GRB7
Protein 7, vezan za receptor faktora rasta, poznat i kao GRB7, jest protein koji je kod ljudi kodiran genom GRB7.[5][6]
Koristeći metod CORT (kloniranje ciljeva receptora) koju su osmislili Skolnik et al. (1991) za prikaz visoko ekspresijske biblioteke miša, Margolis et al. (1992) izolirali su gen za mišji Grb7, koji kodira protein od 535 aminokiselina. GRB7 je homolog ras-GAP (protein koji aktivira ras-GTPazu). Sadrži domen SH2 i vrlo je eksprimiran u jetri i bubrezima. Ovaj gen definira porodicu GRB7, čiji članovi uključuju mišji gen Grb10 i ljudski GRB14.
Tanaka et al. (1998) izolirali su cDNK navodne molekule za transdukciju signala GRB7 i novoprerađene varijante, GRB7V, iz invazivnog karcinoma jednjaka. Iako obje izoforme GRB7 dijele homologiju s migracijskim genom Mig10 Caenorhabditis elegans, izoformi GRB7V nedostaje 88 baznih parova na C kraju; rezultirajuće pomjeranje okvira dovodi do supstitucije SH2 domena kratkom hidrofobnom sekvencom.[7][8]
Aminokiselinska sekvenca[uredi | uredi izvor]
Dužina polipeptidnog lanca je 532 aminokiseline, a molekulska težina 59.681 Da.[9]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MELDLSPPHL | SSSPEDLCPA | PGTPPGTPRP | PDTPLPEEVK | RSQPLLIPTT | ||||
| GRKLREEERR | ATSLPSIPNP | FPELCSPPSQ | SPILGGPSSA | RGLLPRDASR | ||||
| PHVVKVYSED | GACRSVEVAA | GATARHVCEM | LVQRAHALSD | ETWGLVECHP | ||||
| HLALERGLED | HESVVEVQAA | WPVGGDSRFV | FRKNFAKYEL | FKSSPHSLFP | ||||
| EKMVSSCLDA | HTGISHEDLI | QNFLNAGSFP | EIQGFLQLRG | SGRKLWKRFF | ||||
| CFLRRSGLYY | STKGTSKDPR | HLQYVADVNE | SNVYVVTQGR | KLYGMPTDFG | ||||
| FCVKPNKLRN | GHKGLRIFCS | EDEQSRTCWL | AAFRLFKYGV | QLYKNYQQAQ | ||||
| SRHLHPSCLG | SPPLRSASDN | TLVAMDFSGH | AGRVIENPRE | ALSVALEEAQ | ||||
| AWRKKTNHRL | SLPMPASGTS | LSAAIHRTQL | WFHGRISREE | SQRLIGQQGL | ||||
| VDGLFLVRES | QRNPQGFVLS | LCHLQKVKHY | LILPSEEEGR | LYFSMDDGQT | ||||
| RFTDLLQLVE | FHQLNRGILP | CLLRHCCTRV | AL |
- Simboli
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[uredi | uredi izvor]
Proizvod ovog gena pripada maloj porodici adapterskih proteina za koje je poznato da stupaju u interakciju s velikim brojem receptora tirozin-kinaze i signalnih molekula. Ovaj gen kodira protein koji veže receptor faktora rasta koji stupa u interakciju sa receptora epidermnog faktora rasta (EGFR) i receptora efrina. Protein ima ulogu u integrinskom signalnom putu i migraciji ćelija, vezanjem sa fokusnom adhezionom kinazom (FAK). Alternativna prerada rezultira u više varijanti transkripta koji kodiraju različite izoforme, iako su do sada utvrđene prirode pune dužine samo dvije varijante.[5]
Klinički značaj[uredi | uredi izvor]
GRB7 je adapterski protein domena SH2, koji se veže na receptor tirozin-kinaze i pruža unutarćelijsku direktnu vezu do Ras proto-onkogen . Ljudski GRB7 nalazi se na dugom kraku hromosoma 17, pored ERBB2 (alias HER2 / neu) proto-onkogena.
Ova dva gena se obično koamplificiraju (prisutna u prekomjernim kopijama) u raku dojke. Za GRB7, za koji se smatra da je uključen u migraciju, dobro je poznato da je prekomjerno eksprimiran u testisima, tumoru germ-ćelija, raku jednjaka i raku želuca.
Interakcije[uredi | uredi izvor]
Pokazano je da GRB7 ima interakcije sa:
Modelni organizmi[uredi | uredi izvor]
U proučavanju PNPO funkcije, korišteni su modelni organizmi. Uvjetna linija nokaut-miševa, zvana Pnpotm1a (KOMP) Wtsi,[15][16] generirana je kao dio programa Međunarosnog konzorcija za miševe – visokopropusnog projekta mutageneze za generiranje i distribuciju životinjskih modela bolesti zainteresiranim naučnicima.[17][18][19]
Muške i ženske životinje prolazile su standardizirani fenotipski skrining, kako bi se utvrdili efekti delecije.[20][21] Od 24 izvedena testa i na mutantnim miševima, nisu uočene značajne abnormalnosti.[20] Tokom gestacije, nije utvrđen homozigotni mutantni embrion, pa tako nijedan nije preživio do odvikavanja. Preostali testovi su izvedeni na mutiranim heterozigotnim odraslim miševima; nisu opažene nikakve dodatne značajne abnormalnosti kod ovih životinja.[20]
| Svojstvo | Fenotip |
|---|---|
| Vijabilnost homozigota | Normalno |
| Studija recesivne letalnosti | Normalno |
| Plodnost | Normalno |
| Tjelesna težina | Normalno |
| Test otvorenog polja: anksioznost | Normalno |
| Neurološka procjena | Normalno |
| Snaga stiska | Normalno |
| Test vruće ploče | Normalno |
| Dismorfologija | Normalno |
| Indirektna kalorimetrija | Normalno |
| Test tolerancije glukoze | Normalno |
| Slušni odgovor moždanog stabla | Normalno |
| DEXA | Normalno |
| Radiografija | Normalno |
| Tjelesna temperatura | Normalno |
| Morfologija ika | Normalno |
| Klinička hemija (nalaz) | Normalno |
| Plazmatski imunoglobulini | Normalno |
| Hematologija | Normalno |
| Leukociti periferne krvi | Normalno |
| Mikronukleus test | Normalno |
| Težina srca | Normalno |
| Histopatologija oka | Normalno |
| Salmonella infekcija | Normalno[22] |
| Citrobacter infekcija | Normalno[23] |
| Svi testovi i analize su iz [20][24] |
Reference[uredi | uredi izvor]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000141738 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019312 - 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 "Entrez Gene: GRB7 growth factor receptor-bound protein 7".
- ^ Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K (Aug 1998). "A novel variant of human Grb7 is associated with invasive esophageal carcinoma". The Journal of Clinical Investigation. 102 (4): 821–7. doi:10.1172/JCI2921. PMC 508945. PMID 9710451.
- ^ Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., Schlessinger, J. Cloning of PI3 kinase- associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65: 83-90, 1991. [PubMed]: 1849461
- ^ Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, J. R., Sugimachi, K. A novel variant of human Grb7 is associated with invasive esophageal carcinoma. J. Clin. Invest. 102: 821-827, 1998. PubMed: 9710451
- ^ "UniProt, Q14451". Pristupljeno 22. 6. 2021.
- ^ Han DC, Shen TL, Miao H, Wang B, Guan JL (Nov 2002). "EphB1 associates with Grb7 and regulates cell migration". The Journal of Biological Chemistry. 277 (47): 45655–61. doi:10.1074/jbc.M203165200. PMID 12223469.
- ^ Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF (Apr 2000). "Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2". Oncogene. 19 (16): 2052–9. doi:10.1038/sj.onc.1203469. PMID 10803466.
- ^ Han DC, Guan JL (Aug 1999). "Association of focal adhesion kinase with Grb7 and its role in cell migration". The Journal of Biological Chemistry. 274 (34): 24425–30. doi:10.1074/jbc.274.34.24425. PMID 10446223.
- ^ Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM (maj 1996). "Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7". The Journal of Biological Chemistry. 271 (18): 10607–10. doi:10.1074/jbc.271.18.10607. PMID 8631863.
- ^ Vayssière B, Zalcman G, Mahé Y, Mirey G, Ligensa T, Weidner KM, Chardin P, Camonis J (Feb 2000). "Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family". FEBS Letters. 467 (1): 91–6. doi:10.1016/s0014-5793(99)01530-6. PMID 10664463. S2CID 4901644.
- ^ "International Knockout Mouse Consortium". Arhivirano s originala, 3. 4. 2012. Pristupljeno 22. 6. 2021.
- ^ "Mouse Genome Informatics".
- ^ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
- ^ a b c d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
- ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
- ^ "Salmonella infection data for Pnpo". Wellcome Trust Sanger Institute.
- ^ "Citrobacter infection data for Pnpo". Wellcome Trust Sanger Institute.
- ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
Dopunska literatura[uredi | uredi izvor]
- Han DC, Shen TL, Guan JL (Oct 2001). "The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions". Oncogene. 20 (44): 6315–21. doi:10.1038/sj.onc.1204775. PMID 11607834.
- Margolis B, Silvennoinen O, Comoglio F, Roonprapunt C, Skolnik E, Ullrich A, Schlessinger J (Oct 1992). "High-efficiency expression/cloning of epidermal growth factor-receptor-binding proteins with Src homology 2 domains". Proceedings of the National Academy of Sciences of the United States of America. 89 (19): 8894–8. Bibcode:1992PNAS...89.8894M. doi:10.1073/pnas.89.19.8894. PMC 50030. PMID 1409582.
- Skotheim RI, Abeler VM, Nesland JM, Fosså SD, Holm R, Wagner U, Flørenes VA, Aass N, Kallioniemi OP, Lothe RA (2003). "Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays". Neoplasia. 5 (5): 397–404. doi:10.1016/s1476-5586(03)80042-8. PMC 1502610. PMID 14670177.
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM (maj 1996). "Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7". The Journal of Biological Chemistry. 271 (18): 10607–10. doi:10.1074/jbc.271.18.10607. PMID 8631863.
- Yokote K, Margolis B, Heldin CH, Claesson-Welsh L (Nov 1996). "Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors". The Journal of Biological Chemistry. 271 (48): 30942–9. doi:10.1074/jbc.271.48.30942. PMID 8940081.
- Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K (Jan 1997). "Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma". Cancer Research. 57 (1): 28–31. PMID 8988034.
- Janes PW, Lackmann M, Church WB, Sanderson GM, Sutherland RL, Daly RJ (Mar 1997). "Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7". The Journal of Biological Chemistry. 272 (13): 8490–7. doi:10.1074/jbc.272.13.8490. PMID 9079677.
- Kishi T, Sasaki H, Akiyama N, Ishizuka T, Sakamoto H, Aizawa S, Sugimura T, Terada M (Mar 1997). "Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer". Biochemical and Biophysical Research Communications. 232 (1): 5–9. doi:10.1006/bbrc.1997.6218. PMID 9125150.
- Dong LQ, Du H, Porter SG, Kolakowski LF, Lee AV, Mandarino LJ, Fan J, Yee D, Liu F, Mandarino J (Nov 1997). "Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma". The Journal of Biological Chemistry. 272 (46): 29104–12. doi:10.1074/jbc.272.46.29104. PMID 9360986.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Fiddes RJ, Campbell DH, Janes PW, Sivertsen SP, Sasaki H, Wallasch C, Daly RJ (Mar 1998). "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3". The Journal of Biological Chemistry. 273 (13): 7717–24. doi:10.1074/jbc.273.13.7717. PMID 9516479.
- Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K (Aug 1998). "A novel variant of human Grb7 is associated with invasive esophageal carcinoma". The Journal of Clinical Investigation. 102 (4): 821–7. doi:10.1172/JCI2921. PMC 508945. PMID 9710451.
- Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L (Jul 1999). "Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor". The Biochemical Journal. 341 (1): 211–6. doi:10.1042/0264-6021:3410211. PMC 1220349. PMID 10377264.
- Han DC, Guan JL (Aug 1999). "Association of focal adhesion kinase with Grb7 and its role in cell migration". The Journal of Biological Chemistry. 274 (34): 24425–30. doi:10.1074/jbc.274.34.24425. PMID 10446223.
- Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ (Oct 1999). "Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration". The Journal of Biological Chemistry. 274 (43): 30896–905. doi:10.1074/jbc.274.43.30896. PMID 10521483.
- Vayssière B, Zalcman G, Mahé Y, Mirey G, Ligensa T, Weidner KM, Chardin P, Camonis J (Feb 2000). "Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family". FEBS Letters. 467 (1): 91–6. doi:10.1016/S0014-5793(99)01530-6. PMID 10664463. S2CID 4901644.
- Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF (Apr 2000). "Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2". Oncogene. 19 (16): 2052–9. doi:10.1038/sj.onc.1203469. PMID 10803466.
- Han DC, Shen TL, Guan JL (Sep 2000). "Role of Grb7 targeting to focal contacts and its phosphorylation by focal adhesion kinase in regulation of cell migration". The Journal of Biological Chemistry. 275 (37): 28911–7. doi:10.1074/jbc.M001997200. PMID 10893408.
- Lee H, Volonte D, Galbiati F, Iyengar P, Lublin DM, Bregman DB, Wilson MT, Campos-Gonzalez R, Bouzahzah B, Pestell RG, Scherer PE, Lisanti MP (Nov 2000). "Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette". Molecular Endocrinology. 14 (11): 1750–75. doi:10.1210/me.14.11.1750. PMID 11075810.
- Skotheim RI, Abeler VM, Nesland JM, Fosså SD, Holm R, Wagner U, Flørenes VA, Aass N, Kallioniemi OP, Lothe RA (2003). "Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays". Neoplasia. 5 (5): 397–404. doi:10.1016/s1476-5586(03)80042-8. PMC 1502610. PMID 14670177.
Vanjski linkovi[uredi | uredi izvor]
- GRB7 Adaptor Protein na US National Library of Medicine Medical Subject Headings (MeSH)