Receptor 2 fibroblasttnog faktora rasta (FGFR2) znan i kao CD332 (klaster diferencijacije 332) je protein koji je kod ljudi kodiran genom FGFR2 sa hromosoma 10.[5][6] FGFR2 je receptor za fibroblastni faktor rasta.

FGFR2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1DJS, 1E0O, 1EV2, 1GJO, 1II4, 1IIL, 1NUN, 1OEC, 1WVZ, 2FDB, 2PSQ, 2PVF, 2PVY, 2PWL, 2PY3, 2PZ5, 2PZP, 2PZR, 2Q0B, 3B2T, 3CAF, 3CLY, 3CU1, 3DAR, 3EUU, 3OJ2, 3OJM, 3RI1, 4J95, 4J96, 4J97, 4J98, 4J99, 4J23, 4WV1

Identifikatori
AliasiFGFR2
Vanjski ID-jeviOMIM: 176943 MGI: 95523 HomoloGene: 22566 GeneCards: FGFR2
Lokacija gena (čovjek)
Hromosom 10 (čovjek)
Hrom.Hromosom 10 (čovjek)[1]
Hromosom 10 (čovjek)
Genomska lokacija za FGFR2
Genomska lokacija za FGFR2
Bend10q26.13Početak121,478,332 bp[1]
Kraj121,598,458 bp[1]
Lokacija gena (miš)
Hromosom 7 (miš)
Hrom.Hromosom 7 (miš)[2]
Hromosom 7 (miš)
Genomska lokacija za FGFR2
Genomska lokacija za FGFR2
Bend7|7 F3Početak129,764,181 bp[2]
Kraj132,725,079 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija heparin binding
kinase activity
transmembrane receptor protein tyrosine kinase activity
fibroblast growth factor binding
ATP binding
protein kinase activity
fibroblast growth factor-activated receptor activity
transferase activity
protein homodimerization activity
GO:0001948, GO:0016582 protein binding
nucleotide binding
protein tyrosine kinase activity
1-phosphatidylinositol-3-kinase activity
phosphatidylinositol-4,5-bisphosphate 3-kinase activity
identical protein binding
Receptorska tirozin-kinaza
transmembrane signaling receptor activity
Ćelijska komponenta citoplazma
membrana
extracellular region
Jedro
cell surface
integral component of membrane
Golđijev aparat
intracellular membrane-bounded organelle
GO:0005578 Vanćelijski matriks
Ćelijska membrana
Nukleoplazma
cell cortex
integral component of plasma membrane
excitatory synapse
GO:0016023 citoplazmatska vezikula
receptor complex
collagen-containing extracellular matrix
Biološki proces fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development
ureteric bud development
organ growth
limb bud formation
embryonic pattern specification
bud elongation involved in lung branching
positive regulation of canonical Wnt signaling pathway
membranous septum morphogenesis
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow
embryonic organ morphogenesis
post-embryonic development
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development
branching morphogenesis of a nerve
reproductive structure development
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell
ventricular cardiac muscle tissue morphogenesis
protein phosphorylation
positive regulation of cardiac muscle cell proliferation
mesenchymal cell differentiation
positive regulation of mesenchymal cell proliferation
regulation of osteoblast differentiation
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis
Angiogeneza
prostate gland morphogenesis
positive regulation of ERK1 and ERK2 cascade
orbitofrontal cortex development
negative regulation of epithelial cell proliferation
animal organ morphogenesis
embryonic digestive tract morphogenesis
hair follicle morphogenesis
morphogenesis of embryonic epithelium
branch elongation involved in salivary gland morphogenesis
GO:0097285 Apoptoza
branching involved in salivary gland morphogenesis
cell fate commitment
lung development
embryonic organ development
fibroblast growth factor receptor signaling pathway involved in hemopoiesis
in utero embryonic development
lateral sprouting from an epithelium
positive regulation of Wnt signaling pathway
gland morphogenesis
positive regulation of cell cycle
branching involved in labyrinthine layer morphogenesis
branching involved in prostate gland morphogenesis
regulation of ERK1 and ERK2 cascade
protein autophosphorylation
mammary gland bud formation
pyramidal neuron development
lacrimal gland development
positive regulation of MAPK cascade
regulation of smooth muscle cell differentiation
regulation of cell fate commitment
bone mineralization
regulation of branching involved in prostate gland morphogenesis
positive regulation of epithelial cell proliferation involved in lung morphogenesis
epithelial cell differentiation
Fosforilacija
multicellular organism growth
positive regulation of epithelial cell proliferation
ventricular zone neuroblast division
epidermis morphogenesis
skeletal system morphogenesis
regulation of morphogenesis of a branching structure
GO:1901227 negative regulation of transcription by RNA polymerase II
outflow tract septum morphogenesis
odontogenesis
epithelial to mesenchymal transition
lung alveolus development
lung lobe morphogenesis
midbrain development
positive regulation of smooth muscle cell proliferation
fibroblast growth factor receptor signaling pathway involved in mammary gland specification
mesenchymal cell proliferation involved in lung development
prostate epithelial cord elongation
mesenchymal cell differentiation involved in lung development
axonogenesis
regulation of multicellular organism growth
otic vesicle formation
epithelial cell proliferation involved in salivary gland morphogenesis
cell-cell signaling
regulation of fibroblast growth factor receptor signaling pathway
bone morphogenesis
MAPK cascade
regulation of osteoblast proliferation
positive regulation of phospholipase activity
fibroblast growth factor receptor signaling pathway
regulation of smoothened signaling pathway
inner ear morphogenesis
positive regulation of cell population proliferation
mesodermal cell differentiation
peptidyl-tyrosine phosphorylation
digestive tract development
lung-associated mesenchyme development
bone development
positive regulation of cell division
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
phosphatidylinositol phosphate biosynthetic process
phosphatidylinositol-3-phosphate biosynthetic process
endochondral bone growth
response to lipopolysaccharide
Zarastanje rana
cellular response to fibroblast growth factor stimulus
response to ethanol
cellular response to retinoic acid
cellular response to transforming growth factor beta stimulus
embryonic cranial skeleton morphogenesis
positive regulation of protein kinase B signaling
negative regulation of signal transduction
Ćelijska diferencijacija
negative regulation of apoptotic process
transmembrane receptor protein tyrosine kinase signaling pathway
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_000141
NM_001144913
NM_001144914
NM_001144915
NM_001144916

NM_001144917
NM_001144918
NM_001144919
NM_022970
NM_022971
NM_022972
NM_022973
NM_022974
NM_022975
NM_022976
NM_023028
NM_023029
NM_023030
NM_001320654
NM_001320658
NM_023031

NM_010207
NM_201601
NM_001347638

RefSeq (bjelančevina)
NP_000132
NP_001138385
NP_001138386
NP_001138387
NP_001138388

NP_001138389
NP_001138390
NP_001138391
NP_001307583
NP_001307587
NP_075259
NP_075418

NP_001334567
NP_034337
NP_963895

Lokacija (UCSC)Chr 10: 121.48 – 121.6 MbChr 7: 129.76 – 132.73 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Protein kodiran ovim genom član je porodice receptori faktora rasta fibroblasta, gdje je aminokiselinska sekvenca visoko konzervirana između članova i tokom evolucije.[7] Članovi porodice FGFR međusobno se razlikuju po afinitetima prema ligandima i tkivnoj raspodjeli. Reprezentativni protein pune dužine sastoji se od vanćelijske regije, sastavljene od tri imunoglobulinska domena, jednog hidrofobnog segmenta koji pokriva membranu i domena citoplazmatske tirozin-kinaze. Vanćelijski dio proteina stupa u interakciju s faktorima rasta fibroblasta, pokrećući kaskadu nizvodnih signala, što na kraju utiče na mitogenezu i diferencijaciju. Ovaj član porodice je receptor visokog afiniteta za kiseli, bazni i/ili keratinocitni faktor rasta, ovisno o izoformama.

Aminokiselinska sekvenca uredi

Dužina polipeptidnog lanca je 821 aminokiselina, а molekulska težina 92.025 Da.[8]

1020304050
MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVY
VAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPR
DSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNN
KRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQ
EHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVE
RSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSK
YGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGI
SFHSAWLTVLPAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVILCRM
KNTTKKPDFSSQPAVHKLTKRIPLRRQVTVSAESSSSMNSNTPLVRITTR
LSSTADTPMLAGVSEYELPEDPKWEFPRDKLTLGKPLGEGCFGQVVMAEA
VGIDKDKPKEAVTVAVKMLKDDATEKDLSDLVSEMEMMKMIGKHKNIINL
LGACTQDGPLYVIVEYASKGNLREYLRARRPPGMEYSYDINRVPEEQMTF
KDLVSCTYQLARGMEYLASQKCIHRDLAARNVLVTENNVMKIADFGLARD
INNIDYYKKTTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLMWEIFTLG
GSPYPGIPVEELFKLLKEGHRMDKPANCTNELYMMMRDCWHAVPSQRPTF
KQLVEDLDRILTLTTNEEYLDLSQPLEQYSPSYPDTRSSCSSGDDSVFSP
DPMPYEPCLPQYPHINGSVKT

Funkcija uredi

FGFR2 ima važnu ulogu u razvoju embriona i obnavljanju tkiva, posebno kostiju i krvnih žila. Kao i ostali članovi porodice receptora faktora rasta fibroblasta, i ovi receptori signaliziraju vezanjem na njihovu ligandsku i dimernu izolaciju (uparivanje receptora), što uzrokuje da domeni tirozin-kinaze iniciraju kaskadu unutarćelijskih signala. Na molekulnom nivou, ovi signali posreduju diobu ćelija, rast i diferencijaciju.

Izoforme uredi

FGFR2 ima dvije prirodne izoforme, FGFR2IIIb i FGFR2IIIc, nastale preradom trećeg domena sličnog imunoglobulinu. FGFR2IIIb se uglavnom nalazi u tkivima izvedenim iz ektoderma i endotelnim organima, tj. koži i unutrašnjim organima.[9] FGFR2IIIc se nalazi u mezenhimu, koji uključuje kraniofacijalnu kost, pa su iz tog razloga mutacije ovog gena i izoforme povezane s kraniosinostozom.

Interakcije uredi

Pokazalo se da receptor 2 za faktor rasta fibroblasta stupa u interakciju sa FGF1.[10][11][12]

prerađene izoforme, međutim, razlikuju se u vezivanju:[13]

These differences in binding are not surprising, since FGF ligand is known to bind to the second and third immunoglobulin domain of the receptor.

Ove razlike u vezivanju ne iznenađuju, budući da je poznato da se FGF ligand veže za drugu i treću domenu imunoglobulina receptora.

Klinički značaj uredi

Mutacije (promjene) povezane su s brojnim medicinskim stanjima koja uključuju abnormalni razvoj kostiju (npr. Sindromi kraniosinostoze) i rak.

Sindromi kraniosinostoze uredi

Rak uredi

  • Rak dojke, mutacija ili jednonukleotidni polimorfizam (SNP) u intronu 2 FGFR2 gena povezan je s većim rizikom od raka dojke; međutim, rizik se samo blago povećava sa oko 10% doživotnog rizika od raka dojke kod prosječne žene u industrijski razvijenom svijetu, na 12-14% rizika kod nositeljki SNP-a.[15]

Misens mutacije FGFR2 nađene su u raku endometrija i melanomima.[16]

Kao cilj lijekova uredi

AZD4547 je inhibitor tirozin-kinaze koji cilja FGFR1-3. Pokazao je rane dokaze o efikasnosti kod pacijenata sa rakom želuca sa visokim nivoom pojačanja FGFR2 (Cancer Discovery 2016). FPA144 je monoklonsko antitijelo koje se veže za FGFR2b (oblik FGFR2) i sprječava vezivanje određenih FGF-a. U 2014. godini započelo je kliničko ispitivanje liječenja tumora želuca koji prekomjerno izražavaju FGFR2b.[17] Drugi pristup ciljanja FGFR2 je upotreba alosternih inhibitora. Alofanib je novi prvi u klasi alosternih inhibitora FGFR2 male molekule. Veže se na vanćelijsko područje FGFR2 i ima inhibitorni učinak na fosforilaciju induciranu FGF2. Glavne prednosti alosternih inhibitora su visoka selektivnost i niska toksičnost (Tsimafeyeu et al., ESMO Asia 2016]. Protokol kliničke studije faze Ib odabran je za ECCO-AACR-EORTC-ESMO radionicu o metodama u kliničkom istraživanju raka, poznatiju kao 'Flimsova radionica', a klinička studija sigurnosti i preliminarne učinkovitosti alofaniba bit će pokrenuta početkom 2017.

Mutacije uredi

Mutacije FGFR2 povezane su sa kraniosinostoznim sindromima, koji su malformacije lobanje uzrokovane preranom fuzijom lobanjskih šavova i drugim obilježjima bolesti prema samoj mutaciji. Analiza hromosomskih anomalija kod pacijenata dovela je do identifikacije i potvrde FGFR2 kao uzroka rascjepa usne i/ili nepca.[18] Na molekuskom nivou, mutacije koje utiču na FGFR2IIIc povezane su sa značajnim promjenama u osteoblastmoj proliferaciji i diferencijaciji.[19] Smatra se da je promjena signalizacije FGFR2 u osnovi sindroma kraniosinostoze. Do danas postoje dva mehanizma promijenjene signalizacije FGFR2. Prvi je povezan s konstitutivnom aktivacijom FGFR-a, gdje receptor FGFR2 uvijek signalizira, bez obzira na količinu FGF-liganda.[20] Ovaj mehanizam se nalazi kod pacijenata sa Crouzonovim i Pfeifferovim sindromom. Drugi, koji je povezan s Apertovim sindromom, je gubitak specifičnosti izoforme FGFR2, što rezultira vezanjem receptora za FGF-ove za koje se normalno ne veže.[21]

Također pogledajte uredi

Reference uredi

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000066468 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030849 - 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. ^ Houssaint E, Blanquet PR, Champion-Arnaud P, Gesnel MC, Torriglia A, Courtois Y, Breathnach R (Oct 1990). "Related fibroblast growth factor receptor genes exist in the human genome". Proceedings of the National Academy of Sciences of the United States of America. 87 (20): 8180–4. Bibcode:1990PNAS...87.8180H. doi:10.1073/pnas.87.20.8180. PMC 54916. PMID 2172978.
  6. ^ Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J (Sep 1990). "Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors". The EMBO Journal. 9 (9): 2685–92. doi:10.1002/j.1460-2075.1990.tb07454.x. PMC 551973. PMID 1697263.
  7. ^ Db=gene&Cmd=ShowDetailView&TermToSearch=2263 "Entrez Gene: FGFR2 fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson–Weiss syndrome)" Provjerite vrijednost parametra |url= (pomoć).
  8. ^ "UniProt, P21802". Pristupljeno 1. 9. 2021.
  9. ^ Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P (Aug 1993). "Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2)". Developmental Biology. 158 (2): 475–86. doi:10.1006/dbio.1993.1205. PMID 8393815.
  10. ^ Stauber DJ, DiGabriele AD, Hendrickson WA (Jan 2000). "Structural interactions of fibroblast growth factor receptor with its ligands". Proceedings of the National Academy of Sciences of the United States of America. 97 (1): 49–54. Bibcode:2000PNAS...97...49S. doi:10.1073/pnas.97.1.49. PMC 26614. PMID 10618369.
  11. ^ Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL (Oct 2000). "Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin". Nature. 407 (6807): 1029–34. Bibcode:2000Natur.407.1029P. doi:10.1038/35039551. PMID 11069186. S2CID 4418272.
  12. ^ Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (Jan 1996). "Expression and biological activity of mouse fibroblast growth factor-9". The Journal of Biological Chemistry. 271 (3): 1726–31. doi:10.1074/jbc.271.3.1726. PMID 8576175. S2CID 27191391.
  13. ^ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (Jun 1996). "Receptor specificity of the fibroblast growth factor family". The Journal of Biological Chemistry. 271 (25): 15292–7. doi:10.1074/jbc.271.25.15292. PMID 8663044. S2CID 31736768.
  14. ^ Sagong B, Jung da J, Baek JI, Kim MA, Lee J, Lee SH, Kim UK, Lee KY (2014). "Identification of causative mutation in a Korean family with Crouzon syndrome using whole exome sequencing". Annals of Clinical and Laboratory Science. 44 (4): 476–83. PMID 25361936.
  15. ^ Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF, Hoover RN, Thomas G, Chanock SJ (Jul 2007). "A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer". Nature Genetics. 39 (7): 870–4. doi:10.1038/ng2075. PMC 3493132. PMID 17529973.
  16. ^ Katoh M, Nakagama H (Mar 2014). "FGF receptors: cancer biology and therapeutics". Medicinal Research Reviews. 34 (2): 280–300. doi:10.1002/med.21288. PMID 23696246. S2CID 27412585.
  17. ^ Open-Label, Dose-Finding Study Evaluating Safety and PK of FPA144 in Patients With Advanced Solid Tumors
  18. ^ Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Review Genetics (12): 167-178.
  19. ^ Lee KM, Santos-Ruiz L, Ferretti P (Mar 2010). "A single-point mutation in FGFR2 affects cell cycle and Tgfbeta signalling in osteoblasts" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1802 (3): 347–55. doi:10.1016/j.bbadis.2009.11.006. PMID 20004243.
  20. ^ Webster MK, Donoghue DJ (Oct 1997). "Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain". Molecular and Cellular Biology. 17 (10): 5739–47. doi:10.1128/mcb.17.10.5739. PMC 232422. PMID 9315632.
  21. ^ Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C (Feb 2009). "Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model". Developmental Dynamics. 238 (2): 376–85. doi:10.1002/dvdy.21648. PMID 18773495. S2CID 39997577.

Dopunska literatura uredi

  • McKeehan WL, Kan M (Sep 1994). "Heparan sulfate fibroblast growth factor receptor complex: structure-function relationships". Molecular Reproduction and Development. 39 (1): 69–81, discussion 81–2. doi:10.1002/mrd.1080390112. PMID 7999363. S2CID 6471340.
  • Johnson DE, Williams LT (1993). Structural and functional diversity in the FGF receptor multigene family. Advances in Cancer Research. 60. str. 1–41. doi:10.1016/S0065-230X(08)60821-0. ISBN 978-0-12-006660-5. PMID 8417497.
  • Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW (Jul 1995). "Novel FGFR2 mutations in Crouzon and Jackson–Weiss syndromes show allelic heterogeneity and phenotypic variability". Human Molecular Genetics. 4 (7): 1229–33. doi:10.1093/hmg/4.7.1229. PMID 8528214.
  • Marie PJ, Debiais F, Haÿ E (2003). "Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling". Histology and Histopathology. 17 (3): 877–85. doi:10.14670/HH-17.877. PMID 12168799.
  • Ibrahimi OA, Chiu ES, McCarthy JG, Mohammadi M (Jan 2005). "Understanding the molecular basis of Apert syndrome". Plastic and Reconstructive Surgery. 115 (1): 264–70. doi:10.1097/01.PRS.0000146703.08958.95 (neaktivno 31. 5. 2021). PMID 15622262.CS1 održavanje: DOI nije aktivan od 2021 (link)

Vanjski linkovi uredi

FGFR2 detalji ljudskog genoma u UCSC Genome Browser.