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{{Primary sources|date=June 2016}}{{Infobox_gene}}
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The '''phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha''' (the [[Human Genome Organisation|HUGO]]-approved official symbol = '''PIK3CA'''; HGNC ID, '''HGNC:8975'''), also called p110α protein, is a [[class I PI 3-kinase]] catalytic [[Protein subunit|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 | title = Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit | journal = Cell | volume = 70 | issue = 3 | pages = 419–29 | date = August 1992 | pmid = 1322797 | doi = 10.1016/0092-8674(92)90166-A }}</ref>
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| update_citations = no
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
Its role was uncovered by [[Molecular Pathological Epidemiology|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 | url = | journal = Oncogene | volume =  33| issue = | pages =  2949–2955| doi = 10.1038/onc.2013.244 | pmid=23792451}}</ref>
{{GNF_Protein_box
| image = Pi3k_p110a_pik-93.png
| image_source =  PI3 Kinase 110 alpha bound to the inhibitor PIK-93 (yellow).
| PDB =
| Name = Phosphoinositide-3-kinase, catalytic, alpha polypeptide
| HGNCid = 8975
| Symbol = PIK3CA
| AltSymbols =; MGC142161; MGC142163; PI3K; p110-alpha
| OMIM = 171834
| ECnumber = 
| Homologene = 21249
| MGIid = 1206581
| GeneAtlas_image1 = PBB_GE_PIK3CA_204369_at_tn.png
| Function = {{GNF_GO|id=GO:0004428 |text = inositol or phosphatidylinositol kinase activity}} {{GNF_GO|id=GO:0016303 |text = 1-phosphatidylinositol-3-kinase activity}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0043560 |text = insulin receptor substrate binding}} {{GNF_GO|id=GO:0046934 |text = phosphatidylinositol-4,5-bisphosphate 3-kinase activity}}
| Component = {{GNF_GO|id=GO:0005942 |text = phosphoinositide 3-kinase complex}} {{GNF_GO|id=GO:0030027 |text = lamellipodium}}
| Process = {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0040014 |text = regulation of body size}} {{GNF_GO|id=GO:0043491 |text = protein kinase B signaling cascade}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5290
    | Hs_Ensembl = ENSG00000121879
    | Hs_RefseqProtein = NP_006209
    | Hs_RefseqmRNA = NM_006218
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 180349005
    | Hs_GenLoc_end = 180435189
    | Hs_Uniprot = P42336
    | Mm_EntrezGene = 18706
    | Mm_Ensembl = ENSMUSG00000027665
    | Mm_RefseqmRNA = NM_008839
    | Mm_RefseqProtein = NP_032865
    | Mm_GenLoc_db =   
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 32627755
    | Mm_GenLoc_end = 32654380
    | Mm_Uniprot = Q0VGQ5
  }}
}}


The '''p110α''' protein is a [[class I PI 3-kinase]] catalytic subunit.
== Function ==


The human p110α protein is encoded by the PIK3CA gene. Recent evidence has shown that the PIK3CA gene is mutated in a range of human cancers. Due to the association between p110α and cancer it is believed to be a promising drug target. A number of pharmaceutical companies are currently designing and charactering potential p110α isoform specific inhibitors.
[[Phosphatidylinositol-4,5-bisphosphate 3-kinase]] (also called [[phosphatidylinositol 3-kinase]] (PI3K)) is composed of an 85 kDa regulatory [[Protein subunit|subunit]] and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses [[Adenosine triphosphate|ATP]] to phosphorylate [[phosphatidylinositol]]s (PtdIns), [[Phosphatidylinositol 4-phosphate|PtdIns4P]] and [[phosphatidylinositol 4,5-bisphosphate|PtdIns(4,5)P2]].<ref name="entrez">{{cite web | title = Entrez Gene: PIK3CA | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5290 | accessdate = }}</ref>


==See also==
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 journal | vauthors = Samuels Y, Waldman T | title = Oncogenic mutations of PIK3CA in human cancers | journal = Current Topics in Microbiology and Immunology | volume = 347 | pages = 21–41 | date = 2010-01-01 | pmid = 20535651 | pmc = 3164550 | doi = 10.1007/82_2010_68  | publisher = Springer Berlin Heidelberg | editor-last2 = Vanhaesebroeck | isbn = 9783642148156 | series = Current Topics in Microbiology and Immunology | editor-first = Christian | editor-first3 = Peter K. | editor-first2 = Bart | editor-last3 = Vogt | editor-last = Rommel | name-list-format = vanc }}</ref> It has been found to be [[Oncogene|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 | title = PIK3CA as an oncogene in cervical cancer | journal = Oncogene | volume = 19 | issue = 23 | pages = 2739–44 | date = May 2000 | pmid = 10851074 | doi = 10.1038/sj.onc.1203597 }}</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. 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 | volume = 0 | issue = 0 | pages = 1–13 | date = September 2016 | 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 | title = PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data | journal = Breast Cancer Research | volume = 16 | issue = 1 | pages = 201 | date = January 2014 | pmid = 25192370 | pmc = 4054885 | doi = 10.1186/bcr3605 }}</ref>
 
PIK3CA participates in a complex interaction within the [[tumor microenvironment]] in this phenomenon.<ref>{{cite journal | vauthors = Fuchs CS, Ogino S | title = Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex! | journal = Journal of Clinical Oncology | volume = 31 | issue = 34 | pages = 4358–61 | date = December 2013 | pmid = 24166520 | doi = 10.1200/jco.2013.52.0080 }}</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 | title = High frequency of mutations of the PIK3CA gene in human cancers | journal = Science | volume = 304 | issue = 5670 | pages = 554 | date = April 2004 | pmid = 15016963 | doi = 10.1126/science.1096502 }}</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 | title = Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment | journal = Endocrine-Related Cancer | volume = 8 | issue = 3 | pages = 237–48 | date = September 2001 | pmid = 11566615 | doi = 10.1677/erc.0.0080237 | publisher = [[Bioscientifica]] }}</ref><ref name="pmid17997386">{{cite journal | vauthors = Marone R, Cmiljanovic V, Giese B, Wymann MP | title = Targeting phosphoinositide 3-kinase: moving towards therapy | journal = Biochimica et Biophysica Acta | volume = 1784 | issue = 1 | pages = 159–85 | date = January 2008 | pmid = 17997386 | doi = 10.1016/j.bbapap.2007.10.003 }}</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 | title = Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival | journal = The New England Journal of Medicine | volume = 367 | issue = 17 | pages = 1596–606 | date = October 2012 | pmid = 23094721 | doi = 10.1056/nejmoa1207756 | pmc=3532946}}</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 | 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 = 4297–305 | date = December 2013 | pmid = 24062397 | doi = 10.1200/jco.2013.50.0322 }}</ref>
 
Somatic activating mutations in PIK3CA are found in [[Klippel-Trenaunay syndrome]].<ref>{{cite journal | vauthors = Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M | title = Somatic Activating PIK3CA Mutations Cause Venous Malformation | journal = American Journal of Human Genetics | volume = 97 | issue = 6 | pages = 914–21 | date = December 2015 | pmid = 26637981 | doi = 10.1016/j.ajhg.2015.11.011 }}</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 }}</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 journal | vauthors =  Mirzaa G, Conway R, Graham JM Jr, Dobyns WB| title = PIK3CA-Related Segmental Overgrowth | date = 1993-01-01 | pmid = 23946963 | url = https://www.ncbi.nlm.nih.gov/books/NBK153722/ | editor-first9 = Heather C. | editor-first8 = Chin-To | editor-first7 = Thomas D. | editor-first6 = Lora JH | editor-first5 = Anne | editor-first4 = Stephanie E. | editor-first3 = Holly H. | editor-first2 = Margaret P. | editor-last2 = Adam | editor-last3 = Ardinger | editor-last4 = Wallace | editor-last5 = Amemiya | editor-last6 = Bean | editor-last7 = Bird | editor-last8 = Fong | editor-last9 = Mefford | editor-last = Pagon | publisher = University of Washington, Seattle | editor-first = Roberta A. | name-list-format = vanc }}</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 | volume = 0 | issue = 0 | pages = 1–13 | date = September 2016 | pmid = 27581627 | doi = 10.1080/07391102.2016.1231082 }}</ref><ref>{{cite journal | vauthors = Kumar DT, Doss CG | 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 = 267–97 | date = 2016-01-01 | pmid = 26827608 | doi = 10.1016/bs.apcsb.2015.09.008 }}</ref>
 
== Pharmacology ==
In September 2017 [[Copanlisib]], inhibiting predominantly p110α and p110δ, got [[Food and Drug Administration|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 | title = FDA approves new treatment for adults with relapsed follicular lymphoma | date = September 14, 2017 | publisher = US Food and Drug Administration}}</ref>
 
 
== See also ==
*[[Phosphoinositide 3-kinase]]
*[[Phosphoinositide 3-kinase]]
*[[Phosphoinositide 3-kinase inhibitor]]


==References==
== Interactions ==
{{reflist|2}}


==Further reading==
P110α has been shown to [[Protein-protein interaction|interact]] with:
{{refbegin}}
{{div col|colwidth=20em}}
*Stein RC ( 2001) Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment ''Endocr Relat Cancer'' '''8''':237-248 [http://erc.endocrinology-journals.org/cgi/content/abstract/8/3/237]
* [[ARHGEF1]],<ref name = pmid12754211>{{cite journal | vauthors = Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB | title = Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28793–8 | date = August 2003 | pmid = 12754211 | doi = 10.1074/jbc.M303900200 }}</ref>
* [[Centaurin, alpha 1|ADAP1]],<ref name = pmid12893243>{{cite journal | vauthors = Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A | 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 = 459–65 | date = August 2003 | pmid = 12893243 | doi = 10.1016/s0006-291x(03)01187-2 }}</ref>
* [[DGKZ]],<ref name = pmid12890670>{{cite journal | vauthors = Luo B, Prescott SM, Topham MK | title = Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39542–7 | date = October 2003 | pmid = 12890670 | doi = 10.1074/jbc.M307153200 }}</ref>
* [[HRAS]],<ref name = pmid14724584>{{cite journal | vauthors = Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J | title = The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors | journal = Oncogene | volume = 23 | issue = 2 | pages = 559–68 | date = January 2004 | pmid = 14724584 | doi = 10.1038/sj.onc.1207161 }}</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 | pmid = 10783161 | pmc = 316541 | doi =  }}</ref><ref name = pmid8665852>{{cite journal | vauthors = Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J | title = Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation | journal = The EMBO Journal | volume = 15 | issue = 10 | pages = 2442–51 | date = May 1996 | pmid = 8665852 | pmc = 450176 | doi =  }}</ref> and
* [[Lck]].<ref name = pmid14583609>{{cite journal | vauthors = Sade H, Krishna S, Sarin A | 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 = 2937–44 | date = January 2004 | pmid = 14583609 | doi = 10.1074/jbc.M309924200 }}</ref><ref name = pmid8246987>{{cite journal | vauthors = Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE | 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 = 7708–17 | date = December 1993 | pmid = 8246987 | pmc = 364842 | doi = 10.1128/mcb.13.12.7708 }}</ref>
{{Div col end}}
{{Clear}}


*Foster FM, Traer CJ, Abraham SM, and Fry MJ (2003) The phosphoinositide (PI) 3-kinase family ''J Cell Sci'' '''116''':3037-3040.[http://jcs.biologists.org/cgi/content/full/116/15/3037]
== References ==
{{reflist|33em}}


* Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM., Riggins GJ., Willson JK.V., Markowitz S, Kinzler KW., Vogelstein B, Velculescu VE. (2004) High Frequency of Mutations of the PIK3CA Gene in Human Cancers ''Science'' '''304''': 554 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15016963&query_hl=2&itool=pubmed_DocSum PMID: 15016963][http://www.sciencemag.org/cgi/content/full/304/5670/554 requires free registration]
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Foster FM, Traer CJ, Abraham SM, Fry MJ | title = The phosphoinositide (PI) 3-kinase family | journal = Journal of Cell Science | volume = 116 | issue = Pt 15 | pages = 3037–40 | date = August 2003 | pmid = 12829733 | doi = 10.1242/jcs.00609 }}
* {{cite journal | vauthors = Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY | title = Mutations of PIK3CA in gastric adenocarcinoma | journal = BMC Cancer | volume = 5 | issue =  | pages = 29 | date = March 2005 | pmid = 15784156 | pmc = 1079799 | doi = 10.1186/1471-2407-5-29 }}
* {{cite journal | vauthors = Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM | title = The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations | journal = Science | volume = 318 | issue = 5857 | pages = 1744–8 | date = December 2007 | pmid = 18079394 | doi = 10.1126/science.1150799 }}
* {{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 | pages = 11479 | date = May 2016 | pmid = 27161491 | pmc = 4866047 | doi = 10.1038/ncomms11479 }}
{{refend}}


*Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY. (2005) Mutations of PIK3CA in gastric adenocarcinoma. ''BMC Cancer.'' 2005 '''5''':29. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15784156&dopt=Abstract&holding=f1000  PMID:15784156][http://www.biomedcentral.com/1471-2407/5/29]
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{{DEFAULTSORT:P110}}
[[Category:EC 2.7.1]]
[[Category:EC 2.7.1]]
{{Cell-biology-stub}}
{{transferase-stub}}
{{WikiDoc Sources}}

Revision as of 23:00, 3 October 2017

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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. 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-Trenaunay syndrome.[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. ↑ Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, Thompson A, Totty NF (August 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.
  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: 2949–2955. doi:10.1038/onc.2013.244. PMID 23792451.
  3. ↑ "Entrez Gene: PIK3CA".
  4. ↑ Samuels Y, Waldman T (2010-01-01). Rommel C, Vanhaesebroeck B, Vogt PK, eds. "Oncogenic mutations of PIK3CA in human cancers". Current Topics in Microbiology and Immunology. Current Topics in Microbiology and Immunology. Springer Berlin Heidelberg. 347: 21–41. doi:10.1007/82_2010_68. ISBN 9783642148156. PMC 3164550. PMID 20535651.
  5. ↑ 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.
  6. ↑ Thirumal Kumar D, George Priya Doss C (September 2016). "Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach". Journal of Biomolecular Structure & Dynamics. 0 (0): 1–13. doi:10.1080/07391102.2016.1231082. PMID 27581627.
  7. ↑ Zardavas D, Phillips WA, Loi S (January 2014). "PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data". Breast Cancer Research. 16 (1): 201. doi:10.1186/bcr3605. PMC 4054885. PMID 25192370.
  8. ↑ Fuchs CS, Ogino S (December 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.
  9. ↑ 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 (April 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science. 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963.
  10. ↑ Stein RC (September 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.
  11. ↑ Marone R, Cmiljanovic V, Giese B, Wymann MP (January 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.
  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 (October 2012). "Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival". The New England Journal of Medicine. 367 (17): 1596–606. doi:10.1056/nejmoa1207756. PMC 3532946. PMID 23094721.
  13. ↑ Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, Davidson B, Kerr DJ, Tomlinson IP, Midgley R (December 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.
  14. ↑ Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M (December 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.
  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 (April 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.
  16. ↑ Mirzaa G, Conway R, Graham JM Jr, Dobyns WB (1993-01-01). Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong C, Mefford HC, eds. "PIK3CA-Related Segmental Overgrowth". University of Washington, Seattle. PMID 23946963.
  17. ↑ Thirumal Kumar D, George Priya Doss C (September 2016). "Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach". Journal of Biomolecular Structure & Dynamics. 0 (0): 1–13. doi:10.1080/07391102.2016.1231082. PMID 27581627.
  18. ↑ Kumar DT, Doss CG (2016-01-01). "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. 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.
  20. ↑ Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB (August 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.
  21. ↑ Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A (August 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.
  22. ↑ Luo B, Prescott SM, Topham MK (October 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.
  23. ↑ Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J (January 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.
  24. ↑ Li W, Han M, Guan KL (April 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 316541. PMID 10783161.
  25. ↑ 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 450176. PMID 8665852.
  26. ↑ Sade H, Krishna S, Sarin A (January 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.
  27. ↑ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (December 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 364842. PMID 8246987.

Further reading

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