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Gene Review

GRB10  -  growth factor receptor-bound protein 10

Homo sapiens

Synonyms: GRB-IR, GRB10 adapter protein, GRBIR, Grb-10, Growth factor receptor-bound protein 10, ...
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Disease relevance of GRB10

  • Owing to its location in 7p11.2-p12, GRB10 has been considered a candidate gene for the imprinted growth disorder, the Silver-Russell syndrome (SRS), but its predominantly biallelic expression argues against involvement in the syndrome [1].
  • Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10 and evaluation of its role in Hirschsprung disease [2].
  • We demonstrated increased expression of Grb10 mRNA in more than one half of primary cervical squamous cell cancers (12 of 15 cases) when compared to corresponding non-cancerous uterine squamous cell tissues [3].
  • Up-regulation of growth factor receptor-bound protein 10 in cervical squamous cell carcinoma [3].
  • These data suggest that a beneficial response to GH occurs in some patients with IUGR-associated short stature and that little difference exists in the responses in patients with RSS/PSS compared with those in patients with unclassified IUGR [4].

Psychiatry related information on GRB10

  • Levels of both IRBP protein and message in affected Abyssinian cat retinas were significantly reduced below normal as early as 4 weeks of age at the earliest stage of retinal disorientation [5].
  • Simple RSS allow for rapid decision making in the emergency department [6].

High impact information on GRB10

  • The recombination frequencies from pairwise linkage analysis between the disease and two marker loci D10S5 and IRBP were 0.19 and 0.11, with maximum lod scores of 3.6 and 8.0 respectively [7].
  • The linkage led us to investigate other chromosome 10 markers and demonstrate linkage between the disease locus and the interstitial retinol-binding protein (IRBP) gene [7].
  • We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific [8].
  • In addition, lack of IRBP expression solely in the thymus, even in the presence of aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity [9].
  • Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag) [10].

Chemical compound and disease context of GRB10


Biological context of GRB10

  • The human homologue GRB10 on chromosome 7q11.2-12 is a candidate gene for Silver-Russell syndrome [14].
  • The fact that monoallelic GRB10 expression was observed from the maternal allele in this study suggests but does not prove that these maternally transmitted mutant alleles contribute to the RSS phenotype [15].
  • As part of a systematic screen for novel imprinted genes of human chromosome 7 we have investigated GRB10, which belongs to a small family of adapter proteins, known to interact with a number of receptor tyrosine kinases and signalling molecules [16].
  • These data suggest that while GRB10 may be important for signal transduction in developing embryos, it does not play an obvious role in HSCR [2].
  • As a first step in testing this hypothesis, we examined common sequence variants in IGF2R and GRB10, two genes involved in the regulation of growth and subject to parental imprinting [17].

Anatomical context of GRB10

  • We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting [18].
  • In the present study, we first demonstrated that the GRB10 gene is also monoallelically expressed in human fetal brain tissues and is transcribed from the maternally derived allele in somatic-cell hybrids [15].
  • In skeletal muscle, one GRB10 isoform, gamma1, is expressed from the maternal allele alone, whereas in numerous other fetal tissues, all GRB10 splice variants are transcribed from both parental alleles [16].
  • Upon allele-specific transcription analysis involving multiple distinct splice variants in various fetal tissues, we found that human GRB10 is imprinted in a highly isoform- and tissue-specific manner [16].
  • Maternal repression of GRB10 was observed specifically in the developing central nervous system including brain and spinal cord, with biallelic expression in peripheral tissues [19].

Associations of GRB10 with chemical compounds


Physical interactions of GRB10

  • The SH2-containing adapter protein GRB10 interacts with BCR-ABL [24].
  • Here we demonstrate the existence of a second novel domain within Grb10 that interacts with the IR and insulin-like growth factor receptor in a kinase-dependent manner [25].
  • Two-hybrid analysis shows that the Grb10-binding site on Raf-1 co-localizes with its Ras-binding domain [26].

Regulatory relationships of GRB10

  • In the present manuscript, we demonstrate that Grb10 stimulates VEGF-R2 expression by inhibiting the Nedd4-mediated VEGF-R2 degradation [27].
  • Thus, we infer that Grb10 may regulate signaling between plasma membrane receptors and the apoptosis-inducing machinery on the mitochondrial outer membrane by modulating the anti-apoptotic activity of mitochondrial Raf-1 [26].
  • Many recent reports have suggested a very important role of Grb10 in regulating IGF-IR signaling [28].
  • The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors [29].

Other interactions of GRB10


Analytical, diagnostic and therapeutic context of GRB10

  • Using reverse-transcript PCR, we now confirm GRB10 imprinting in these two tissues is isoform-specific and, more importantly, demonstrate absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth [33].
  • The D10S5 locus was sublocalized to 10q21.1 by hybridization in situ and the IRBP gene to p11.2----q11.2 with a secondary site at q24----q25 [7].
  • (ii) Microinjection of the (dominant-negative) Grb10 SH2 domain interfered with PDGF-BB- and insulin-induced DNA synthesis [34].
  • Using immunofluorescence microscopy and subcellular fractionation we now show that most of the Grb10 molecules are peripherally associated with mitochondria [26].
  • We used this principle to design a strategy for gene therapy of experimental autoimmune uveitis, a cell-mediated autoimmune disease model for human uveitis induced with the uveitogenic interphotoreceptor retinoid-binding protein (IRBP) [35].


  1. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Arnaud, P., Monk, D., Hitchins, M., Gordon, E., Dean, W., Beechey, C.V., Peters, J., Craigen, W., Preece, M., Stanier, P., Moore, G.E., Kelsey, G. Hum. Mol. Genet. (2003) [Pubmed]
  2. Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10 and evaluation of its role in Hirschsprung disease. Angrist, M., Bolk, S., Bentley, K., Nallasamy, S., Halushka, M.K., Chakravarti, A. Oncogene (1998) [Pubmed]
  3. Up-regulation of growth factor receptor-bound protein 10 in cervical squamous cell carcinoma. Okino, K., Konishi, H., Doi, D., Yoneyama, K., Ota, Y., Jin, E., Kawanami, O., Takeshita, T. Oncol. Rep. (2005) [Pubmed]
  4. Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: the National Cooperative Growth Study experience. Chernausek, S.D., Breen, T.J., Frank, G.R. J. Pediatr. (1996) [Pubmed]
  5. An early decrease in interphotoreceptor retinoid-binding protein gene expression in Abyssinian cats homozygous for hereditary rod-cone degeneration. Wiggert, B., van Veen, T., Kutty, G., Lee, L., Nickerson, J., Si, J.S., Nilsson, S.E., Chader, G.J., Narfström, K. Cell Tissue Res. (1994) [Pubmed]
  6. Cardiac risk assessment: matching intensity of therapy to risk. Vesely, M.R., Kelemen, M.D. Cardiology clinics. (2006) [Pubmed]
  7. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Simpson, N.E., Kidd, K.K., Goodfellow, P.J., McDermid, H., Myers, S., Kidd, J.R., Jackson, C.E., Duncan, A.M., Farrer, L.A., Brasch, K. Nature (1987) [Pubmed]
  8. Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity. Grajewski, R.S., Silver, P.B., Agarwal, R.K., Su, S.B., Chan, C.C., Liou, G.I., Caspi, R.R. J. Exp. Med. (2006) [Pubmed]
  9. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. Devoss, J., Hou, Y., Johannes, K., Lu, W., Liou, G.I., Rinn, J., Chang, H., Caspi, R., Fong, L., Anderson, M.S. J. Exp. Med. (2006) [Pubmed]
  10. A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice. Pennesi, G., Mattapallil, M.J., Sun, S.H., Avichezer, D., Silver, P.B., Karabekian, Z., David, C.S., Hargrave, P.A., McDowell, J.H., Smith, W.C., Wiggert, B., Donoso, L.A., Chan, C.C., Caspi, R.R. J. Clin. Invest. (2003) [Pubmed]
  11. Butyrate enhances the synthesis of interphotoreceptor retinoid-binding protein (IRBP) by Y-79 human retinoblastoma cells. Kyritsis, A.P., Wiggert, B., Lee, L., Chader, G.J. J. Cell. Physiol. (1985) [Pubmed]
  12. Regulation of interphotoreceptor retinoid-binding protein (IRBP) gene expression by cAMP in differentiated retinoblastoma cells. El-Remessy, A.E., Rabie, A.M., El-Shishtawy, M.M., Eissa, L.A., Liou, G.I. Mol. Vis. (2000) [Pubmed]
  13. Variation in seasonal ultrastructure of sexual granules in the renal sexual segment of the Northern Water Snake, Nerodia sipedon sipedon. Krohmer, R.W. J. Morphol. (2004) [Pubmed]
  14. 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]
  15. Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. Yoshihashi, H., Maeyama, K., Kosaki, R., Ogata, T., Tsukahara, M., Goto, Y., Hata, J., Matsuo, N., Smith, R.J., Kosaki, K. Am. J. Hum. Genet. (2000) [Pubmed]
  16. Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Blagitko, N., Mergenthaler, S., Schulz, U., Wollmann, H.A., Craigen, W., Eggermann, T., Ropers, H.H., Kalscheuer, V.M. Hum. Mol. Genet. (2000) [Pubmed]
  17. Lack of association of birth size with polymorphisms of two imprinted genes, IGF2R and GRB10. Kukuvitis, A., Georgiou, I., Syrrou, M., Andronikou, S., Dickerman, Z., Islam, A., McCann, J., Polychronakos, C. Journal of pediatric endocrinology & metabolism : JPEM. (2004) [Pubmed]
  18. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome. Monk, D., Wakeling, E.L., Proud, V., Hitchins, M., Abu-Amero, S.N., Stanier, P., Preece, M.A., Moore, G.E. Am. J. Hum. Genet. (2000) [Pubmed]
  19. Maternal repression of the human GRB10 gene in the developing central nervous system; evaluation of the role for GRB10 in Silver-Russell syndrome. Hitchins, M.P., Monk, D., Bell, G.M., Ali, Z., Preece, M.A., Stanier, P., Moore, G.E. Eur. J. Hum. Genet. (2001) [Pubmed]
  20. The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. Pandey, A., Duan, H., Di Fiore, P.P., Dixit, V.M. J. Biol. Chem. (1995) [Pubmed]
  21. Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity. Stein, E.G., Ghirlando, R., Hubbard, S.R. J. Biol. Chem. (2003) [Pubmed]
  22. Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family. Langlais, P., Dong, L.Q., Hu, D., Liu, F. Oncogene (2000) [Pubmed]
  23. Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb10zeta as major phosphorylation sites. Langlais, P., Wang, C., Dong, L.Q., Carroll, C.A., Weintraub, S.T., Liu, F. Biochemistry (2005) [Pubmed]
  24. The SH2-containing adapter protein GRB10 interacts with BCR-ABL. Bai, R.Y., Jahn, T., Schrem, S., Munzert, G., Weidner, K.M., Wang, J.Y., Duyster, J. Oncogene (1998) [Pubmed]
  25. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. He, W., Rose, D.W., Olefsky, J.M., Gustafson, T.A. J. Biol. Chem. (1998) [Pubmed]
  26. Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool. Nantel, A., Huber, M., Thomas, D.Y. J. Biol. Chem. (1999) [Pubmed]
  27. Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. Murdaca, J., Treins, C., Monthouël-Kartmann, M.N., Pontier-Bres, R., Kumar, S., Van Obberghen, E., Giorgetti-Peraldi, S. J. Biol. Chem. (2004) [Pubmed]
  28. Grb10 adapter protein as regulator of insulin-like growth factor receptor signaling. Morrione, A. J. Cell. Physiol. (2003) [Pubmed]
  29. The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors. Stein, E.G., Gustafson, T.A., Hubbard, S.R. FEBS Lett. (2001) [Pubmed]
  30. Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome. Joyce, C.A., Sharp, A., Walker, J.M., Bullman, H., Temple, I.K. Hum. Genet. (1999) [Pubmed]
  31. Detection of maternal uniparental disomy at the two imprinted genes on chromosome 7, GRB10 and PEG1/MEST, in a Silver-Russell syndrome patient using methylation-specific PCR assays. Kim, Y., Kim, S.S., Kim, G., Park, S., Park, I.S., Yoo, H.W. Clin. Genet. (2005) [Pubmed]
  32. Possible parent-of-origin effect of Dopa decarboxylase in susceptibility to bipolar affective disorder. Børglum, A.D., Kirov, G., Craddock, N., Mors, O., Muir, W., Murray, V., McKee, I., Collier, D.A., Ewald, H., Owen, M.J., Blackwood, D., Kruse, T.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  33. Evidence against GRB10 as the gene responsible for Silver-Russell syndrome. McCann, J.A., Zheng, H., Islam, A., Goodyer, C.G., Polychronakos, C. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  34. Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis. Wang, J., Dai, H., Yousaf, N., Moussaif, M., Deng, Y., Boufelliga, A., Swamy, O.R., Leone, M.E., Riedel, H. Mol. Cell. Biol. (1999) [Pubmed]
  35. Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis. Agarwal, R.K., Kang, Y., Zambidis, E., Scott, D.W., Chan, C.C., Caspi, R.R. J. Clin. Invest. (2000) [Pubmed]
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