GRB7 explained

Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the GRB7 gene.^{[1] [2]}

Function

The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with epidermal growth factor receptor (EGFR) and ephrin receptors. The protein plays a role in the integrin signaling pathway and cell migration by binding with focal adhesion kinase (FAK). Alternative splicing results in multiple transcript variants encoding different isoforms, although the full-length natures of only two of the variants have been determined to date.

Clinical significance

GRB7 is an SH2-domain adaptor protein that binds to receptor tyrosine kinases and provides the intra-cellular direct link to the Ras proto-oncogene.Human GRB7 is located on the long arm of chromosome 17, next to the ERBB2 (alias HER2/neu) proto-oncogene.

These two genes are commonly co-amplified (present in excess copies) in breast cancers.GRB7, thought to be involved in migration, is well known to be over-expressed in testicular germ cell tumors, esophageal cancers, and gastric cancers.

Interactions

GRB7 has been shown to interact with:

• EPH receptor B1,^[3]
• Insulin receptor,^[4]
• PTK2,^[5]
• RET proto-oncogene,^[6] and
• Rnd1^[7]

Further reading

• Han DC, Shen TL, Guan JL . The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions . Oncogene . 20 . 44 . 6315–21 . Oct 2001 . 11607834 . 10.1038/sj.onc.1204775 . free .
• Margolis B, Silvennoinen O, Comoglio F, Roonprapunt C, Skolnik E, Ullrich A, Schlessinger J . 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 . Oct 1992 . 1409582 . 50030 . 10.1073/pnas.89.19.8894 . 1992PNAS...89.8894M . free .
• Skotheim RI, Abeler VM, Nesland JM, Fosså SD, Holm R, Wagner U, Flørenes VA, Aass N, Kallioniemi OP, Lothe RA . Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays . Neoplasia . 5 . 5 . 397–404 . 2003 . 14670177 . 1502610 . 10.1016/s1476-5586(03)80042-8 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM . 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 . May 1996 . 8631863 . 10.1074/jbc.271.18.10607 . free .
• Yokote K, Margolis B, Heldin CH, Claesson-Welsh L . Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors . The Journal of Biological Chemistry . 271 . 48 . 30942–9 . Nov 1996 . 8940081 . 10.1074/jbc.271.48.30942 . free .
• Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K . Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma . Cancer Research . 57 . 1 . 28–31 . Jan 1997 . 8988034 .
• Janes PW, Lackmann M, Church WB, Sanderson GM, Sutherland RL, Daly RJ . 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 . Mar 1997 . 9079677 . 10.1074/jbc.272.13.8490 . free .
• Kishi T, Sasaki H, Akiyama N, Ishizuka T, Sakamoto H, Aizawa S, Sugimura T, Terada M . 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 . Mar 1997 . 9125150 . 10.1006/bbrc.1997.6218 .
• Dong LQ, Du H, Porter SG, Kolakowski LF, Lee AV, Mandarino LJ, Fan J, Yee D, Liu F, Mandarino J . 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 . Nov 1997 . 9360986 . 10.1074/jbc.272.46.29104 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Fiddes RJ, Campbell DH, Janes PW, Sivertsen SP, Sasaki H, Wallasch C, Daly RJ . 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 . Mar 1998 . 9516479 . 10.1074/jbc.273.13.7717 . free .
• Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K . A novel variant of human Grb7 is associated with invasive esophageal carcinoma . The Journal of Clinical Investigation . 102 . 4 . 821–7 . Aug 1998 . 9710451 . 508945 . 10.1172/JCI2921 .
• Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L . 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 . Jul 1999 . 10377264 . 1220349 . 10.1042/0264-6021:3410211 .
• Han DC, Guan JL . Association of focal adhesion kinase with Grb7 and its role in cell migration . The Journal of Biological Chemistry . 274 . 34 . 24425–30 . Aug 1999 . 10446223 . 10.1074/jbc.274.34.24425 . free .
• Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ . 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 . Oct 1999 . 10521483 . 10.1074/jbc.274.43.30896 . free .
• Vayssière B, Zalcman G, Mahé Y, Mirey G, Ligensa T, Weidner KM, Chardin P, Camonis J . Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family . FEBS Letters . 467 . 1 . 91–6 . Feb 2000 . 10664463 . 10.1016/S0014-5793(99)01530-6 . 4901644 . free .
• Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF . 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 . Apr 2000 . 10803466 . 10.1038/sj.onc.1203469 . free .
• Han DC, Shen TL, Guan JL . 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 . Sep 2000 . 10893408 . 10.1074/jbc.M001997200 . free .
• 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 . 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 . Nov 2000 . 11075810 . 10.1210/mend.14.11.0553 . free .
• Skotheim RI, Abeler VM, Nesland JM, Fosså SD, Holm R, Wagner U, Flørenes VA, Aass N, Kallioniemi OP, Lothe RA . Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays . Neoplasia . 5 . 5 . 397–404 . 2003 . 14670177 . 1502610 . 10.1016/s1476-5586(03)80042-8 .

Notes and References

1. Web site: Entrez Gene: GRB7 growth factor receptor-bound protein 7.
2. Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K . A novel variant of human Grb7 is associated with invasive esophageal carcinoma . The Journal of Clinical Investigation . 102 . 4 . 821–7 . Aug 1998 . 9710451 . 508945 . 10.1172/JCI2921 .
3. Han DC, Shen TL, Miao H, Wang B, Guan JL . EphB1 associates with Grb7 and regulates cell migration . The Journal of Biological Chemistry . 277 . 47 . 45655–61 . Nov 2002 . 12223469 . 10.1074/jbc.M203165200 . free .
4. Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF . 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 . Apr 2000 . 10803466 . 10.1038/sj.onc.1203469 . free .
5. Han DC, Guan JL . Association of focal adhesion kinase with Grb7 and its role in cell migration . The Journal of Biological Chemistry . 274 . 34 . 24425–30 . Aug 1999 . 10446223 . 10.1074/jbc.274.34.24425. free .
6. Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM . 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 . May 1996 . 8631863 . 10.1074/jbc.271.18.10607. free .
7. Vayssière B, Zalcman G, Mahé Y, Mirey G, Ligensa T, Weidner KM, Chardin P, Camonis J . Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family . FEBS Letters . 467 . 1 . 91–6 . Feb 2000 . 10664463 . 10.1016/s0014-5793(99)01530-6. 4901644 . free .