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Gene Review

GRB2  -  growth factor receptor-bound protein 2

Homo sapiens

Synonyms: ASH, Adapter protein GRB2, EGFRBP-GRB2, Grb3-3, Growth factor receptor-bound protein 2, ...
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Disease relevance of GRB2

  • We have used liposomes to deliver nuclease-resistant antisense oligodeoxynucleotides (oligos) specific for the GRB2 mRNA to breast cancer cells [1].
  • Interestingly, when the phage display peptides were then phosphorylated on tyrosine, their affinity for GRB2 increased dramatically [2].
  • IRS1 and GRB2 as members of the IGF signal transduction pathway are not associated with intrauterine growth retardation and Silver-Russell syndrome [3].
  • We have identified several bands in glial and medulloblastoma tumours that are recognized by Grb2 but these did not correspond to any known protein [4].
  • Taken together, this study indicates that Grb3-3 is a cellular factor that can be up-regulated by HIV-1 [5].

Psychiatry related information on GRB2


High impact information on GRB2

  • Here we report the cloning of the cDNA for a highly tyrosine-phosphorylated 36-38 kDa protein, previously characterized by its association with Grb2, phospholipase C-gamma1, and the p85 subunit of phosphoinositide 3-kinase [7].
  • We demonstrate that BCR-ABL exists in a complex with GRB-2 in vivo [8].
  • The SH2/SH3 domain-containing GRB-2 protein links tyrosine kinases to Ras signaling [8].
  • Immunoblotting experiments indicate that GRB2 associates with tyrosine-phosphorylated epidermal growth factor receptors (EGFRs) and platelet-derived growth factor receptors (PDGFRs) via its SH2 domain [9].
  • It also binds SHP-1 and Grb2 in vitro and has negative regulatory effects on cellular responses induced by growth factors, oncogenes or insulin [10].

Chemical compound and disease context of GRB2


Biological context of GRB2


Anatomical context of GRB2


Associations of GRB2 with chemical compounds


Physical interactions of GRB2

  • PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains [27].
  • Cdc42 and Grb2 bind simultaneously to N-WASp and enhance actin polymerization synergistically [28].
  • In these cells, CBLB constitutively binds the GRB2 adaptor predominantly through its N-terminal SH3 domain, to form a complex that is distinct from the GRB2.CBL and GRB2.SOS1 complexes [29].
  • Finally, the PKAI-EGF-R association occurs through the binding of RIalpha to the SH3 domain(s) of Grb2 adaptor protein, thus allowing the recruitment of the PKAI holoenzyme to the activated EGF-R [30].
  • The Grb2 SH3(C) binding region of Gab1 has significant homology to a region of the adapter protein SLP-76 [31].

Enzymatic interactions of GRB2

  • Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated betac receptor and Grb2 and its early activation are required for the coupling of the receptor to the Ras signaling pathway and for prevention of eosinophil death by IL-5 [32].
  • Combined cell lysates were affinity-purified over the SH2 domain of the adapter protein Grb2 (GST-SH2 fusion protein) that specifically binds phosphorylated EGFR and Src homologous and collagen (Shc) protein [33].
  • A constitutive complex of Grb2 and Cbl could be recruited to both receptor isoforms via docking of Shc to phosphorylated Tyr-1062 in RET [34].
  • Enzyme-linked immunosorbent assays confirmed the interaction between the SH2 domain of Grb2 and a tyrosine-phosphorylated MAP-2 peptide spanning the pY(67)SN motif [35].
  • Grb2 binding is mediated through a phosphorylated tyrosine residue (Y177) located within a consensus Grb2 binding site encoded by the first exon of the BCR gene [36].

Regulatory relationships of GRB2


Other interactions of GRB2

  • To relate the effects on gene transcription to a functional ERBB2 protein, signaling from the receptor was inhibited by the antibody 4D5, which blocks phosphorylation of ERBB2 on tyrosine residues and association of the protein with the GRB2/Sem5 protein [40].
  • In addition to the EGF receptor, PI3K-C2beta(2-298) also isolated both Shc and Grb2 from A431 cell lysates [41].
  • Activation of the epidermal growth factor (EGF) receptor induces formation of EGF receptor- and Grb2-containing clathrin-coated pits [42].
  • GAB1 was also associated with the molecular adapter GRB2 in unstimulated cells, and this association dramatically increased after Epo stimulation [43].
  • Phospho-Y1230/Y1231 directly recruits growth factor receptor-bonus protein (GRB2) to the receptor, inducing the activation of both AKT and extracellular signal-related kinase 1/2 (ERK1/2) signaling [44].

Analytical, diagnostic and therapeutic context of GRB2


  1. Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells. Tari, A.M., Hung, M.C., Li, K., Lopez-Berestein, G. Oncogene (1999) [Pubmed]
  2. Potent inhibitory ligands of the GRB2 SH2 domain from recombinant peptide libraries. Hart, C.P., Martin, J.E., Reed, M.A., Keval, A.A., Pustelnik, M.J., Northrop, J.P., Patel, D.V., Grove, J.R. Cell. Signal. (1999) [Pubmed]
  3. IRS1 and GRB2 as members of the IGF signal transduction pathway are not associated with intrauterine growth retardation and Silver-Russell syndrome. Eggermann, T., Kloos, P., Mergenthaler, S., Eggermann, K., Dobos, M., Ranke, M., Wollmann, H. Clin. Genet. (2001) [Pubmed]
  4. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Holgado-Madruga, M., Emlet, D.R., Moscatello, D.K., Godwin, A.K., Wong, A.J. Nature (1996) [Pubmed]
  5. Grb3-3 is up-regulated in HIV-1-infected T-cells and can potentiate cell activation through NFATc. Li, X., Multon, M.C., Henin, Y., Schweighoffer, F., Venot, C., Josef, J., Zhou, C., LaVecchio, J., Stuckert, P., Raab, M., Mhashilkar, A., Tocque, B., Marasco, W.A. J. Biol. Chem. (2000) [Pubmed]
  6. Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli. McShea, A., Zelasko, D.A., Gerst, J.L., Smith, M.A. Brain Res. (1999) [Pubmed]
  7. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., Samelson, L.E. Cell (1998) [Pubmed]
  8. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Pendergast, A.M., Quilliam, L.A., Cripe, L.D., Bassing, C.H., Dai, Z., Li, N., Batzer, A., Rabun, K.M., Der, C.J., Schlessinger, J. Cell (1993) [Pubmed]
  9. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Lowenstein, E.J., Daly, R.J., Batzer, A.G., Li, W., Margolis, B., Lammers, R., Ullrich, A., Skolnik, E.Y., Bar-Sagi, D., Schlessinger, J. Cell (1992) [Pubmed]
  10. A family of proteins that inhibit signalling through tyrosine kinase receptors. Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., Ullrich, A. Nature (1997) [Pubmed]
  11. Decreased mitogenic response to epidermal growth factor in human squamous cell carcinoma lines overexpressing epidermal growth factor receptor owing to limiting amounts of the adaptor protein Grb2: rescue by retinoic acid treatment. Crowe, D.L., Tsang, K.J. Mol. Carcinog. (2001) [Pubmed]
  12. Adenosine deaminase is a specific partner for the Grb2 isoform Grb3-3. Ramos-Morales, F., Domínguez, A., Rios, R.M., Barroso, S.I., Infante, C., Schweighoffer, F., Tocqué, B., Pintor-Toro, J.A., Tortolero, M. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  13. Downregulated expression of the signaling molecules Nck, c-Crk, Grb2/Ash, PI 3-kinase p110 alpha and WRN during fibroblast aging in vitro. Matuoka, K., Takenawa, T. Biochim. Biophys. Acta (1998) [Pubmed]
  14. Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain. Long, Y.Q., Guo, R., Luo, J.H., Yang, D., Roller, P.P. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Schlaepfer, D.D., Hanks, S.K., Hunter, T., van der Geer, P. Nature (1994) [Pubmed]
  16. Dominant-negative zeta-associated protein 70 inhibits T cell antigen receptor signaling. Qian, D., Mollenauer, M.N., Weiss, A. J. Exp. Med. (1996) [Pubmed]
  17. Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo. den Hertog, J., Tracy, S., Hunter, T. EMBO J. (1994) [Pubmed]
  18. Tight association of GRB2 with receptor protein-tyrosine phosphatase alpha is mediated by the SH2 and C-terminal SH3 domains. den Hertog, J., Hunter, T. EMBO J. (1996) [Pubmed]
  19. GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation. Sieh, M., Batzer, A., Schlessinger, J., Weiss, A. Mol. Cell. Biol. (1994) [Pubmed]
  20. Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. Motto, D.G., Ross, S.E., Wu, J., Hendricks-Taylor, L.R., Koretzky, G.A. J. Exp. Med. (1996) [Pubmed]
  21. Epidermal growth factor induces coupling of protein-tyrosine phosphatase 1D to GRB2 via the COOH-terminal SH3 domain of GRB2. Wong, L., Johnson, G.R. J. Biol. Chem. (1996) [Pubmed]
  22. Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells. Linseman, D.A., Benjamin, C.W., Jones, D.A. J. Biol. Chem. (1995) [Pubmed]
  23. Mapping GRB2, a signal transduction gene in the human and the mouse. Yulug, I.G., Egan, S.E., See, C.G., Fisher, E.M. Genomics (1994) [Pubmed]
  24. Regulation of GRB2 and FLICE2 expression by TNF-alpha in rheumatoid synovium. Huh, S.J., Paik, D.J., Chung, H.S., Youn, J. Immunol. Lett. (2003) [Pubmed]
  25. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Chardin, P., Camonis, J.H., Gale, N.W., van Aelst, L., Schlessinger, J., Wigler, M.H., Bar-Sagi, D. Science (1993) [Pubmed]
  26. soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling. Selfors, L.M., Schutzman, J.L., Borland, C.Z., Stern, M.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  27. p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation. Raab, M., Cai, Y.C., Bunnell, S.C., Heyeck, S.D., Berg, L.J., Rudd, C.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  28. GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott-Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex. Carlier, M.F., Nioche, P., Broutin-L'Hermite, I., Boujemaa, R., Le Clainche, C., Egile, C., Garbay, C., Ducruix, A., Sansonetti, P., Pantaloni, D. J. Biol. Chem. (2000) [Pubmed]
  29. The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells. Lavagna-Sévenier, C., Marchetto, S., Birnbaum, D., Rosnet, O. J. Biol. Chem. (1998) [Pubmed]
  30. The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor. Tortora, G., Damiano, V., Bianco, C., Baldassarre, G., Bianco, A.R., Lanfrancone, L., Pelicci, P.G., Ciardiello, F. Oncogene (1997) [Pubmed]
  31. The C-terminal SH3 domain of the adapter protein Grb2 binds with high affinity to sequences in Gab1 and SLP-76 which lack the SH3-typical P-x-x-P core motif. Lewitzky, M., Kardinal, C., Gehring, N.H., Schmidt, E.K., Konkol, B., Eulitz, M., Birchmeier, W., Schaeper, U., Feller, S.M. Oncogene (2001) [Pubmed]
  32. Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. Pazdrak, K., Adachi, T., Alam, R. J. Exp. Med. (1997) [Pubmed]
  33. A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling. Blagoev, B., Kratchmarova, I., Ong, S.E., Nielsen, M., Foster, L.J., Mann, M. Nat. Biotechnol. (2003) [Pubmed]
  34. Distinct turnover of alternatively spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase. Scott, R.P., Eketjäll, S., Aineskog, H., Ibáñez, C.F. J. Biol. Chem. (2005) [Pubmed]
  35. Fyn phosphorylates human MAP-2c on tyrosine 67. Zamora-Leon, S.P., Bresnick, A., Backer, J.M., Shafit-Zagardo, B. J. Biol. Chem. (2005) [Pubmed]
  36. Bcr phosphorylated on tyrosine 177 binds Grb2. Ma, G., Lu, D., Wu, Y., Liu, J., Arlinghaus, R.B. Oncogene (1997) [Pubmed]
  37. T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras. Schneider, H., Cai, Y.C., Prasad, K.V., Shoelson, S.E., Rudd, C.E. Eur. J. Immunol. (1995) [Pubmed]
  38. Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin. Pruett, W., Yuan, Y., Rose, E., Batzer, A.G., Harada, N., Skolnik, E.Y. Mol. Cell. Biol. (1995) [Pubmed]
  39. Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. Liu, L., Damen, J.E., Cutler, R.L., Krystal, G. Mol. Cell. Biol. (1994) [Pubmed]
  40. Overexpression of ERBB2 in human mammary epithelial cells signals inhibition of transcription of the E-cadherin gene. D'souza, B., Taylor-Papadimitriou, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  41. Recruitment of the class II phosphoinositide 3-kinase C2beta to the epidermal growth factor receptor: role of Grb2. Wheeler, M., Domin, J. Mol. Cell. Biol. (2001) [Pubmed]
  42. Activation of the epidermal growth factor (EGF) receptor induces formation of EGF receptor- and Grb2-containing clathrin-coated pits. Johannessen, L.E., Pedersen, N.M., Pedersen, K.W., Madshus, I.H., Stang, E. Mol. Cell. Biol. (2006) [Pubmed]
  43. Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Lecoq-Lafon, C., Verdier, F., Fichelson, S., Chrétien, S., Gisselbrecht, S., Lacombe, C., Mayeux, P. Blood (1999) [Pubmed]
  44. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Salameh, A., Galvagni, F., Bardelli, M., Bussolino, F., Oliviero, S. Blood (2005) [Pubmed]
  45. Cloning of a Grb2 isoform with apoptotic properties. Fath, I., Schweighoffer, F., Rey, I., Multon, M.C., Boiziau, J., Duchesne, M., Tocqué, B. Science (1994) [Pubmed]
  46. Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2. Wiederhold, T., Lee, M.F., James, M., Neujahr, R., Smith, N., Murthy, A., Hartwig, J., Gusella, J.F., Ramesh, V. Oncogene (2004) [Pubmed]
  47. Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. Nel, A.E., Gupta, S., Lee, L., Ledbetter, J.A., Kanner, S.B. J. Biol. Chem. (1995) [Pubmed]
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