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Gene Review

Grb2  -  growth factor receptor bound protein 2

Mus musculus

Synonyms: AA408164, Adapter protein GRB2, Ash, Growth factor receptor-bound protein 2, SH2/SH3 adapter GRB2
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Disease relevance of Grb2


High impact information on Grb2

  • Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation [1].
  • Analysis of mutant embryonic stem cells, embryos, and chimeras reveals that Grb2 is required during embyrogenesis for the differentiation of endodermal cells and formation of the epiblast [1].
  • Shc is subsequently phosphorylated at tyrosine 317 and recruits Grb2 [5].
  • Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development [6].
  • Activation of growth factor receptors results in tyrosine autophosphorylation and recruitment of SH2 domain-containing effectors, including Grb2 [7].

Chemical compound and disease context of Grb2

  • When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 or Shc signaling pathways the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis [8].
  • A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells [9].
  • BACKGROUND: The v-abl oncogene of the Abelson murine leukemia virus (A-MuLV) encodes a cytoplasmic tyrosine kinase that can associate with phosphoinositide 3-kinase, Shc and Grb2, and activate the pathway that leads from Ras to mitogen-activated protein (MAP) kinase [10].

Biological context of Grb2


Anatomical context of Grb2

  • A non-phosphorylated Spry mutant cannot bind Grb2 and acts as a dominant negative, inducing prolonged activation of ERK in response to FGF and promoting the FGF-induced outgrowth of neurites in PC12 cells [16].
  • Thus, PTEN/phosphatidylinositol 3' kinase signaling requires Grb2 during both embryonic development and fibroblast survival, but Grb2 heterozygosity does not effect tumorigenesis in pten-deficient mice [17].
  • Mitogenic signaling of NGF in NIH 3T3 cells ectopically expressing Trk receptors also takes place without detectable association between Grb2 and Trk [18].
  • Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5'-phosphatase isoform that partners with the Grb2 adapter protein [19].
  • Mona/Gads is a Grb2-related, Src homology 3 (SH3) and SH2 domain-containing adapter protein whose expression is restricted to cells of hematopoietic lineage (i.e., monocytes and T lymphocytes) [20].

Associations of Grb2 with chemical compounds

  • Expression of GrpL is restricted to hematopoietic tissues, and it is distinguished from Grb2 by having a proline-rich region [21].
  • The latter effect probably abates Grb2 inhibition of the phosphotyrosine displacement process that is required specifically for Src dephosphorylation and causes a mitotic increase in transient PTPalpha-Src binding [22].
  • The molecular adapter c-Cbl is rapidly tyrosine phosphorylated following stimulation through the TCR and associates with Src homology domain-2 (SH2)/SH3 domain-containing adapters such as Grb2, Crk, and Crk-L, which interact with guanine nucleotide exchange factors specific for the Ras family [23].
  • Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner [24].
  • This involves serine phosphorylation-dependent differential modulation of the affinity of Tyr(P)789 for the Src and Grb2 SH2 domains [25].

Physical interactions of Grb2

  • The Grb2 SH2 domain binds to Tyr1068 of EGFR and Tyr317 of Shc while its SH3 domains bind to mSos1 [26].
  • E3 or laminin-1 increase Grb2-binding and Rac1 activation [27].
  • Fms also formed complexes with Grb2 and Sos1, and neither contained phosphotyrosine [28].
  • These results demonstrate that tyrosine-phosphorylated Shc specifically interacts with the SH2 domain of Grb2 [29].
  • Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region [30].

Enzymatic interactions of Grb2

  • In FGF-2 treated proliferating EC, FRS2 as well as Shc are tyrosine phosphorylated and interact with Grb2 [31].
  • Pyk2 became phosphorylated at the major autophosphorylation site (Tyr-402) and the potential Grb2-binding site (Tyr-881) during EMT [32].

Regulatory relationships of Grb2


Other interactions of Grb2

  • Molecular cloning of the mouse grb2 gene: differential interaction of the Grb2 adaptor protein with epidermal growth factor and nerve growth factor receptors [18].
  • How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear [38].
  • Together, these data suggest that Grap, unlike Grb2, acts as a negative regulator of TCR-stimulated intracellular signaling by downregulating signal relay through the Ras/Erk pathway [39].
  • Grb2-mSos1 bound to both EGFR- and Shc-derived phosphopeptides with higher affinities (KD of 0.3 microM and 31 nM, respectively) than Grb2 alone [26].
  • Activation of both PKB and Erk as well as survival in low serum-containing media are all rescued by reexpression of Grb2 containing mutations within the N-terminal Src homology 3 (SH3) domain, but not by C-terminal SH3 domain mutants [17].

Analytical, diagnostic and therapeutic context of Grb2


  1. Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cheng, A.M., Saxton, T.M., Sakai, R., Kulkarni, S., Mbamalu, G., Vogel, W., Tortorice, C.G., Cardiff, R.D., Cross, J.C., Muller, W.J., Pawson, T. Cell (1998) [Pubmed]
  2. A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase. Million, R.P., Harakawa, N., Roumiantsev, S., Varticovski, L., Van Etten, R.A. Mol. Cell. Biol. (2004) [Pubmed]
  3. Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus. Finkelstein, L.D., Ney, P.A., Liu, Q.P., Paulson, R.F., Correll, P.H. Oncogene (2002) [Pubmed]
  4. Overexpression of Grb2 in inflammatory lesions and preneoplastic foci and tumors induced by N-nitrosodimethylamine in Helicobacter hepaticus-infected and -noninfected A/J mice. Diwan, B.A., Ramakrishna, G., Anderson, L.M., Ramljak, D. Toxicologic pathology. (2000) [Pubmed]
  5. A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Wary, K.K., Mariotti, A., Zurzolo, C., Giancotti, F.G. Cell (1998) [Pubmed]
  6. Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Maina, F., Casagranda, F., Audero, E., Simeone, A., Comoglio, P.M., Klein, R., Ponzetto, C. Cell (1996) [Pubmed]
  7. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Aronheim, A., Engelberg, D., Li, N., al-Alawi, N., Schlessinger, J., Karin, M. Cell (1994) [Pubmed]
  8. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J., Massagué, J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  9. A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells. Jücker, M., Schiffer, C.A., Feldman, R.A. Blood (1997) [Pubmed]
  10. Rac is required for v-Abl tyrosine kinase to activate mitogenesis. Renshaw, M.W., Lea-Chou, E., Wang, J.Y. Curr. Biol. (1996) [Pubmed]
  11. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Gong, Q., Cheng, A.M., Akk, A.M., Alberola-Ila, J., Gong, G., Pawson, T., Chan, A.C. Nat. Immunol. (2001) [Pubmed]
  12. Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling. Li, S., Couvillon, A.D., Brasher, B.B., Van Etten, R.A. EMBO J. (2001) [Pubmed]
  13. A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain. O'Bryan, J.P., Songyang, Z., Cantley, L., Der, C.J., Pawson, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  14. Identification of a novel 135-kDa Grb2-binding protein in osteoclasts. Sahni, M., Zhou, X.M., Bakiri, L., Schlessinger, J., Baron, R., Levy, J.B. J. Biol. Chem. (1996) [Pubmed]
  15. Distinct recruitment and function of Gab1 and Gab2 in Met receptor-mediated epithelial morphogenesis. Lock, L.S., Maroun, C.R., Naujokas, M.A., Park, M. Mol. Biol. Cell (2002) [Pubmed]
  16. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Hanafusa, H., Torii, S., Yasunaga, T., Nishida, E. Nat. Cell Biol. (2002) [Pubmed]
  17. grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten+/- mice. Cully, M., Elia, A., Ong, S.H., Stambolic, V., Pawson, T., Tsao, M.S., Mak, T.W. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. Molecular cloning of the mouse grb2 gene: differential interaction of the Grb2 adaptor protein with epidermal growth factor and nerve growth factor receptors. Suen, K.L., Bustelo, X.R., Pawson, T., Barbacid, M. Mol. Cell. Biol. (1993) [Pubmed]
  19. Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5'-phosphatase isoform that partners with the Grb2 adapter protein. Tu, Z., Ninos, J.M., Ma, Z., Wang, J.W., Lemos, M.P., Desponts, C., Ghansah, T., Howson, J.M., Kerr, W.G. Blood (2001) [Pubmed]
  20. Induced expression and association of the Mona/Gads adapter and Gab3 scaffolding protein during monocyte/macrophage differentiation. Bourgin, C., Bourette, R.P., Arnaud, S., Liu, Y., Rohrschneider, L.R., Mouchiroud, G. Mol. Cell. Biol. (2002) [Pubmed]
  21. GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation. Law, C.L., Ewings, M.K., Chaudhary, P.M., Solow, S.A., Yun, T.J., Marshall, A.J., Hood, L., Clark, E.A. J. Exp. Med. (1999) [Pubmed]
  22. Two mechanisms activate PTPalpha during mitosis. Zheng, X.M., Shalloway, D. EMBO J. (2001) [Pubmed]
  23. Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells. Marengère, L.E., Mirtsos, C., Kozieradzki, I., Veillette, A., Mak, T.W., Penninger, J.M. J. Immunol. (1997) [Pubmed]
  24. 'Srcasm: a novel Src activating and signaling molecule. Seykora, J.T., Mei, L., Dotto, G.P., Stein, P.L. J. Biol. Chem. (2002) [Pubmed]
  25. Mitotic activation of protein-tyrosine phosphatase alpha and regulation of its Src-mediated transforming activity by its sites of protein kinase C phosphorylation. Zheng, X.M., Resnick, R.J., Shalloway, D. J. Biol. Chem. (2002) [Pubmed]
  26. The Grb2-mSos1 complex binds phosphopeptides with higher affinity than Grb2. Chook, Y.M., Gish, G.D., Kay, C.M., Pai, E.F., Pawson, T. J. Biol. Chem. (1996) [Pubmed]
  27. Binding of laminin alpha1-chain LG4-5 domain to alpha-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling. Zhou, Y.W., Thomason, D.B., Gullberg, D., Jarrett, H.W. Biochemistry (2006) [Pubmed]
  28. Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Lioubin, M.N., Myles, G.M., Carlberg, K., Bowtell, D., Rohrschneider, L.R. Mol. Cell. Biol. (1994) [Pubmed]
  29. Endothelin induces tyrosine phosphorylation and GRB2 association of Shc in astrocytes. Cazaubon, S.M., Ramos-Morales, F., Fischer, S., Schweighoffer, F., Strosberg, A.D., Couraud, P.O. J. Biol. Chem. (1994) [Pubmed]
  30. Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. Zhou, D., Noviello, C., D'Ambrosio, C., Scaloni, A., D'Adamio, L. J. Biol. Chem. (2004) [Pubmed]
  31. Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Klint, P., Kanda, S., Kloog, Y., Claesson-Welsh, L. Oncogene (1999) [Pubmed]
  32. Different modes and qualities of tyrosine phosphorylation of Fak and Pyk2 during epithelial-mesenchymal transdifferentiation and cell migration: analysis of specific phosphorylation events using site-directed antibodies. Nakamura, K., Yano, H., Schaefer, E., Sabe, H. Oncogene (2001) [Pubmed]
  33. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Gu, H., Maeda, H., Moon, J.J., Lord, J.D., Yoakim, M., Nelson, B.H., Neel, B.G. Mol. Cell. Biol. (2000) [Pubmed]
  34. The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. Zhang, S., Weinheimer, C., Courtois, M., Kovacs, A., Zhang, C.E., Cheng, A.M., Wang, Y., Muslin, A.J. J. Clin. Invest. (2003) [Pubmed]
  35. Growth factor receptor-bound protein 2 SH2/SH3 domain binding to CD28 and its role in co-signaling. Kim, H.H., Tharayil, M., Rudd, C.E. J. Biol. Chem. (1998) [Pubmed]
  36. Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu. Xie, Y., Pendergast, A.M., Hung, M.C. J. Biol. Chem. (1995) [Pubmed]
  37. Divergent mechanisms for homologous desensitization of p21ras by insulin and growth factors. Klarlund, J.K., Cherniack, A.D., Czech, M.P. J. Biol. Chem. (1995) [Pubmed]
  38. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Murphy, M.A., Schnall, R.G., Venter, D.J., Barnett, L., Bertoncello, I., Thien, C.B., Langdon, W.Y., Bowtell, D.D. Mol. Cell. Biol. (1998) [Pubmed]
  39. Grap negatively regulates T-cell receptor-elicited lymphocyte proliferation and interleukin-2 induction. Shen, R., Ouyang, Y.B., Qu, C.K., Alonso, A., Sperzel, L., Mustelin, T., Kaplan, M.H., Feng, G.S. Mol. Cell. Biol. (2002) [Pubmed]
  40. Interleukin-11 induces complex formation of Grb2, Fyn, and JAK2 in 3T3L1 cells. Wang, X.Y., Fuhrer, D.K., Marshall, M.S., Yang, Y.C. J. Biol. Chem. (1995) [Pubmed]
  41. Changes in structural dynamics of the Grb2 adaptor protein upon binding of phosphotyrosine ligand to its SH2 domain. de Mol, N.J., Catalina, M.I., Fischer, M.J., Broutin, I., Maier, C.S., Heck, A.J. Biochim. Biophys. Acta (2004) [Pubmed]
  42. Insulin-stimulated disassociation of the SOS-Grb2 complex. Waters, S.B., Yamauchi, K., Pessin, J.E. Mol. Cell. Biol. (1995) [Pubmed]
  43. Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor. D'Ambrosio, D., Hippen, K.L., Cambier, J.C. Eur. J. Immunol. (1996) [Pubmed]
  44. High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia. Feller, S.M., Tuchscherer, G., Voss, J. Leuk. Lymphoma (2003) [Pubmed]
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