Transformirajući faktor rasta alfa

Transformirajući faktor rasta alfa
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1GK5, 1MOX, 1YUF, 1YUG, 2TGF, 3E50, 3TGF, 4TGF
Identifikatori
Aliasi	TGFA
Vanjski ID-jevi	OMIM: 190170 MGI: 98724 HomoloGene: 2431 GeneCards: TGFA
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	70,554,193 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	86,252,701 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• epidermal growth factor receptor binding; • GO:0001948, GO:0016582 vezivanje za proteine; • growth factor activity;
Ćelijska komponenta	• integral component of membrane; • endoplasmic reticulum membrane; • membrana; • ćelijska membrana; • integral component of plasma membrane; • extracellular region; • cell surface; • basolateral plasma membrane; • perinuklearno područje citoplazme; • ER to Golgi transport vesicle membrane; • endoplasmic reticulum-Golgi intermediate compartment membrane; • GO:0016023 citoplazmatska vezikula; • Golđijeva membrana; • Vanćelijsko; • clathrin-coated vesicle membrane;
Biološki proces	• positive regulation of epidermal growth factor-activated receptor activity; • positive regulation of epithelial cell proliferation; • endoplasmic reticulum to Golgi vesicle-mediated transport; • COPII vesicle coating; • Ćelijska proliferacija; • positive regulation of mitotic nuclear division; • positive regulation of cell division; • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II; • epidermal growth factor receptor signaling pathway; • positive regulation of cell population proliferation; • MAPK cascade; • GO:0072468 Transdukcija signala; • negative regulation of epidermal growth factor receptor signaling pathway; • positive regulation of protein kinase B signaling; • membrane organization; • GO:0007243 intracellular signal transduction;
	Izvori:Amigo / QuickGO
Ortolozi
	7039
	21802
	ENSG00000163235
	ENSMUSG00000029999
	P01135
	P48030
	NM_001099691; NM_001308158; NM_001308159; NM_003236
	NM_031199
	NP_001093161; NP_001295087; NP_001295088; NP_003227
	NP_112476; NP_001390047
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Transformirajući faktor rasta alfa (TGF-α) jest protein koji je kod ljudi kodiran genom TGFA sa hromosoma 2.^[5] Kao član porodice sličnih EGF članova epidermnog faktora rasta (EGF), TGF-α je mitogeni polipeptid.^[6] Protein se aktivira kada se veže za receptore koji su sposobni za aktivnost protein-kinaza za ćelijsku signalizaciju.

TGF-α je transformirajući faktor rasta koji je ligand za receptor epidermnog faktora rasta, koji aktivira signalni put za proliferaciju, diferencijaciju i razvoj ćelija. Ovaj protein može djelovati ili kao transmembranski vezani ili kao rastvorljivi ligand. Ovaj gen povezan je sa mnogim tipovima karcinoma, a može biti uključen i u nekim slučajevima rascjepa usne/nepca.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 160 aminokiselina, a molekulska težina 17.006 Da.^[5]

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

10	20	30	40	50
MVPSAGQLAL	FALGIVLAAC	QALENSTSPL	SADPPVAAAV	VSHFNDCPDS
HTQFCFHGTC	RFLVQEDKPA	CVCHSGYVGA	RCEHADLLAV	VAASQKKQAI
TALVVVSIVA	LAVLIITCVL	IHCCQVRKHC	EWCRALICRH	EKPSALLKGR
TACCHSETVV

Funkcija

TGF-α se može proizvesti u makrofagima, ćelijama mozga i keratinocitima. TGF-α indukuje razvoj epitela. S obzirom da je TGF-α član porodice EGF, biološka dejstva TGF-α i EGF-a su slična. Naprimjer, TGF-α i EGF se vezuju za isti receptor. Kada se TGF-α veže za EGFR, može pokrenuti višestruke događaje ćelijske proliferacije.^[7] Ćelijske proliferacije koje uključuju TGF-α vezan za EGFR obuhvataju zarastanje rana i embriogenezu. TGF-α je također uključen u tumerigenezu, a vjeruje se da promovira angiogenezu.^[8]

Također se pokazalo da TGF-α stimuliše neuronske ćelije za proliferaciju kod povreda mozga odraslih.^[9]

Sinteza

TGF-α se sintetizira interno kao dio transmembranskog prekursora od 160 (ljudski) ili 159 (pacov) aminokiselina.^[8] Prekursor se sastoji od vanćelijskog domena koji sadrži hidrofobni transmembranski domen, od 50 aminokiselina TGF-α i citoplazmatski domen od 35 ostataka.^[8] U svom najmanjem obliku, TGF-α ima šest cisteina povezanih preko tri disulfidna mosta. Zajedno, svi članovi porodice EGF/TGF-α dijele ovu strukturu. Protein, međutim, nije direktno povezan sa TGF-β.

Ograničeni uspjeh rezultat je pokušaja da se sintetizira redukcijski molekul za TGF-α koji eksprimira sličan biološki profil.^[7]

Sinteza u želucu

U želucu, TGF-α se proizvodi unutar normalne želučane sluznice.^[10] Pokazalo se da TGF-α inhibira lučenje želučane kiseline.

Receptor

Glikozilirani protein od 170 kDa poznat kao EGF receptor vezuje se za TGF-α, omogućavajući polipeptidu da funkcioniše na različitim signalnim putevima.^[6] EGF receptor karakteriše postojanje vanćelijskog domena koji ima brojne aminokiselinske motive. EGFR je neophodan za jedan transmembranski domen, unutartćelijski domen (sadrži aktivnost tirozin-kinaza) i prepoznavanje liganda.^[6] Kao faktor rasta usidren membranom, TGF-α se može otcijepiti od integralnog membranskog glikoproteina putem proteaza.^[8] Rastvorljivi oblici TGF-α koji nastaju cijepanjem imaju kapacitet da aktiviraju EGFR. EGFR se također može aktivirati iz faktora rasta koji je ugrađen u membranu.

Kada se TGF-α veže za EGFR, dimerizira, izazivajući fosforilaciju protein-tirozin kinaze. Aktivnost protein-tirozin kinaze uzrokuje autofosforilaciju između nekoliko ostataka tirozina unutar EGFR, utičući na aktivaciju i signalizaciju drugih proteina koji djeluju u mnogim putevima prijenosa signala.

Signalni put nakon vezivanja za TGF-α receptora epidermnog faktora rasta (EGFR).

Studije na životinjama

U životinjskom modelu Parkinsonove bolesti gdje su dopaminski neuroni oštećeni 6-hidroksidopaminom, infuzija TGF-α u mozak izazvala je povećanje broja neuronskih prekursorskih ćelija.^[9] Međutim, tretman TGF-α nije rezultirao neurogenezom dopaminskih neurona.^[11]

Studije na ljudima

Neuroendokrini sistem

Pokazalo se da porodica EGF/TGF-α reguliše luteinizirajući hormon-oslobađajući hormon (LHRH), preko glija-neuronskog interaktivnog procesa.^[6] Proizveden u astrocitima hipotalamusa, TGF -α indirektno stimuliše oslobađanje LHRH putem različitih intermedijera. Kao rezultat toga, TGF-α je fiziološka komponenta neophodna za početak procesa ženskog puberteta.^[6]

Suprahijazmatsko jezgro

Primijećeno je također da je TGF-α visoko eksprimiran u suprahijazmatskom jezgru (SCN) (5). Ovaj nalaz ukazuje na ulogu EGFR signalizacije u regulaciji SATA i cirkadijskih ritmova unutar SCN-a..^[12] Slične studije pokazale su da, kada se ubrizgava u treću komoru, TGF-α može potisnuti cirkadijskoo lokomotorno ponašanje zajedno s aktivnostima pića ili jela.^[12]

Tumori

Ovaj protein pokazuje potencijalnu upotrebu kao prognostičkog biomarkera kod različitih tumora, kao što je karcinom želuca^[13] ili melanom (što je sugerirano).^[14] Povećanje TGF-α vezano je za Menetrierovu bolest, predkancerozno stanje želuca.^[15]

Interakcije

Pokazalo se da TGF alfa reaguje sa GORASP1^[16] i GORASP2.^[16]

Također pogledajte

Transformirajući faktor rasta

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000163235 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000029999 - 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.
^ ^a ^b ^c "Entrez Gene: TGFA transforming growth factor alpha".
^ ^a ^b ^c ^d ^e Ojeda, S. R.; Ma, Y. J.; Rage, F. (septembar 1997). "The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty". Molecular Psychiatry. 2 (5): 355–358. doi:10.1038/sj.mp.4000307. PMID 9322223.
^ ^a ^b McInnes, C; Wang, J; Al Moustafa, AE; Yansouni, C; O'Connor-McCourt, M; Sykes, BD (1998). "Structure-based minimization of transforming growth factor-alpha (TGF-alpha) through NMR analysis of the receptor-bound ligand. Design, solution structure, and activity of TGF-alpha 8-50"". J. Biol. Chem. 273 (42): 27357–63. doi:10.1074/jbc.273.42.27357. PMID 9765263.
^ ^a ^b ^c ^d Ferrer, I.; Alcantara, S.; Ballabriga, J.; Olive, M.; Blanco, R.; Rivera, R.; Carmona, M.; Berruezo, M.; Pitarch, S.; Planas, A. Transforming growth factor- α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol. 1996, 49, 99.
^ ^a ^b Fallon J, Reid S, Kinyamu R, Opole I, Opole R, Baratta J, Korc M, Endo TL, Duong A, Nguyen G, Karkehabadhi M, Twardzik D, Patel S, Loughlin S (2000). "In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain". Proceedings of the National Academy of Sciences of the United States of America. 97 (26): 14686–91. Bibcode:2000PNAS...9714686F. doi:10.1073/pnas.97.26.14686. PMC 18979. PMID 11121069.CS1 održavanje: upotreba parametra authors (link)
^ Coffey, R.; Gangarosa, L.; Damstrup, L.; Dempsey, P. Osnovne akcije transformacije faktora rasta-α i srodnih peptida. EUR. J. Gastroen. Hepat. 1995, 7, 923.
^ Cooper O, Isacson O (oktobar 2004). "Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons". J. Neurosci. 24 (41): 8924–31. doi:10.1523/JNEUROSCI.2344-04.2004. PMC 2613225. PMID 15483111.
^ ^a ^b Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res. 2006, 1088, 45.
^ Fanelli MF (Aug 2012). "The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer". Histopathology. 61 (2): 153–61. doi:10.1111/j.1365-2559.2011.04139.x. PMID 22582975. S2CID 6566296.
^ Tarhini AA (Jan 2014). "A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma". J Transl Med. 12: 19. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.
^ Coffey, Robert J.; Washington, Mary Kay; Corless, Christopher L.; Heinrich, Michael C. (2007). "Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach". Journal of Clinical Investigation. 117 (1): 70–80. doi:10.1172/JCI30491. PMC 1716220. PMID 17200708.
^ ^a ^b Barr FA, Preisinger C, Kopajtich R, Körner R (decembar 2001). "Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus". J. Cell Biol. 155 (6): 885–91. doi:10.1083/jcb.200108102. PMC 2150891. PMID 11739402.

Dopunska literatura

Luetteke NC, Lee DC (1991). "Transforming growth factor alpha: expression, regulation and biological action of its integral membrane precursor". Semin. Cancer Biol. 1 (4): 265–75. PMID 2103501.
Greten FR, Wagner M, Weber CK, Zechner U, Adler G, Schmid RM (2002). "TGF alpha transgenic mice. A model of pancreatic cancer development". Pancreatology. 1 (4): 363–8. doi:10.1159/000055835. PMID 12120215. S2CID 84256727.
Vieira AR (2006). "Association between the transforming growth factor alpha gene and nonsyndromic oral clefts: a HuGE review". Am. J. Epidemiol. 163 (9): 790–810. doi:10.1093/aje/kwj103. PMID 16495466.
Nasim MM, Thomas DM, Alison MR, Filipe MI (1992). "Transforming growth factor alpha expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric carcinoma--an immunohistochemical study". Histopathology. 20 (4): 339–43. doi:10.1111/j.1365-2559.1992.tb00991.x. PMID 1577411. S2CID 73067240.
Thomas DM, Nasim MM, Gullick WJ, Alison MR (1992). "Immunoreactivity of transforming growth factor alpha in the normal adult gastrointestinal tract". Gut. 33 (5): 628–31. doi:10.1136/gut.33.5.628. PMC 1379291. PMID 1612477.
Bean MF, Carr SA (1992). "Characterization of disulfide bond position in proteins and sequence analysis of cystine-bridged peptides by tandem mass spectrometry". Anal. Biochem. 201 (2): 216–26. doi:10.1016/0003-2697(92)90331-Z. PMID 1632509.
Lei ZM, Rao CV (1992). "Expression of epidermal growth factor (EGF) receptor and its ligands, EGF and transforming growth factor-alpha, in human fallopian tubes". Endocrinology. 131 (2): 947–57. doi:10.1210/en.131.2.947. PMID 1639032.
Werner S, Roth WK, Bates B, Goldfarb M, Hofschneider PH (1991). "Fibroblast growth factor 5 proto-oncogene is expressed in normal human fibroblasts and induced by serum growth factors". Oncogene. 6 (11): 2137–44. PMID 1658709.
Saeki T, Cristiano A, Lynch MJ, Brattain M, Kim N, Normanno N, Kenney N, Ciardiello F, Salomon DS (1992). "Regulation by estrogen through the 5'-flanking region of the transforming growth factor alpha gene". Mol. Endocrinol. 5 (12): 1955–63. doi:10.1210/mend-5-12-1955. PMID 1791840.
Harvey TS, Wilkinson AJ, Tappin MJ, Cooke RM, Campbell ID (1991). "The solution structure of human transforming growth factor alpha". Eur. J. Biochem. 198 (3): 555–62. doi:10.1111/j.1432-1033.1991.tb16050.x. PMID 2050136.
Kline TP, Brown FK, Brown SC, Jeffs PW, Kopple KD, Mueller L (1991). "Solution structures of human transforming growth factor alpha derived from 1H NMR data". Biochemistry. 29 (34): 7805–13. doi:10.1021/bi00486a005. PMID 2261437.
Jakowlew SB, Kondaiah P, Dillard PJ, Sporn MB, Roberts AB (1989). "A novel low molecular weight ribonucleic acid (RNA) related to transforming growth factor alpha messenger RNA". Mol. Endocrinol. 2 (11): 1056–63. doi:10.1210/mend-2-11-1056. PMID 2464748.
Jakobovits EB, Schlokat U, Vannice JL, Derynck R, Levinson AD (1989). "The human transforming growth factor alpha promoter directs transcription initiation from a single site in the absence of a TATA sequence". Mol. Cell. Biol. 8 (12): 5549–54. doi:10.1128/mcb.8.12.5549. PMC 365660. PMID 2907605.
Tricoli JV, Nakai H, Byers MG, Rall LB, Bell GI, Shows TB (1986). "The gene for human transforming growth factor alpha is on the short arm of chromosome 2". Cytogenet. Cell Genet. 42 (1–2): 94–8. doi:10.1159/000132258. PMID 3459638.
Lee DC, Rose TM, Webb NR, Todaro GJ (1985). "Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha". Nature. 313 (6002): 489–91. Bibcode:1985Natur.313..489L. doi:10.1038/313489a0. PMID 3855503. S2CID 4358296.
Derynck R, Roberts AB, Winkler ME, Chen EY, Goeddel DV (1984). "Human transforming growth factor-alpha: precursor structure and expression in E. coli". Cell. 38 (1): 287–97. doi:10.1016/0092-8674(84)90550-6. PMID 6088071. S2CID 53275849.
Ogbureke KU, MacDaniel RK, Jacob RS, Durban EM (1995). "Distribution of immunoreactive transforming growth factor-alpha in non-neoplastic human salivary glands". Histol. Histopathol. 10 (3): 691–6. PMID 7579819.
Walz TM, Malm C, Nishikawa BK, Wasteson A (1995). "Transforming growth factor-alpha (TGF-alpha) in human bone marrow: demonstration of TGF-alpha in erythroblasts and eosinophilic precursor cells and of epidermal growth factor receptors in blastlike cells of myelomonocytic origin". Blood. 85 (9): 2385–92. doi:10.1182/blood.V85.9.2385.bloodjournal8592385. PMID 7727772.
Patel B, Hiscott P, Charteris D, Mather J, McLeod D, Boulton M (1994). "Retinal and preretinal localisation of epidermal growth factor, transforming growth factor alpha, and their receptor in proliferative diabetic retinopathy". The British Journal of Ophthalmology. 78 (9): 714–8. doi:10.1136/bjo.78.9.714. PMC 504912. PMID 7947554.

Vanjski linkovi

Transforming Growth Factor alpha na US National Library of Medicine Medical Subject Headings (MeSH)

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000163235 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000029999 - 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.

[entrez-5] "Entrez Gene: TGFA transforming growth factor alpha".

[Ojeda-6] Ojeda, S. R.; Ma, Y. J.; Rage, F. (septembar 1997). "The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty". Molecular Psychiatry. 2 (5): 355–358. doi:10.1038/sj.mp.4000307. PMID 9322223.

[McInnes-7] McInnes, C; Wang, J; Al Moustafa, AE; Yansouni, C; O'Connor-McCourt, M; Sykes, BD (1998). "Structure-based minimization of transforming growth factor-alpha (TGF-alpha) through NMR analysis of the receptor-bound ligand. Design, solution structure, and activity of TGF-alpha 8-50"". J. Biol. Chem. 273 (42): 27357–63. doi:10.1074/jbc.273.42.27357. PMID 9765263.

[Ferrer-8] Ferrer, I.; Alcantara, S.; Ballabriga, J.; Olive, M.; Blanco, R.; Rivera, R.; Carmona, M.; Berruezo, M.; Pitarch, S.; Planas, A. Transforming growth factor- α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol. 1996, 49, 99.

[Fallon_2000-9] Fallon J, Reid S, Kinyamu R, Opole I, Opole R, Baratta J, Korc M, Endo TL, Duong A, Nguyen G, Karkehabadhi M, Twardzik D, Patel S, Loughlin S (2000). "In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain". Proceedings of the National Academy of Sciences of the United States of America. 97 (26): 14686–91. Bibcode:2000PNAS...9714686F. doi:10.1073/pnas.97.26.14686. PMC 18979. PMID 11121069.CS1 održavanje: upotreba parametra authors (link)

[Coffey-10] Coffey, R.; Gangarosa, L.; Damstrup, L.; Dempsey, P. Osnovne akcije transformacije faktora rasta-α i srodnih peptida. EUR. J. Gastroen. Hepat. 1995, 7, 923.

[pmid15483111-11] Cooper O, Isacson O (oktobar 2004). "Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons". J. Neurosci. 24 (41): 8924–31. doi:10.1523/JNEUROSCI.2344-04.2004. PMC 2613225. PMID 15483111.

[Hao-12] Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res. 2006, 1088, 45.

[pmid_=_22582975-13] Fanelli MF (Aug 2012). "The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer". Histopathology. 61 (2): 153–61. doi:10.1111/j.1365-2559.2011.04139.x. PMID 22582975. S2CID 6566296.

[pmid_=_24457057-14] Tarhini AA (Jan 2014). "A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma". J Transl Med. 12: 19. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.

[15] Coffey, Robert J.; Washington, Mary Kay; Corless, Christopher L.; Heinrich, Michael C. (2007). "Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach". Journal of Clinical Investigation. 117 (1): 70–80. doi:10.1172/JCI30491. PMC 1716220. PMID 17200708.

[pmid11739402-16] Barr FA, Preisinger C, Kopajtich R, Körner R (decembar 2001). "Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus". J. Cell Biol. 155 (6): 885–91. doi:10.1083/jcb.200108102. PMC 2150891. PMID 11739402.

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