PIK3CA

S Wikipedije, slobodne enciklopedije
PIK3CA
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

2ENQ, 2RD0, 3HHM, 3HIZ, 3ZIM, 4JPS, 4L1B, 4L23, 4L2Y, 4OVU, 4OVV, 4TUU, 4TV3, 4WAF, 4YKN, 5DXH, 5DXT, 5FI4, 4ZOP

Identifikatori
AliasiPIK3CA
Vanjski ID-jeviOMIM: 171834 MGI: 1206581 HomoloGene: 21249 GeneCards: PIK3CA
EC broj2.7.11.1
Lokacija gena (čovjek)
Hromosom 3 (čovjek)
Hrom.Hromosom 3 (čovjek)[1]
Hromosom 3 (čovjek)
Genomska lokacija za PIK3CA
Genomska lokacija za PIK3CA
Bend3q26.32Početak179,148,114 bp[1]
Kraj179,240,093 bp[1]
Lokacija gena (miš)
Hromosom 3 (miš)
Hrom.Hromosom 3 (miš)[2]
Hromosom 3 (miš)
Genomska lokacija za PIK3CA
Genomska lokacija za PIK3CA
Bend3 A3|3 15.7 cMPočetak32,451,820 bp[2]
Kraj32,522,635 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• transferase activity
• nucleotide binding
• protein kinase activator activity
• 1-phosphatidylinositol-4-phosphate 3-kinase activity
• protein serine/threonine kinase activity
• GO:0001948, GO:0016582 vezivanje za proteine
• insulin receptor substrate binding
• ATP binding
• 1-phosphatidylinositol-3-kinase activity
• phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• kinase activity
• phosphatidylinositol 3-kinase activity
• phosphatidylinositol-3,4-bisphosphate 5-kinase activity
Ćelijska komponenta• phosphatidylinositol 3-kinase complex
• citosol
• phosphatidylinositol 3-kinase complex, class IA
• ćelijska membrana
• lamellipodium
• citoplazma
• membrana
Biološki proces• GO:1904089 negative regulation of neuron apoptotic process
• cardiac muscle contraction
• epidermal growth factor receptor signaling pathway
• protein kinase B signaling
• Fc-gamma receptor signaling pathway involved in phagocytosis
• regulation of multicellular organism growth
• T cell costimulation
• hypomethylation of CpG island
• positive regulation of peptidyl-serine phosphorylation
• platelet activation
• Fc-epsilon receptor signaling pathway
• phosphatidylinositol phosphate biosynthetic process
• vascular endothelial growth factor receptor signaling pathway
• vasculature development
• Angiogeneza
• insulin receptor signaling pathway via phosphatidylinositol 3-kinase
• glucose metabolic process
• Fagocitoza
• energy homeostasis
• negative regulation of fibroblast apoptotic process
• Regulacija ekspresije gena
• liver development
• adipose tissue development
• regulation of cellular respiration
• T cell receptor signaling pathway
• activation of protein kinase activity
• regulation of genetic imprinting
• negative regulation of anoikis
• cellular response to glucose stimulus
• endothelial cell migration
• phosphatidylinositol-mediated signaling
• leukocyte migration
• ERBB2 signaling pathway
• phosphatidylinositol-3-phosphate biosynthetic process
• axon guidance
• negative regulation of macroautophagy
• Fosforilacija
• positive regulation of TOR signaling
• anoikis
• adaptive immune response
• protein phosphorylation
• inflammatory response
• Urođeni imunski sistem
• cell chemotaxis
• G protein-coupled receptor signaling pathway
• positive regulation of protein kinase B signaling
• phosphatidylinositol 3-kinase signaling
• cytokine-mediated signaling pathway
• Ćelijska migracija
• positive regulation of phosphatidylinositol 3-kinase signaling
• phosphatidylinositol biosynthetic process
• regulation of protein phosphorylation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

5290

18706

Ensembl

ENSG00000121879

ENSMUSG00000027665

UniProt

P42336

P42337

RefSeq (mRNK)

NM_006218

NM_008839

RefSeq (bjelančevina)

NP_006209

NP_032865

Lokacija (UCSC)Chr 3: 179.15 – 179.24 MbChr 3: 32.45 – 32.52 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Katalitska podjedinica alfa fosfatidilinozitol-4,5-bisfosfat 3-kinaze (službeni simbol koji je odobrila HUGO = PIK3CA; HGNC ID, HGNC:8975), zvana i protein p110α, jest protein koji je kod ljudi kodiran genom PIK3CA sa hromosoma 3. To je klasa I PI 3-kinaza, katalitskih katalitskih podjedinica. Ljudski p110α protein je kodiran ovim genom.[5]

Njegovu ulogu otkrila je molekulska patološka epidemiologija (MPE).[6]

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 1.068 aminokiselina, а molekulska težina 124.284 Da.[7]

1020304050
MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELF
KEARKYPLHQLLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLK
VIEPVGNREEKILNREIGFAIGMPVCEFDMVKDPEVQDFRRNILNVCKEA
VDLRDLNSPHSRAMYVYPPNVESSPELPKHIYNKLDKGQIIVVIWVIVSP
NNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLKLCVLEYQGKY
ILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD
CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRD
IDKIYVRTGIYHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAA
RLCLSICSVKGRKGAKEEHCPLAWGNINLFDYTDTLVSGKMALNLWPVPH
GLEDLLNPIGVTGSNPNKETPCLELEFDWFSSVVKFPDMSVIEEHANWSV
SREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPLSEITEQEKDF
LWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME
LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLV
RFLLKKALTNQRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLK
HLNRQVEAMEKLINLTDILKQEKKDETQKVQMKFLVEQMRRPDFMDALQG
FLSPLNPAHQLGNLRLEECRIMSSAKRPLWLNWENPDIMSELLFQNNEII
FKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLSIGDCVGLIEV
VRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS
CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRE
RVPFVLTQDFLIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFIN
LFSMMLGSGMPELQSFDDIAYIRKTLALDKTEQEALEYFMKQMNDAHHGG
WTTKMDWIFHTIKQHALN

Funkcija[uredi | uredi izvor]

Fosfatidilinozitol-4,5-bisfosfat 3-kinaza (takođe zvana fosfatidilinozitol 3-kinaza (PI3K)) se sastoji od 85 kDa regulatorne podjedinice i 110 kDa katalitske podjedinice . Protein kodiran ovim genom predstavlja katalitsku podjedinicu koja koristi ATP za fosforilaciju fosfatidilinozitol (PtdIns), [[fosfatidilinozitol 4-fosfat|PtdIns4P]4] i fosfatidilinozitola i PtdIns(4,5)P2.[8]

O učešću p110α u ljudskom karcinomu se pretpostavlja od 1995. Potpora za ovu hipotezu došla je iz genetilkih i funkcionalnih studija, uključujući otkriće uobičajenih aktivirajućih misens mutacija PIK3CA u uobičajenim ljudskim tumorima.[9] Utvrđeno je da je onkogena i da je upletena u rak grlića maternice.[10] Mutacije PIK3CA prisutne su u više od jedne trećine karcinoma dojke, sa obogaćenjem lumenskih i 2-pozitivnih podtipova receptora epidermnog faktora rasta (HER2+). Tri pozicije mutacije žarišnih tačaka (GLU542, GLU545 i HIS1047) su do danas naširoko prijavljivane.[11] Dok značajni pretklinički podaci pokazuju povezanost sa snažnom aktivacijom puta i rezistencijom na uobičajene terapije, klinički podaci ne ukazuju da su takve mutacije povezane s visokim razinama aktivacije puta ili s lošom prognozom. Nije poznato da li mutacija predviđa povećanu osjetljivost na agense koji ciljaju P3K put.[12]

PIK3CA učestvuje u složenoj interakciji unutar tumorskog mikrookruženja u ovom fenomenu.[13]

Klinički značaj[uredi | uredi izvor]

Zbog povezanosti između p110α i raka,[14] to može biti odgovarajuća meta lijeka. Farmaceutske kompanije dizajniraju i karakteriziraju potencijalne inhibitore specifične za izoformu p110α.[15][16]

Prisustvo [a] PIK3CA mutacije može predvidjeti odgovor na terapiju aspirinom za kolorektumski karcinom.[17][18]

Somatske aktivirajuće mutacije u PIK3CA nalaze se u poremećajima zvanim Klippel-Trenaunayev sindrom i venska malformacija.[19][20]

PIK3CA vezani segmentni rast uključuje poremećaje mozga kao što su makrocefalija-kapilarna malformacija (MCAP) i hemimegalencefalija. Također je povezan s kongenitalnim, lipomatoznim prekomjernim rastom vaskularnih malformacija, epidermnim nevusima i skeletnim/spinalnim anomalijama (CLOVES sindrom) i fibroadipoznom hiperplazijom (FH). Stanja su uzrokovana heterozigotnim (obično somatskim mozaičnim) mutacijama.[21]

Inhibicija[uredi | uredi izvor]

Sve PI 3-kinaze inhibiraju lijekovi wortmannin i LY294002, ali wortmannin pokazuje bolju efikasnost od LY294002 na pozicijama žarišta mutacije.[11][22]

Farmakologija[uredi | uredi izvor]

U septembru 2017. Copanlisib, koji inhibira pretežno p110α i p110δ, dobio je FDA odobrenje za liječenje odraslih pacijenata s relapsom folikulskog limfoma (FL) koji su primili najmanje dva prethodne sistemske terapije.[23]

Interakcije[uredi | uredi izvor]

Pokazalo se da P110α u interakciji sa:

Također pogledajte[uredi | uredi izvor]

Reference[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000121879 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027665 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT (2013). "Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology". Oncogene. 33 (23): 2949–2955. doi:10.1038/onc.2013.244. PMC 3818472. PMID 23792451.
  7. ^ "UniProt, P42336" (jezik: engleski). Pristupljeno 9. 11. 2021.
  8. ^ "Entrez Gene: PIK3CA".
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  11. ^ a b Thirumal Kumar D, George Priya Doss C (septembar 2016). "Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach". Journal of Biomolecular Structure & Dynamics. 35 (12): 2745–2757. doi:10.1080/07391102.2016.1231082. PMID 27581627.
  12. ^ Zardavas D, Phillips WA, Loi S (januar 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.
  13. ^ Fuchs CS, Ogino S (decembar 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.
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  15. ^ Stein RC (septembar 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.
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  19. ^ Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M (decembar 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. PMC 4678782. PMID 26637981.
  20. ^ 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. PMC 4498659. PMID 25681199.
  21. ^ Mirzaa G, Conway R, Graham JM Jr, Dobyns WB (1. 1. 1993). Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong C, Mefford HC (ured.). "PIK3CA-Related Segmental Overgrowth". University of Washington, Seattle. PMID 23946963. journal zahtijeva |journal= (pomoć)
  22. ^ Kumar DT, Doss CG (1. 1. 2016). "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.
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  27. ^ Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J (januar 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.
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  29. ^ Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J (maj 1996). "Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation". The EMBO Journal. 15 (10): 2442–51. doi:10.1002/j.1460-2075.1996.tb00602.x. PMC 450176. PMID 8665852.
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Dopunska literatura[uredi | uredi izvor]

Vanjski linkovi[uredi | uredi izvor]

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