIANT 546 546 Q -> P (found in an anaplastic FT astrocytoma sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:15289301}. FT /FTId=VAR_026181. FT VARIANT 546 546 Q -> R (in BC; unknown pathological FT significance). FT {ECO:0000269|PubMed:16353168}. FT /FTId=VAR_026182. FT VARIANT 726 726 E -> K (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069256. FT VARIANT 914 914 G -> R (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069257. FT VARIANT 1007 1007 G -> R (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026183. FT VARIANT 1021 1021 Y -> C (in MCAP; also found in an FT endometrial carcinoma sample). FT {ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026184. FT VARIANT 1021 1021 Y -> H (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026185. FT VARIANT 1021 1021 Y -> N (found in a glioblastoma FT multiforme sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:15289301}. FT /FTId=VAR_026186. FT VARIANT 1023 1023 R -> Q (in CRC; unknown pathological FT significance). FT {ECO:0000269|PubMed:15994075}. FT /FTId=VAR_026187. FT VARIANT 1025 1025 T -> A (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069258. FT VARIANT 1025 1025 T -> N (found in a glioblastoma FT multiforme sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:15924253}. FT /FTId=VAR_026188. FT VARIANT 1035 1035 A -> V (in MCAP; also found in an FT endometrial carcinoma sample). FT {ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026189. FT VARIANT 1043 1043 M -> I (in MCAP and CRC; also found in an FT endometrial carcinoma sample; shows an FT increase in lipid kinase activity). FT {ECO:0000269|PubMed:15930273, FT ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026190. FT VARIANT 1047 1047 H -> L (in BC; unknown pathological FT significance). FT {ECO:0000269|PubMed:15289301, FT ECO:0000269|PubMed:15520168, FT ECO:0000269|PubMed:15994075, FT ECO:0000269|PubMed:16353168}. FT /FTId=VAR_026191. FT VARIANT 1047 1047 H -> R (in CLOVE, KERSEB, CRC, BC and OC; FT also found in an endometrial carcinoma FT sample; shows an increase in lipid kinase FT activity; oncogenic in vivo; requires FT binding to p85 regulatory subunit to FT induce cellular transformation but not FT interaction with RAS; may mimic the FT conformatitonal change triggered by the FT interaction with RAS; enhances FT invadopodia-mediated extracellular matrix FT degradation and invasion in breast cancer FT cells; increases lipid kinase activity; FT may alter the interaction of the PI3K/ FT PI4K kinase domain with the cell FT membrane). {ECO:0000269|PubMed:15016963, FT ECO:0000269|PubMed:15289301, FT ECO:0000269|PubMed:15520168, FT ECO:0000269|PubMed:15712344, FT ECO:0000269|PubMed:15784156, FT ECO:0000269|PubMed:15930273, FT ECO:0000269|PubMed:15994075, FT ECO:0000269|PubMed:16114017, FT ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:16353168, FT ECO:0000269|PubMed:16432179, FT ECO:0000269|PubMed:16533766, FT ECO:0000269|PubMed:17673550, FT ECO:0000269|PubMed:19805105, FT ECO:0000269|PubMed:21708979, FT ECO:0000269|PubMed:22658544}. FT /FTId=VAR_026192. FT VARIANT 1047 1047 H -> Y (in MCAP; also found in an FT endometrial carcinoma sample). FT {ECO:0000269|PubMed:16322209, FT ECO:0000269|PubMed:22729224}. FT /FTId=VAR_026193. FT VARIANT 1049 1049 G -> S (in MCAP). FT {ECO:0000269|PubMed:22729224}. FT /FTId=VAR_069259. FT VARIANT 1050 1050 G -> D (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026194. FT VARIANT 1052 1052 T -> K (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026195. FT VARIANT 1065 1065 H -> L (found in an endometrial carcinoma FT sample; unknown pathological FT significance). FT {ECO:0000269|PubMed:16322209}. FT /FTId=VAR_026196. FT VARIANT 1065 1065 H -> Y (found in brain tumors; unknown FT pathological significance). FT {ECO:0000269|PubMed:15289301}. FT /FTId=VAR_026197. FT CONFLICT 170 170 N -> H (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 187 187 K -> R (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 286 287 ML -> KM (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 346 346 V -> L (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 723 723 K -> R (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 751 751 F -> L (in Ref. 1; CAA82333). FT {ECO:0000305}. FT CONFLICT 767 767 E -> K (in Ref. 1; CAA82333). FT {ECO:0000305}. FT STRAND 5 10 {ECO:0000244|PDB:4JPS}. FT STRAND 13 15 {ECO:0000244|PDB:4JPS}. FT STRAND 18 25 {ECO:0000244|PDB:4JPS}. FT STRAND 31 37 {ECO:0000244|PDB:4JPS}. FT HELIX 42 52 {ECO:0000244|PDB:4JPS}. FT HELIX 53 55 {ECO:0000244|PDB:4JPS}. FT STRAND 56 58 {ECO:0000244|PDB:2RD0}. FT HELIX 59 61 {ECO:0000244|PDB:4JPS}. FT HELIX 65 67 {ECO:0000244|PDB:4JPS}. FT STRAND 69 74 {ECO:0000244|PDB:4JPS}. FT STRAND 75 77 {ECO:0000244|PDB:4OVU}. FT STRAND 79 82 {ECO:0000244|PDB:4JPS}. FT HELIX 89 91 {ECO:0000244|PDB:4JPS}. FT STRAND 94 102 {ECO:0000244|PDB:4JPS}. FT HELIX 108 121 {ECO:0000244|PDB:4JPS}. FT HELIX 126 130 {ECO:0000244|PDB:4JPS}. FT HELIX 134 142 {ECO:0000244|PDB:4JPS}. FT HELIX 144 155 {ECO:0000244|PDB:4JPS}. FT TURN 156 159 {ECO:0000244|PDB:4JPS}. FT HELIX 160 166 {ECO:0000244|PDB:4JPS}. FT HELIX 179 182 {ECO:0000244|PDB:4JPS}. FT STRAND 185 198 {ECO:0000244|PDB:4JPS}. FT TURN 199 202 {ECO:0000244|PDB:4JPS}. FT STRAND 203 212 {ECO:0000244|PDB:4JPS}. FT HELIX 217 226 {ECO:0000244|PDB:4JPS}. FT TURN 230 232 {ECO:0000244|PDB:3ZIM}. FT HELIX 237 242 {ECO:0000244|PDB:4WAF}. FT TURN 243 245 {ECO:0000244|PDB:4L1B}. FT HELIX 246 248 {ECO:0000244|PDB:4JPS}. FT STRAND 249 254 {ECO:0000244|PDB:4JPS}. FT TURN 255 258 {ECO:0000244|PDB:3HIZ}. FT HELIX 267 269 {ECO:0000244|PDB:4JPS}. FT HELIX 271 279 {ECO:0000244|PDB:4JPS}. FT STRAND 284 289 {ECO:0000244|PDB:4JPS}. FT HELIX 290 294 {ECO:0000244|PDB:4JPS}. FT HELIX 306 309 {ECO:0000244|PDB:4JPS}. FT TURN 320 323 {ECO:0000244|PDB:4OVU}. FT STRAND 324 326 {ECO:0000244|PDB:4WAF}. FT HELIX 327 329 {ECO:0000244|PDB:4JPS}. FT STRAND 332 342 {ECO:0000244|PDB:4JPS}. FT TURN 348 350 {ECO:0000244|PDB:4JPS}. FT STRAND 353 362 {ECO:0000244|PDB:4JPS}. FT STRAND 365 368 {ECO:0000244|PDB:4JPS}. FT STRAND 376 379 {ECO:0000244|PDB:4TUU}. FT STRAND 382 392 {ECO:0000244|PDB:4JPS}. FT HELIX 393 395 {ECO:0000244|PDB:4JPS}. FT STRAND 401 413 {ECO:0000244|PDB:4JPS}. FT STRAND 416 430 {ECO:0000244|PDB:4JPS}. FT STRAND 434 436 {ECO:0000244|PDB:4JPS}. FT STRAND 439 444 {ECO:0000244|PDB:4JPS}. FT STRAND 454 456 {ECO:0000244|PDB:3ZIM}. FT STRAND 458 460 {ECO:0000244|PDB:2RD0}. FT STRAND 468 470 {ECO:0000244|PDB:4JPS}. FT STRAND 472 477 {ECO:0000244|PDB:4JPS}. FT STRAND 481 485 {ECO:0000244|PDB:4WAF}. FT HELIX 489 492 {ECO:0000244|PDB:4JPS}. FT HELIX 495 498 {ECO:0000244|PDB:2RD0}. FT TURN 505 508 {ECO:0000244|PDB:4TUU}. FT STRAND 511 513 {ECO:0000244|PDB:3HHM}. FT HELIX 517 520 {ECO:0000244|PDB:4L23}. FT HELIX 526 536 {ECO:0000244|PDB:4JPS}. FT STRAND 539 541 {ECO:0000244|PDB:4TUU}. FT HELIX 545 553 {ECO:0000244|PDB:4JPS}. FT TURN 554 557 {ECO:0000244|PDB:4JPS}. FT HELIX 558 560 {ECO:0000244|PDB:4JPS}. FT HELIX 562 564 {ECO:0000244|PDB:4JPS}. FT HELIX 565 571 {ECO:0000244|PDB:4JPS}. FT HELIX 577 589 {ECO:0000244|PDB:4JPS}. FT HELIX 595 598 {ECO:0000244|PDB:4JPS}. FT HELIX 599 602 {ECO:0000244|PDB:4JPS}. FT HELIX 609 622 {ECO:0000244|PDB:4JPS}. FT HELIX 625 638 {ECO:0000244|PDB:4JPS}. FT HELIX 639 641 {ECO:0000244|PDB:4JPS}. FT STRAND 643 646 {ECO:0000244|PDB:4JPS}. FT HELIX 648 657 {ECO:0000244|PDB:4JPS}. FT HELIX 661 672 {ECO:0000244|PDB:4JPS}. FT TURN 673 676 {ECO:0000244|PDB:4JPS}. FT TURN 678 680 {ECO:0000244|PDB:4JPS}. FT HELIX 681 694 {ECO:0000244|PDB:4JPS}. FT HELIX 698 720 {ECO:0000244|PDB:4JPS}. FT TURN 721 725 {ECO:0000244|PDB:4JPS}. FT HELIX 728 739 {ECO:0000244|PDB:4JPS}. FT HELIX 742 748 {ECO:0000244|PDB:4JPS}. FT STRAND 749 753 {ECO:0000244|PDB:4JPS}. FT STRAND 756 761 {ECO:0000244|PDB:4JPS}. FT HELIX 766 768 {ECO:0000244|PDB:4JPS}. FT STRAND 774 776 {ECO:0000244|PDB:3HHM}. FT STRAND 779 784 {ECO:0000244|PDB:4JPS}. FT HELIX 790 792 {ECO:0000244|PDB:4JPS}. FT STRAND 795 805 {ECO:0000244|PDB:4JPS}. FT HELIX 808 825 {ECO:0000244|PDB:4JPS}. FT TURN 826 828 {ECO:0000244|PDB:4JPS}. FT STRAND 838 842 {ECO:0000244|PDB:4JPS}. FT STRAND 845 849 {ECO:0000244|PDB:4JPS}. FT STRAND 852 856 {ECO:0000244|PDB:4JPS}. FT HELIX 857 861 {ECO:0000244|PDB:4JPS}. FT TURN 865 867 {ECO:0000244|PDB:3HHM}. FT HELIX 871 873 {ECO:0000244|PDB:2RD0}. FT HELIX 876 884 {ECO:0000244|PDB:4JPS}. FT HELIX 887 889 {ECO:0000244|PDB:4JPS}. FT HELIX 890 911 {ECO:0000244|PDB:4JPS}. FT STRAND 920 924 {ECO:0000244|PDB:4JPS}. FT STRAND 929 931 {ECO:0000244|PDB:4JPS}. FT TURN 938 941 {ECO:0000244|PDB:4YKN}. FT HELIX 942 945 {ECO:0000244|PDB:4JPS}. FT HELIX 958 964 {ECO:0000244|PDB:4JPS}. FT TURN 965 967 {ECO:0000244|PDB:4JPS}. FT STRAND 969 971 {ECO:0000244|PDB:4JPS}. FT STRAND 972 974 {ECO:0000244|PDB:3HHM}. FT HELIX 975 993 {ECO:0000244|PDB:4JPS}. FT HELIX 995 1003 {ECO:0000244|PDB:4JPS}. FT TURN 1004 1007 {ECO:0000244|PDB:4JPS}. FT STRAND 1013 1015 {ECO:0000244|PDB:4TUU}. FT HELIX 1016 1025 {ECO:0000244|PDB:4JPS}. FT TURN 1026 1029 {ECO:0000244|PDB:4JPS}. FT HELIX 1032 1047 {ECO:0000244|PDB:4JPS}. FT STRAND 1053 1055 {ECO:0000244|PDB:3HHM}. FT STRAND 1056 1058 {ECO:0000244|PDB:4JPS}. SQ SEQUENCE 1068 AA; 124284 MW; 041487231A9A1207 CRC64; MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN //