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Gene Review

Grb10  -  growth factor receptor bound protein 10

Mus musculus

Synonyms: 5730571D09Rik, AI325020, GRB10 adapter protein, Growth factor receptor-bound protein 10, Maternally expressed gene 1 protein, ...
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High impact information on Grb10

  • In conclusion, Grb10 interacts preferentially with insulin vs. IGF-I receptors in intact cells and, thus, may have a role in mediating insulin receptor-specific cellular responses [1].
  • The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts [1].
  • Subsequent cloning of the full-length Grb10 sequence from a mouse fat cDNA library defined a previously unknown Grb10 variant, that appears to be the predominant isoform in mouse tissues [1].
  • Because Grb10 is a signaling protein capable of interacting with tyrosine kinase receptors, we tested genetically whether Grb10 might act downstream of insulin-like growth factor 2, a paternally expressed growth-promoting gene [2].
  • The result indicates that Grb10 action is essentially independent of insulin-like growth factor 2, providing evidence that imprinting acts on at least two major fetal growth axes in a manner consistent with parent-offspring conflict theory [2].

Biological context of Grb10

  • Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene [3].
  • Published data from transfection/overexpression studies support both positive and negative regulatory effects of Grb10, thus leaving its physiological role unclear [4].
  • Although IGF-I receptor autophosphorylation normally correlates with receptor signaling, we demonstrate a decrease in IGF-I-stimulated receptor phosphorylation in Grb10 knockdown cells [5].
  • Our experiments confirm that Grb10 is subject to genomic imprinting with the majority of Grb10 expression arising from the maternally inherited allele [2].
  • The role of different Grb10 splice variants in signal transduction of growth factors like insulin or insulin-like growth factor has been described as inhibitory or stimulatory depending on the presence of a functional PH and/or SH2 domain [6].

Anatomical context of Grb10

  • Dominant-negative Grb10 domains, in particular the SH2 domain, eliminated the metabolic response to insulin in differentiated 3T3-L1 adipocytes [7].
  • At least three forms of Grb10 exist in fibroblasts apparently due to alternate translational start sites [8].
  • We propose a model in which Grb10 acts as a coactivator for Akt by virtue of its ability to form a complex with Akt and its SH2 domain-dependent translocation to the cell membrane [6].
  • A self-phosphorylated recombinant, baculovirus-expressed GST-ELKcy fusion protein bound Grb10 and Grb2 from human renal microvascular endothelial cell extracts, while the unphosphorylated fusion form did not [9].
  • Binding of Grb10 or Grb14 to autophosphorylated IR in vitro inhibits tyrosine kinase activity towards other substrates, but studies on cultured cell lines have been conflicting as to whether Grb10 plays a positive or negative role in insulin signalling [10].

Associations of Grb10 with chemical compounds


Physical interactions of Grb10

  • Grb10 interacting with Nedd4 was not ubiquitinated in vivo, raising the possibility that this interaction may be used to target other proteins, like tyrosine kinase receptors, for ubiquitination [14].

Regulatory relationships of Grb10

  • We found that overexpression of Grb10 inhibited the insulin-stimulated phosphorylation of Shc, a positive regulator of the MAPK signaling pathway [15].

Other interactions of Grb10

  • The interaction with Grb10 in the two-hybrid system was confirmed using the full-length Nedd4, and it was abolished by deleting the last 148 amino acids of Grb10, a region that includes the SH2 domain and the newly identified BPS domain [14].
  • Grb10 is highly related to Grb7, an SH2 domain protein that we have previously identified [8].
  • These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice [16].
  • Receptor-deficient R- cells (fibroblasts from mice with homologous disruption of the IGF-I receptor gene) and transfected R- cells expressing either insulin receptors (R-IR cells) or IGF-I receptors (R+ cells) were used to investigate the specificity of Grb10 interaction with the two related receptors [1].
  • Meg1/Grb10 maps about 15 cM from U2af1-rs1 and is separated by conserved regions showing homology with two different human chromosomes [17].

Analytical, diagnostic and therapeutic context of Grb10

  • Reverse transcriptase PCR analysis revealed that the imprinted paternal expression of Grb10 in the brain implied neuron-specific and developmental stage-specific expression from the paternal brain type promoter, whereas in glial cells and fibroblasts, Grb10 was reciprocally expressed from the maternal major-type promoter [18].


  1. The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. Laviola, L., Giorgino, F., Chow, J.C., Baquero, J.A., Hansen, H., Ooi, J., Zhu, J., Riedel, H., Smith, R.J. J. Clin. Invest. (1997) [Pubmed]
  2. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Charalambous, M., Smith, F.M., Bennett, W.R., Crew, T.E., Mackenzie, F., Ward, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene. Miyoshi, N., Kuroiwa, Y., Kohda, T., Shitara, H., Yonekawa, H., Kawabe, T., Hasegawa, H., Barton, S.C., Surani, M.A., Kaneko-Ishino, T., Ishino, F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. Giovannone, B., Lee, E., Laviola, L., Giorgino, F., Cleveland, K.A., Smith, R.J. J. Biol. Chem. (2003) [Pubmed]
  5. The adapter protein GRB10 is an endogenous negative regulator of insulin-like growth factor signaling. Dufresne, A.M., Smith, R.J. Endocrinology (2005) [Pubmed]
  6. Role for the adaptor protein Grb10 in the activation of Akt. Jahn, T., Seipel, P., Urschel, S., Peschel, C., Duyster, J. Mol. Cell. Biol. (2002) [Pubmed]
  7. Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. Deng, Y., Bhattacharya, S., Swamy, O.R., Tandon, R., Wang, Y., Janda, R., Riedel, H. J. Biol. Chem. (2003) [Pubmed]
  8. The cloning of Grb10 reveals a new family of SH2 domain proteins. Ooi, J., Yajnik, V., Immanuel, D., Gordon, M., Moskow, J.J., Buchberg, A.M., Margolis, B. Oncogene (1995) [Pubmed]
  9. Ligand activation of ELK receptor tyrosine kinase promotes its association with Grb10 and Grb2 in vascular endothelial cells. Stein, E., Cerretti, D.P., Daniel, T.O. J. Biol. Chem. (1996) [Pubmed]
  10. Grb10 and Grb14: enigmatic regulators of insulin action--and more? Holt, L.J., Siddle, K. Biochem. J. (2005) [Pubmed]
  11. Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling. Mori, K., Giovannone, B., Smith, R.J. Mol. Cell. Endocrinol. (2005) [Pubmed]
  12. Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Smith, F.M., Holt, L.J., Garfield, A.S., Charalambous, M., Koumanov, F., Perry, M., Bazzani, R., Sheardown, S.A., Hegarty, B.D., Lyons, R.J., Cooney, G.J., Daly, R.J., Ward, A. Mol. Cell. Biol. (2007) [Pubmed]
  13. Peripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivo. Wang, L., Balas, B., Christ-Roberts, C.Y., Kim, R.Y., Ramos, F.J., Kikani, C.K., Li, C., Deng, C., Reyna, S., Musi, N., Dong, L.Q., DeFronzo, R.A., Liu, F. Mol. Cell. Biol. (2007) [Pubmed]
  14. mGrb10 interacts with Nedd4. Morrione, A., Plant, P., Valentinis, B., Staub, O., Kumar, S., Rotin, D., Baserga, R. J. Biol. Chem. (1999) [Pubmed]
  15. Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10. Langlais, P., Dong, L.Q., Ramos, F.J., Hu, D., Li, Y., Quon, M.J., Liu, F. Mol. Endocrinol. (2004) [Pubmed]
  16. Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. Shiura, H., Miyoshi, N., Konishi, A., Wakisaka-Saito, N., Suzuki, R., Muguruma, K., Kohda, T., Wakana, S., Yokoyama, M., Ishino, F., Kaneko-Ishino, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  17. Association of a redefined proximal mouse chromosome 11 imprinting region and U2afbp-rs/U2af1-rs1 expression. Cattanach, B.M., Shibata, H., Hayashizaki, Y., Townsend, K.M., Ball, S., Beechey, C.V. Cytogenet. Cell Genet. (1998) [Pubmed]
  18. Role of DNA methylation and histone h3 lysine 27 methylation in tissue-specific imprinting of mouse grb10. Yamasaki-Ishizaki, Y., Kayashima, T., Mapendano, C.K., Soejima, H., Ohta, T., Masuzaki, H., Kinoshita, A., Urano, T., Yoshiura, K., Matsumoto, N., Ishimaru, T., Mukai, T., Niikawa, N., Kishino, T. Mol. Cell. Biol. (2007) [Pubmed]
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