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]

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 aktivnost sa transferazom
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
Ensembl
UniProt
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

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

Aminokiselinska sekvenca

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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

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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

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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

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

Farmakologija

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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

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Pokazalo se da P110α u interakciji sa:

Također pogledajte

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Reference

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  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.
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  7. ^ "UniProt, P42336" (jezik: engleski). Pristupljeno 9. 11. 2021.
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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.
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  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

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Vanjski linkovi

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