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Gene Review

Grb2  -  growth factor receptor bound protein 2

Rattus norvegicus

Synonyms: Adapter protein GRB2, Ash, Growth factor receptor-bound protein 2, Protein Ash, SH2/SH3 adapter GRB2
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Disease relevance of Grb2

  • Mitogenic G protein-coupled receptors, such as those for lysophosphatidic acid (LPA) and thrombin, activate the Ras/MAP kinase pathway via pertussis toxin (PTX)-sensitive Gi, tyrosine kinase activity and recruitment of Grb2, which targets guanine nucleotide exchange activity to Ras [1].
  • Therefore, we studied Raf-1 activity, its potential activators protein kinase C (PKC) and Ras, and expression and associations of adapter proteins Shc, Grb2, and Sos during experimental gastric ulcer healing [2].
  • Different interactions of Grb2/Ash molecule with the NGF and EGF receptors in rat pheochromocytoma PC12 cells [3].
  • In the present study, we investigated the adrenergic control of insulin-induced Shc phosphorylation and Shc-Grb2 association, and the modulating effect of streptozotocin-induced diabetes mellitus on Shc phosphorylation and Shc/Grb2 association [4].
  • OBJECTIVE: To define the nature and mechanisms of neuromuscular effects of toxic principles in bark of Southern Prickly Ash tree (Zanthoxylum clava-herculis) that might contribute to its clinical toxicity in cattle [5].

High impact information on Grb2

  • The Grb2 binding domain of mSos1 is not required for downstream signal transduction [6].
  • These data argue against a role for Grb2 in the direct recruitment of Sos proteins to the plasma membrane and suggest that Grb2 may function to overcome negative regulation of Sos by its C terminus [6].
  • We propose that Pyk2 acts with Src to link Gi- and Gq-coupled receptors with Grb2 and Sos to activate the MAP kinase signalling pathway in PC12 cells [7].
  • The carboxy terminus, which is of different lengths in adult and developing neurons owing to the alternative use of two termination sites, is proline-rich, consistent with the reported interaction of synaptojanin with the SH3 domains of Grb2 (refs 1, 2) [8].
  • LPA- or bradykinin-induced MAP kinase activation was also inhibited by overexpression of dominant interfering mutants of Grb2 and Sos [7].

Biological context of Grb2


Anatomical context of Grb2

  • In situ hybridization analysis revealed a more than 2-fold induction of Grb2 mRNA in the hippocampal dentate gyrus as well as superficial and deep layers of the cortex with both acute and chronic ECS [13].
  • CONCLUSIONS: Long-term ethanol feeding suppressed EGF-induced receptor autophosphorylation in rat hepatocytes with differential inhibition of downstream signaling processes mediated by PLC gamma, Shc, and Grb2 [14].
  • To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts [15].
  • Here we show that v-Crk complexes with both the tyrosine-phosphorylated EGF receptor and the Ras guanine nucleotide exchange factor SOS in PC12 cells and is involved in an pathway analogous to that of Grb2 [16].
  • Antigen receptors on T- and B-cells activate Ras through a signaling pathway that results in the tyrosine phosphorylation of Shc and the formation of a complex of Shc with the Grb2 adaptor protein [17].

Associations of Grb2 with chemical compounds


Physical interactions of Grb2


Enzymatic interactions of Grb2

  • We report here that Grb2 also interacts with tyrosine-phosphorylated IRS-1 in response to gastrin [27].
  • Instead, we detect a 100 kDa tyrosine-phosphorylated protein (p100) that binds to the C-terminal SH3 domain of Grb2 in a strictly Gi- and agonist-dependent manner [1].
  • Both TRH and EGF induced the association of tyrosine phosphorylated Shc proteins with a fusion protein containing SH2 and SH3 domains of Grb2, another important component in ras activation [28].

Regulatory relationships of Grb2

  • In addition, PI 3-kinase was activated by insulin treatment in this cell line and Grb2, Ras-GAP, and MAP kinase were coprecipitated with Ras from both insulin-treated and NGF-treated cells [29].
  • Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein [15].
  • Both NGF and EGF induced rapid tyrosine phosphorylation of Shc and its association with both the receptors and with Grb2/Ash [3].
  • Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex [30].

Other interactions of Grb2

  • Importantly, 3-13-fold more Grb2 was associated with Shc than with IRS-1 [9].
  • Our results demonstrate that gastric ulceration significantly increases Raf-1 kinase activity, Grb2 and Ras protein, and Shc-Grb2 and Grb2-Sos complex levels [2].
  • We show that phosphorylation of tyrosine 490, but not 785, of Trk is essential for activation of both Ras and PI 3-kinase in vivo, correlating with tyrosine phosphorylation of Shc and binding of Shc to the adaptor Grb2 and the Ras exchange factor Sos [31].
  • Moreover, insulin/IGF-I markedly increased the amount of Grb-2-associated SHC proteins by the same extent [32].
  • However, IRS-2-associated Grb-2 phosphorylation was barely detected [32].

Analytical, diagnostic and therapeutic context of Grb2

  • Microinjection of an anti-Grb2/Ash antibody, but not control IgG, inhibited the insulin-induced actin reorganization, whereas the TPA- and 8-bromo-cAMP-induced morphological changes were not inhibited by microinjection of the anti-Grb2/Ash antibody [33].
  • SH3A competes with the SH3 domains of Grb2 in binding to mSos1, and the intersectin-mSos1 complex can be separated from Grb2 by sucrose gradient centrifugation [34].
  • The embryonically expressed ShcA proteins were functionally active, since p52(ShcA) became phosphorylated on tyrosine and associated with Grb2 following intraventricular injection of epidermal growth factor in the embryonic brain [35].
  • Shc is constitutively tyrosine phosphorylated in unstimulated cells and Fc epsilon R1 ligation induces no changes in its phosphorylation or binding to Grb2 [36].
  • The stretch rapidly (within 2 min) induced association of tyrosine-phosphorylated EGFR with adaptor proteins (Shc/Grb2) as revealed by coprecipitation with glutathione-S-transferase-Grb2 fusion protein coupled with immunoblotting with anti-phosphotyrosine, anti-EGFR, and anti-Shc antibodies [37].


  1. Gi-mediated activation of the Ras/MAP kinase pathway involves a 100 kDa tyrosine-phosphorylated Grb2 SH3 binding protein, but not Src nor Shc. Kranenburg, O., Verlaan, I., Hordijk, P.L., Moolenaar, W.H. EMBO J. (1997) [Pubmed]
  2. Activation of Raf-1 during experimental gastric ulcer healing is Ras-mediated and protein kinase C-independent. Pai, R., Jones, M.K., Tomikawa, M., Tarnawski, A.S. Am. J. Pathol. (1999) [Pubmed]
  3. Different interactions of Grb2/Ash molecule with the NGF and EGF receptors in rat pheochromocytoma PC12 cells. Hashimoto, Y., Matuoka, K., Takenawa, T., Muroya, K., Hattori, S., Nakamura, S. Oncogene (1994) [Pubmed]
  4. Regulation of insulin-stimulated tyrosine phosphorylation of Shc and Shc/Grb2 association in liver, muscle, and adipose tissue of epinephrine- and streptozotocin-treated rats. Páez-Espinosa, V., Rocha, E.M., Velloso, L.A., Saad, M.J. Endocrine (2001) [Pubmed]
  5. Neuromuscular effects of toxins isolated from southern prickly ash (Zanthoxylum clava-herculis) bark. Bowen, J.M., Cole, R.J., Bedell, D., Schabdach, D. Am. J. Vet. Res. (1996) [Pubmed]
  6. The Grb2 binding domain of mSos1 is not required for downstream signal transduction. Wang, W., Fisher, E.M., Jia, Q., Dunn, J.M., Porfiri, E., Downward, J., Egan, S.E. Nat. Genet. (1995) [Pubmed]
  7. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S.A., Schlessinger, J. Nature (1996) [Pubmed]
  8. A presynaptic inositol-5-phosphatase. McPherson, P.S., Garcia, E.P., Slepnev, V.I., David, C., Zhang, X., Grabs, D., Sossin, W.S., Bauerfeind, R., Nemoto, Y., De Camilli, P. Nature (1996) [Pubmed]
  9. Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. Sasaoka, T., Draznin, B., Leitner, J.W., Langlois, W.J., Olefsky, J.M. J. Biol. Chem. (1994) [Pubmed]
  10. The critical role of c-Src and the Shc/Grb2/ERK2 signaling pathway in angiotensin II-dependent VSMC proliferation. Sayeski, P.P., Ali, M.S. Exp. Cell Res. (2003) [Pubmed]
  11. A novel insulin receptor substrate protein, xIRS-u, potentiates insulin signaling: functional importance of its pleckstrin homology domain. Ohan, N., Bayaa, M., Kumar, P., Zhu, L., Liu, X.J. Mol. Endocrinol. (1998) [Pubmed]
  12. CrkII signals from epidermal growth factor receptor to Ras. Kizaka-Kondoh, S., Matsuda, M., Okayama, H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  13. Regulation of growth factor receptor bound 2 by electroconvulsive seizure. Newton, S.S., Collier, E.F., Bennett, A.H., Russell, D.S., Duman, R.S. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  14. Differential inhibition of epidermal growth factor signaling pathways in rat hepatocytes by long-term ethanol treatment. Saso, K., Moehren, G., Higashi, K., Hoek, J.B. Gastroenterology (1997) [Pubmed]
  15. Activation of the JNK pathway is essential for transformation by the Met oncogene. Rodrigues, G.A., Park, M., Schlessinger, J. EMBO J. (1997) [Pubmed]
  16. v-Crk modulation of growth factor-induced PC12 cell differentiation involves the Src homology 2 domain of v-Crk and sustained activation of the Ras/mitogen-activated protein kinase pathway. Teng, K.K., Lander, H., Fajardo, J.E., Hanafusa, H., Hempstead, B.L., Birge, R.B. J. Biol. Chem. (1995) [Pubmed]
  17. Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2. Jabril-Cuenod, B., Zhang, C., Scharenberg, A.M., Paolini, R., Numerof, R., Beaven, M.A., Kinet, J.P. J. Biol. Chem. (1996) [Pubmed]
  18. A complex of GRB2-dynamin binds to tyrosine-phosphorylated insulin receptor substrate-1 after insulin treatment. Ando, A., Yonezawa, K., Gout, I., Nakata, T., Ueda, H., Hara, K., Kitamura, Y., Noda, Y., Takenawa, T., Hirokawa, N. EMBO J. (1994) [Pubmed]
  19. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Eguchi, S., Numaguchi, K., Iwasaki, H., Matsumoto, T., Yamakawa, T., Utsunomiya, H., Motley, E.D., Kawakatsu, H., Owada, K.M., Hirata, Y., Marumo, F., Inagami, T. J. Biol. Chem. (1998) [Pubmed]
  20. Cholesterol depletion of caveolae causes hyperactivation of extracellular signal-related kinase (ERK). Furuchi, T., Anderson, R.G. J. Biol. Chem. (1998) [Pubmed]
  21. Growth hormone stimulates the tyrosine kinase activity of JAK2 and induces tyrosine phosphorylation of insulin receptor substrates and Shc in rat tissues. Thirone, A.C., Carvalho, C.R., Saad, M.J. Endocrinology (1999) [Pubmed]
  22. The signaling pathway coupling epidermal growth factor receptors to activation of p21ras. Sasaoka, T., Langlois, W.J., Leitner, J.W., Draznin, B., Olefsky, J.M. J. Biol. Chem. (1994) [Pubmed]
  23. The liver response to in vivo heat shock involves the activation of MAP kinases and RAF and the tyrosine phosphorylation of Shc proteins. Bendinelli, P., Piccoletti, R., Maroni, P., Bernelli-Zazzera, A. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  24. A comparison of epidermal growth factor receptor-mediated mitogenic signaling in response to transforming growth factor alpha and epidermal growth factor in cultured fetal rat hepatocytes. Lipeski, L.E., Boylan, J.M., Gruppuso, P.A. Biochem. Mol. Biol. Int. (1996) [Pubmed]
  25. Protein tyrosine kinase activity is required for oxidant-induced extracellular signal-regulated protein kinase activation and c-fos and c-jun expression. Rao, G.N. Cell. Signal. (1997) [Pubmed]
  26. Gi-mediated tyrosine phosphorylation of Grb2 (growth-factor-receptor-bound protein 2)-bound dynamin-II by lysophosphatidic acid. Kranenburg, O., Verlaan, I., Moolenaar, W.H. Biochem. J. (1999) [Pubmed]
  27. Gastrin stimulates tyrosine phosphorylation of insulin receptor substrate 1 and its association with Grb2 and the phosphatidylinositol 3-kinase. Kowalski-Chauvel, A., Pradayrol, L., Vaysse, N., Seva, C. J. Biol. Chem. (1996) [Pubmed]
  28. Thyrotropin-releasing hormone stimulates MAP kinase activity in GH3 cells by divergent pathways. Evidence of a role for early tyrosine phosphorylation. Ohmichi, M., Sawada, T., Kanda, Y., Koike, K., Hirota, K., Miyake, A., Saltiel, A.R. J. Biol. Chem. (1994) [Pubmed]
  29. Insulin activates Ras in the PC12 cell line. Hwang, J.J., Kwon, J.H., Hur, K.C. Mol. Cells (1997) [Pubmed]
  30. Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex. Seva, C., Kowalski-Chauvel, A., Blanchet, J.S., Vaysse, N., Pradayrol, L. FEBS Lett. (1996) [Pubmed]
  31. Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase. Hallberg, B., Ashcroft, M., Loeb, D.M., Kaplan, D.R., Downward, J. Oncogene (1998) [Pubmed]
  32. Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin/insulin-like growth factor-I pathways in fetal brown adipocytes. Valverde, A.M., Lorenzo, M., Pons, S., White, M.F., Benito, M. Mol. Endocrinol. (1998) [Pubmed]
  33. Cytoskeletal reorganization induced by insulin: involvement of Grb2/Ash, Ras and phosphatidylinositol 3-kinase signalling. Tobe, K., Asai, S., Matuoka, K., Yamamoto, T., Chida, K., Kaburagi, Y., Akanuma, Y., Kuroki, T., Takenawa, T., Kimura, S., Nagai, R., Kadowaki, T. Genes Cells (2003) [Pubmed]
  34. The endocytic protein intersectin is a major binding partner for the Ras exchange factor mSos1 in rat brain. Tong, X.K., Hussain, N.K., de Heuvel, E., Kurakin, A., Abi-Jaoude, E., Quinn, C.C., Olson, M.F., Marais, R., Baranes, D., Kay, B.K., McPherson, P.S. EMBO J. (2000) [Pubmed]
  35. Expression and activation of SH2/PTB-containing ShcA adaptor protein reflects the pattern of neurogenesis in the mammalian brain. Conti, L., De Fraja, C., Gulisano, M., Migliaccio, E., Govoni, S., Cattaneo, E. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  36. Regulation of the adapter molecule Grb2 by the Fc epsilon R1 in the mast cell line RBL2H3. Turner, H., Reif, K., Rivera, J., Cantrell, D.A. J. Biol. Chem. (1995) [Pubmed]
  37. Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor. Iwasaki, H., Eguchi, S., Ueno, H., Marumo, F., Hirata, Y. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
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