Wikipedia

RAC1

(Preusmjereno sa P21-Rac1)

Rac1, poznat i kao Ras-srodni C3 supstrat botulinum toksina 1, je protein koji se nalazi u ljudskim ćelijama. Kodiran je genom RAC1.[5][6] Ovaj gen može proizvesti razne alternativna prerade verzija proteina Rac1, za koje se čini da imaju različite funkcije.[7]

RAC1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1E96, 1FOE, 1G4U, 1HE1, 1HH4, 1I4D, 1I4L, 1I4T, 1MH1, 1RYF, 1RYH, 2FJU, 2H7V, 2NZ8, 2P2L, 2RMK, 2VRW, 2WKP, 2WKQ, 2WKR, 2YIN, 3B13, 3BJI, 3RYT, 3SBD, 3SBE, 3SU8, 3SUA, 3TH5, 4GZL, 4GZM, 4YON, 5FI0

Identifikatori
AliasiRAC1
Vanjski ID-jeviOMIM: 602048 MGI: 97845 HomoloGene: 69035 GeneCards: RAC1
Lokacija gena (čovjek)
Hromosom 7 (čovjek)
Hrom.Hromosom 7 (čovjek)[1]
Hromosom 7 (čovjek)
Genomska lokacija za RAC1
Genomska lokacija za RAC1
Bend7p22.1Početak6,374,527 bp[1]
Kraj6,403,967 bp[1]
Lokacija gena (miš)
Hromosom 5 (miš)
Hrom.Hromosom 5 (miš)[2]
Hromosom 5 (miš)
Genomska lokacija za RAC1
Genomska lokacija za RAC1
Bend5 G2|5 82.22 cMPočetak143,489,389 bp[2]
Kraj143,513,791 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• histone deacetylase binding
• Rho GDP-dissociation inhibitor binding
• GTP-dependent protein binding
• GO:0006184 GTPase activity
• vezivanje enzima
• GO:0001948, GO:0016582 vezivanje za proteine
• thioesterase binding
• protein kinase binding
• nucleotide binding
• GTP binding
• protein serine/threonine kinase activity
• GO:0032403 protein-containing complex binding
• phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• ATPase binding
Ćelijska komponenta• citoplazma
• citosol
• membrana
• focal adhesion
• Melanosom
• ruffle membrane
• trans-Golđijeva mreža
• jedro
• projekcija ćelije
• extrinsic component of plasma membrane
• Egzosom
• lamellipodium
• early endosome membrane
• ćelijska membrana
• Mikronit
• cytoplasmic ribonucleoprotein granule
• endoplasmic reticulum membrane
• Golđijeva membrana
• phagocytic cup
• GO:0016023 citoplazmatska vezikula
• GO:0005578 Vanćelijski matriks
• secretory granule membrane
• dendritična kičma
• recycling endosome membrane
• postsynapse
• glutamatergic synapse
• ficolin-1-rich granule membrane
Biološki proces• positive regulation of Rho protein signal transduction
• regulation of respiratory burst
• non-canonical Wnt signaling pathway
• positive regulation of protein phosphorylation
• positive regulation of actin filament polymerization
• regulation of neuron maturation
• negative regulation of receptor-mediated endocytosis
• platelet activation
• Fc-epsilon receptor signaling pathway
• cellular response to mechanical stimulus
• phagocytosis, engulfment
• vascular endothelial growth factor receptor signaling pathway
• substrate adhesion-dependent cell spreading
• Ćelijska proliferacija
• ruffle assembly
• lamellipodium assembly
• dopaminergic neuron differentiation
• cell-cell junction organization
• Fc-gamma receptor signaling pathway involved in phagocytosis
• ruffle organization
• actin filament organization
• cell motility
• anatomical structure morphogenesis
• bone resorption
• response to wounding
• protein localization to plasma membrane
• inflammatory response
• regulation of small GTPase mediated signal transduction
• positive regulation of cell-substrate adhesion
• G protein-coupled receptor signaling pathway
• neuron projection morphogenesis
• epithelial cell morphogenesis
• dendrite morphogenesis
• regulation of hydrogen peroxide metabolic process
• engulfment of apoptotic cell
• dendrite development
• auditory receptor cell morphogenesis
• hyperosmotic response
• cerebral cortex GABAergic interneuron development
• Hemotaksija
• positive regulation of DNA replication
• actin filament polymerization
• Ćelijska adhezija
• negative regulation of interleukin-23 production
• homeostasis of number of cells within a tissue
• cell-matrix adhesion
• localization within membrane
• actin cytoskeleton organization
• regulation of cell size
• anatomical structure arrangement
• GO:0007243 intracellular signal transduction
• regulation of cell migration
• Endocitoza
• ephrin receptor signaling pathway
• T cell costimulation
• Koagulacija (krv)
• GO:0019049, GO:0030683 mitigation of host defenses by virus
• synaptic transmission, GABAergic
• mast cell chemotaxis
• positive regulation of phosphatidylinositol 3-kinase activity
• positive regulation of substrate adhesion-dependent cell spreading
• embryonic olfactory bulb interneuron precursor migration
• cytoskeleton organization
• cochlea morphogenesis
• positive regulation of neutrophil chemotaxis
• positive regulation of apoptotic process
• regulation of cell morphogenesis
• positive regulation of focal adhesion assembly
• regulation of fibroblast migration
• positive regulation of lamellipodium assembly
• cerebral cortex radially oriented cell migration
• Ćelijska migracija
• semaphorin-plexin signaling pathway
• positive regulation of stress fiber assembly
• axon guidance
• small GTPase mediated signal transduction
• GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
• Wnt signaling pathway, planar cell polarity pathway
• midbrain dopaminergic neuron differentiation
• neuron migration
• protein phosphorylation
• Rho protein signal transduction
• regulation of lamellipodium assembly
• Rac protein signal transduction
• cell projection assembly
• positive regulation of microtubule polymerization
• neutrophil degranulation
• regulation of nitric oxide biosynthetic process
• phosphatidylinositol phosphate biosynthetic process
• hepatocyte growth factor receptor signaling pathway
• regulation of stress fiber assembly
• positive regulation of protein kinase B signaling
• motor neuron axon guidance
• regulation of neutrophil migration
• positive regulation of insulin secretion involved in cellular response to glucose stimulus
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

5879

19353

Ensembl

ENSG00000136238

ENSMUSG00000001847

UniProt

P63000

P63001

RefSeq (mRNK)

NM_198829
NM_006908
NM_018890

NM_009007
NM_001347530

RefSeq (bjelančevina)

NP_008839
NP_061485

NP_001334459
NP_033033

Lokacija (UCSC)Chr 7: 6.37 – 6.4 MbChr 5: 143.49 – 143.51 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Funkcija

uredi

Rac1 je mal (~ 21 kDa) signalizirajući G protein (tačnije GTPaza) i član je potporodice Rac porodice porodice Rho GTPaza. Članovi ove superporodice reguliraju raznolik niz ćelijskih događaja, uključujući kontrolu GLUT4,[8][9] translokaciju do unosa glukoze, rast ćelija, reorganizaciju citoskeleta, antimikrobnu citotoksičnost,[10] i aktivaciju protein kinaza.[11]

Rac1 je plejotropni regulator mnogih ćelijskih procesa, uključujući ćelijski ciklus, adheziju ćelijskih ćelija, pokretljivost (kroz aktinsku mrežu) i epitelnu diferencijaciju (predloženo da je neophodan za održavanje epidermnih matičnih ćelija).

Uloga u kanceru

uredi

Zajedno s drugom potporodicama, Rac i Rho proteina, imaj važnu regulatornu ulogu, posebno u pokretljivosti i rastu ćelija. Rac1 ima sveprisutnu tkivnu ekspresiju i podstiče pokretljivost ćelija stvaranjem lamelipodija.[12] Da bi ćlije raka mogle rasti i napadati lokalna i udaljena tkiva, deregulacija pokretljivosti ćelija jedan je od glavnih događaja u invaziji i [metastaza|[metastaziranju]] ćelija karcinoma.[13] Prekomjerna ekspresija konstitucijski aktivnog Rac1 V12 kod miševa uzrokovala je tumor koji se fenotipski ne razlikuje od ljudsog Kaposijevog sarkoma.[14] Pokazalo se da aktivacijske ili dobitne funkcije mutacije Rac1 imaju aktivnu ulogu u promociji mezenhimskog tipa kretanja ćelija, potpomognutog proteinskim kompleksima NEDD9 i DOCK3.[15] Takva abnormalna pokretljivost ćelija može rezultirati tranzicijom epitelnog mezenhima (EMT) – pokretačkim mehanizmom za metastaziranje tumora, kao i relapse tumora rezistentnog na lijekove.[16][17]

Uloga u transportu glukoze

uredi

Rac1 se ispoljava u značajnim količinama u tkivima osjetljivim na insulin, kau što su masno tkivo i skeletni mišići. Ovdje Rac1 regulira translokaciju prijenosnika glukoze GLUT4 iz unutarćelijskih odjeljaka u plazmamembranu.[9][18][19] U odgovoru na insulin, ovo omogućava ulazak glukoze u krv u ćeliji, radi smanjenja glukoze u krvi. U uvjetima gojaznosti i dijabetesa tipa 2, signalizacija Rac1 u skeletnim mišićima je disfunkcionalna, što sugerira da Rac1 doprinosi napredovanju bolesti.

Protein Rac1 je također neophodan za unos glukoze u skeletne mišiće aktivirane vježbanjem[8][20] i istezanjem.[21]

Klinički značaj

uredi

Aktivirajuće mutacije u Rac1 nedavno su otkrivene u velikim genomskim studijama koje uključuju melanom[22][23][24] i plućni karcinom malih ćelija.[25] Kao rezultat toga, Rac1 se smatra terapijskom metom za mnoge od ovih bolesti.[26]

Nekoliko nedavnih studija također je koristilo ciljanu terapiju za suzbijanje rasta tumora, farmakoinhibicijom aktivnosti Rac1 u metastatskom melanomu i karcinomu jetre, kao i u ljudskom [[Rak dojke|karcinomu dojke.[27][28][29]

Naprimjer, inhibicija puta ovisnog o Rac1 rezultirala je preokretom fenotipa tumorskih ćelija, što sugerira Rac1 kao prediktivni marker i terapijski cilj za rak dojke otporan na trastuzumab. Međutim, s obzirom na ulogu Rac1 u transportu glukoze , lijekovi koji inhibiraju Rac1 mogli bi biti štetni za homeostazu glukoze.

Dominantno negativan ili konstitutivno aktivno, klicne linije mutacije RAC1 uzrokuju različite fenotipove, koji su grupirani kao mentalna retardacija Tip 48.[30] Većina mutacija uzrokuje mikrocefaliju, dok neke specifične promjene rezultiraju makrocefalijom.

Interakcije

uredi

Pokazalo se da RAC1 ima interakcije sa:

Reference

uredi
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136238 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001847 - 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. ^ Zhou C, Licciulli S, Avila JL, Cho M, Troutman S, Jiang P, Kossenkov AV, Showe LC, Liu Q, Vachani A, Albelda SM, Kissil JL (Feb 2013). "The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis". Oncogene. 32 (7): 903–9. doi:10.1038/onc.2012.99. PMC 3384754. PMID 22430205.
  8. ^ a b Sylow, Lykke; Nielsen, Ida L.; Kleinert, Maximilian; Møller, Lisbeth L. V.; Ploug, Thorkil; Schjerling, Peter; Bilan, Philip J.; Klip, Amira; Jensen, Thomas E. (9. 4. 2016). "Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice". The Journal of Physiology. 594 (17): 4997–5008. doi:10.1113/JP272039. ISSN 1469-7793. PMC 5009787. PMID 27061726.
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