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FGFR2
Dostupne strukture
PDB	Pretraga 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
Aliasi	FGFR2
Vanjski ID-jevi	OMIM: 176943 MGI: 95523 HomoloGene: 22566 GeneCards: FGFR2
Lokacija gena (čovjek)
Hrom.	Hromosom 10 (čovjek)
Kraj	121,598,458 bp
Lokacija gena (miš)
Hrom.	Hromosom 7 (miš)
Kraj	132,725,079 bp
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; • aktivnost sa transferazom; • protein homodimerization activity; • GO:0001948, GO:0016582 vezivanje za proteine; • nucleotide binding; • protein tyrosine kinase activity; • 1-phosphatidylinositol-3-kinase activity; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity; • vezivanje identičnih proteina; • 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
	2263
	14183
	ENSG00000066468
	ENSMUSG00000030849
	P21802
	P21803
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
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
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

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.

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

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

10	20	30	40	50
MVSWGRFICL	VVVTMATLSL	ARPSFSLVED	TTLEPEEPPT	KYQISQPEVY
VAAPGESLEV	RCLLKDAAVI	SWTKDGVHLG	PNNRTVLIGE	YLQIKGATPR
DSGLYACTAS	RTVDSETWYF	MVNVTDAISS	GDDEDDTDGA	EDFVSENSNN
KRAPYWTNTE	KMEKRLHAVP	AANTVKFRCP	AGGNPMPTMR	WLKNGKEFKQ
EHRIGGYKVR	NQHWSLIMES	VVPSDKGNYT	CVVENEYGSI	NHTYHLDVVE
RSPHRPILQA	GLPANASTVV	GGDVEFVCKV	YSDAQPHIQW	IKHVEKNGSK
YGPDGLPYLK	VLKAAGVNTT	DKEIEVLYIR	NVTFEDAGEY	TCLAGNSIGI
SFHSAWLTVL	PAPGREKEIT	ASPDYLEIAI	YCIGVFLIAC	MVVTVILCRM
KNTTKKPDFS	SQPAVHKLTK	RIPLRRQVTV	SAESSSSMNS	NTPLVRITTR
LSSTADTPML	AGVSEYELPE	DPKWEFPRDK	LTLGKPLGEG	CFGQVVMAEA
VGIDKDKPKE	AVTVAVKMLK	DDATEKDLSD	LVSEMEMMKM	IGKHKNIINL
LGACTQDGPL	YVIVEYASKG	NLREYLRARR	PPGMEYSYDI	NRVPEEQMTF
KDLVSCTYQL	ARGMEYLASQ	KCIHRDLAAR	NVLVTENNVM	KIADFGLARD
INNIDYYKKT	TNGRLPVKWM	APEALFDRVY	THQSDVWSFG	VLMWEIFTLG
GSPYPGIPVE	ELFKLLKEGH	RMDKPANCTN	ELYMMMRDCW	HAVPSQRPTF
KQLVEDLDRI	LTLTTNEEYL	DLSQPLEQYS	PSYPDTRSSC	SSGDDSVFSP
DPMPYEPCLP	QYPHINGSVK	T

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

Funkcija

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

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

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]

FGFR2IIIb veže se sa FGF-1, -3, -7, -10, -22
FGFR2IIIc sa FGF-1, -2, -4, -6, -8, -9, -17 i -18

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

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

Sindromi kraniosinostoze

Apertov sindrom, najpoznatiji tip akrocefalosindaktilija, koju karakteriziraju abnormalnosti lobanje i lica, kao što je rascjep nepca, te šaka i stopala.
Antley-Bixlerov sindrom, karakteriziran trapezoidnom, kraniofacijalnom i skeletnom sinostozom, plus kamptodaktilija), naslijeđena kao recesivno svojstvo.
Pfeifferov sindrom, drugi tip akrocefalosindaktilije, uključuje široke palčeve i velike prste, naslijeđene na autosomno dominantni način.
Crouzonov sindrom, kraniofacijalni poremećaj bez problema s rukama ili nogama.^[14] i potencijalni rascjep nepca, naslijeđen kao dominantna osobina.
Jackson-Weissov sindrom.

Rak

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

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

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

Klaster diferencijacije

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000066468 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000030849 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ 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).
^ "UniProt, P21802". Pristupljeno 1. 9. 2021.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Open-Label, Dose-Finding Study Evaluating Safety and PK of FPA144 in Patients With Advanced Solid Tumors
^ Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Review Genetics (12): 167-178.
^ 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.
^ 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.
^ 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

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)