grb10 adaptor protein


Summary: A binding partner for several RECEPTOR PROTEIN-TYROSINE KINASES, including INSULIN RECEPTOR and INSULIN-LIKE GROWTH FACTOR RECEPTOR. It contains a C-terminal SH2 DOMAIN and mediates various SIGNAL TRANSDUCTION pathways.

Top Publications

  1. Wang L, Balas B, Christ Roberts C, Kim R, Ramos F, Kikani C, et al. Peripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivo. Mol Cell Biol. 2007;27:6497-505 pubmed
    ..Taken together, our results provide strong evidence that Grb10 is a negative regulator of insulin signaling and action in vivo. ..
  2. Stein E, Ghirlando R, Hubbard S. Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity. J Biol Chem. 2003;278:13257-64 pubmed
    ..Moreover, the structure suggests the mechanism by which the Grb7 SH2 domain binds selectively to pTyr-1139 (pYVNQ) in Her2, which along with Grb7 is co-amplified in human breast cancers. ..
  3. Liu F, Roth R. Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function. Proc Natl Acad Sci U S A. 1995;92:10287-91 pubmed
    ..These findings raise the possibility that Grb-IR is a SH2-domain-containing protein that directly complexes with the IR and serves to inhibit signaling or redirect the IR signaling pathway. ..
  4. Fadool D, Tucker K, Perkins R, Fasciani G, Thompson R, Parsons A, et al. Kv1.3 channel gene-targeted deletion produces "Super-Smeller Mice" with altered glomeruli, interacting scaffolding proteins, and biophysics. Neuron. 2004;41:389-404 pubmed
    ..3 plays a far more reaching role in signal transduction, development, and olfactory coding than that of the classically defined role of a potassium channel-to shape excitability by influencing membrane potential. ..
  5. Mano H, Ohya K, Miyazato A, Yamashita Y, Ogawa W, Inazawa J, et al. Grb10/GrbIR as an in vivo substrate of Tec tyrosine kinase. Genes Cells. 1998;3:431-41 pubmed
    ..We also reveal that expression of Grb10/GrbIR suppresses the cytokine-driven and Tec-driven activation of the c-fos promoter. Our results indicate a novel role of Grb10/GrbIR as an effector molecule to a subset of nonreceptor PTKs. ..
  6. Lim M, Riedel H, Liu F. Grb10: more than a simple adaptor protein. Front Biosci. 2004;9:387-403 pubmed
  7. Holt L, Daly R. Adapter protein connections: the MRL and Grb7 protein families. Growth Factors. 2005;23:193-201 pubmed
  8. Bereziat V, Kasus Jacobi A, Perdereau D, Cariou B, Girard J, Burnol A. Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. J Biol Chem. 2002;277:4845-52 pubmed
    ..These findings show that Grb14 is a direct inhibitor of the IR catalytic activity and could be considered as a modulator of insulin signaling. ..
  9. Morrione A. Grb10 adapter protein as regulator of insulin-like growth factor receptor signaling. J Cell Physiol. 2003;197:307-11 pubmed

More Information


  1. Frantz J, Giorgetti Peraldi S, Ottinger E, Shoelson S. Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains. J Biol Chem. 1997;272:2659-67 pubmed
    ..We conclude that hGrb-IRbeta/Grb10 is a widely expressed, PH and SH2 domain-containing, SH3 domain-binding protein that functions downstream from activated insulin and growth factor receptors. ..
  2. Yu Y, Yoon S, Poulogiannis G, Yang Q, Ma X, Villen J, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322-6 pubmed publisher
  3. Arnaud P, Monk D, Hitchins M, Gordon E, Dean W, Beechey C, et al. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Hum Mol Genet. 2003;12:1005-19 pubmed
    ..In the mouse this DMR is a gametic methylation mark. Our results suggest that the difference in imprinted expression in mouse and human is not due to acquisition of an imprint mark but in differences in the reading of this mark. ..
  4. Riedel H. Grb10 exceeding the boundaries of a common signaling adapter. Front Biosci. 2004;9:603-18 pubmed
    ..Thus, to think of Grb10 as either a positive or negative signaling mediator will be inadequate in reflecting the complexity that underlies the final output of the Grb10 signal. ..
  5. Zhang J, Zhang N, Liu M, Li X, Zhou L, Huang W, et al. Disruption of growth factor receptor-binding protein 10 in the pancreas enhances ?-cell proliferation and protects mice from streptozotocin-induced ?-cell apoptosis. Diabetes. 2012;61:3189-98 pubmed publisher
    ..This is critical for effective therapeutic treatment of both type 1 and 2 diabetes. ..
  6. Garfield A, Cowley M, Smith F, Moorwood K, Stewart Cox J, Gilroy K, et al. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature. 2011;469:534-8 pubmed publisher
    ..Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues. ..
  7. Hikichi T, Kohda T, Kaneko ishino T, Ishino F. Imprinting regulation of the murine Meg1/Grb10 and human GRB10 genes; roles of brain-specific promoters and mouse-specific CTCF-binding sites. Nucleic Acids Res. 2003;31:1398-406 pubmed
  8. Di Paola R, Ciociola E, Boonyasrisawat W, Nolan D, Duffy J, Miscio G, et al. Association of hGrb10 genetic variations with type 2 diabetes in Caucasian subjects. Diabetes Care. 2006;29:1181-3 pubmed
  9. Doiron B, Hu W, Norton L, DeFronzo R. Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels. Diabetologia. 2012;55:719-28 pubmed publisher
    ..GRB10 is critically involved in alpha cell survival and, as a result, plays an important role in regulating basal glucagon secretion and glucose tolerance in adult mice. ..
  10. Smith F, Holt L, Garfield A, Charalambous M, Koumanov F, Perry M, et al. Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Mol Cell Biol. 2007;27:5871-86 pubmed
    ..Thus, Grb10 forms a link between fetal growth and glucose-regulated metabolism in postnatal life and is a candidate for involvement in the process of fetal programming of adult metabolic health. ..
  11. He W, Rose D, Olefsky J, Gustafson T. 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 . J Biol Chem. 1998;273:6860-7 pubmed
    ..In summary, our findings demonstrate the existence of a previously unidentified tyrosine kinase activity-dependent binding domain located between the Pleckstrin homology and SH2 domains of Grb10. ..
  12. Shiura H, Miyoshi N, Konishi A, Wakisaka Saito N, Suzuki R, Muguruma K, et al. Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. Biochem Biophys Res Commun. 2005;329:909-16 pubmed
    ..Taken together, these results indicate that Meg1/Grb10 interacts with both insulin and IGF1 receptors in vivo, and negatively regulates the IGF growth pathways via these receptors. ..
  13. Holt L, Siddle K. Grb10 and Grb14: enigmatic regulators of insulin action--and more?. Biochem J. 2005;388:393-406 pubmed
  14. Rampersaud E, Damcott C, Fu M, Shen H, McArdle P, Shi X, et al. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes. 2007;56:3053-62 pubmed
    ..Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study. ..
  15. Hsu P, Kang S, Rameseder J, Zhang Y, Ottina K, Lim D, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317-22 pubmed publisher
    ..Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology. ..
  16. O Neill T, Rose D, Pillay T, Hotta K, Olefsky J, Gustafson T. Interaction of a GRB-IR splice variant (a human GRB10 homolog) with the insulin and insulin-like growth factor I receptors. Evidence for a role in mitogenic signaling. J Biol Chem. 1996;271:22506-13 pubmed
    ..Our findings suggest that GRB10/IR-SV1 may serve to positively link the insulin and IGF-I receptors to an uncharacterized mitogenic signaling pathway. ..
  17. Laviola L, Giorgino F, Chow J, Baquero J, Hansen H, Ooi J, et al. The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. J Clin Invest. 1997;99:830-7 pubmed
    ..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. ..
  18. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003;23:3363-72 pubmed
    ..This is the first demonstration of regulation of stability of a tyrosine kinase receptor by the Nedd4 (HECT) family of E3 ligases. ..
  19. Cook K, Fadool D. Two adaptor proteins differentially modulate the phosphorylation and biophysics of Kv1.3 ion channel by SRC kinase. J Biol Chem. 2002;277:13268-80 pubmed
    ..3 tyrosine phosphorylation, the channel's biophysical properties, and the physical complexes associated with Kv1.3 in the presence of Src kinase. ..
  20. Sanz L, Chamberlain S, Sabourin J, Henckel A, Magnuson T, Hugnot J, et al. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO J. 2008;27:2523-32 pubmed publisher
    ..Our data indicate that bivalent chromatin, in combination with neuronal factors, controls the paternal expression of Grb10 in brain. This finding highlights a novel mechanism to control tissue-specific imprinting. ..
  21. Yamasaki Ishizaki Y, Kayashima T, Mapendano C, Soejima H, Ohta T, Masuzaki H, et al. Role of DNA methylation and histone H3 lysine 27 methylation in tissue-specific imprinting of mouse Grb10. Mol Cell Biol. 2007;27:732-42 pubmed
    ..Here, we propose a molecular model that gametic DNA methylation and chromatin remodeling by PcG proteins during cell differentiation cause tissue-specific imprinting in embryonic tissues. ..
  22. Langlais P, Dong L, Hu D, Liu F. Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family. Oncogene. 2000;19:2895-903 pubmed
    ..Oncogene (2000). ..
  23. Blagitko N, Mergenthaler S, Schulz U, Wollmann H, Craigen W, Eggermann T, et al. Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum Mol Genet. 2000;9:1587-95 pubmed
    ..To our knowledge, this is the first example of a gene that is oppositely imprinted in mouse and human. ..
  24. Ramos F, Langlais P, Hu D, Dong L, Liu F. Grb10 mediates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation. Am J Physiol Endocrinol Metab. 2006;290:E1262-6 pubmed
    ..Together, our results suggest that, in addition to inhibiting IR kinase activity by directly binding to the IR, Grb10 also negatively regulates insulin signaling by mediating insulin-stimulated degradation of the receptor. ..
  25. Charalambous M, Smith F, Bennett W, Crew T, Mackenzie F, Ward A. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc Natl Acad Sci U S A. 2003;100:8292-7 pubmed
  26. Charalambous M, Cowley M, Geoghegan F, Smith F, Radford E, Marlow B, et al. Maternally-inherited Grb10 reduces placental size and efficiency. Dev Biol. 2010;337:1-8 pubmed publisher
    ..This grandparental effect suggests Grb10 can influence reproductive strategy through the allocation of maternal resources such that offspring number is offset against size...
  27. Holt L, Lyons R, Ryan A, Beale S, Ward A, Cooney G, et al. Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. Mol Endocrinol. 2009;23:1406-14 pubmed publisher
  28. Monk D, Arnaud P, Frost J, Hills F, Stanier P, Feil R, et al. Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Hum Mol Genet. 2009;18:3066-74 pubmed publisher
    ..The strong conservation of the opposite allelic expression in placenta versus brain supports the hypothesis that GRB10 imprinting evolved to mediate diverse roles in mammalian growth and behaviour. ..
  29. Depetris R, Wu J, Hubbard S. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nat Struct Mol Biol. 2009;16:833-9 pubmed publisher
  30. Eggermann T, Begemann M, Gogiel M, Palomares M, Vallespin E, Fernandez L, et al. Heterogeneous growth patterns in carriers of chromosome 7p12.2 imbalances affecting GRB10. Am J Med Genet A. 2012;158A:2815-9 pubmed publisher
    ..Indeed, it is necessary to compare the regions of imbalances in 7p12 and the affected genes in the different patients as other genes than GRB10 in 7p12 might cause these aberrant growth phenotypes. ..
  31. Mounier C, Lavoie L, Dumas V, Mohammad Ali K, Wu J, Nantel A, et al. Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway. Mol Cell Endocrinol. 2001;173:15-27 pubmed
    ..These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver. ..
  32. Dong L, Du H, Porter S, Kolakowski L, Lee A, Mandarino L, et al. Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma. J Biol Chem. 1997;272:29104-12 pubmed
  33. Jahn T, Seipel P, Urschel S, Peschel C, Duyster J. Role for the adaptor protein Grb10 in the activation of Akt. Mol Cell Biol. 2002;22:979-91 pubmed
    ..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. ..
  34. Huang Q, Szebenyi D. Structural basis for the interaction between the growth factor-binding protein GRB10 and the E3 ubiquitin ligase NEDD4. J Biol Chem. 2010;285:42130-9 pubmed publisher
    ..This report provides further evidence that SH2 domains can participate in important signaling interactions beyond the classical recognition of phosphotyrosine. ..
  35. Cailliau K, Le Marcis V, Bereziat V, Perdereau D, Cariou B, Vilain J, et al. Inhibition of FGF receptor signalling in Xenopus oocytes: differential effect of Grb7, Grb10 and Grb14. FEBS Lett. 2003;548:43-8 pubmed
    ..This study provided further evidence for specificity of the biological action of the Grb7 adapters on receptor tyrosine kinase signalling. ..
  36. Yoshihashi H, Maeyama K, Kosaki R, Ogata T, Tsukahara M, Goto Y, et al. Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. Am J Hum Genet. 2000;67:476-82 pubmed
    ..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. ..
  37. Nantel A, Huber M, Thomas D. Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool. J Biol Chem. 1999;274:35719-24 pubmed
    ..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. ..
  38. Xia H, Cao J, Jin X, Ma X. MiR199a is implicated in embryo implantation by regulating Grb10 in rat. Reproduction. 2014;147:91-9 pubmed publisher
    ..Enforced miR199a expression suppresses cell proliferation partially through targeting Grb10. ..
  39. Cao X, Lill N, Boase N, Shi P, Croucher D, Shan H, et al. Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal. 2008;1:ra5 pubmed publisher
    ..Thus, in vivo, Nedd4 appears to positively control IGF-1 and insulin signaling partly through the regulation of Grb10 function. ..
  40. Eggermann T, Meyer E, Wollmann H. Quantification of GRB10 in 7p12-p14 by fluorogenic 5' nuclease chemistry and application for genetic diagnosis in Silver-Russell syndrome. Ann Genet. 2004;47:99-102 pubmed
  41. Yao J, Huang Y, Huang R, Shi R, Chen P, Zhu B, et al. Epigenetic modifications and mRNA levels of the imprinted gene Grb10 in serially passaged fibroblast cells. Biochimie. 2012;94:2699-705 pubmed publisher
    ..The major-type transcript level of Grb10 in fibroblasts increased mildly after extended cultivation. These results suggest consecutive passaging may affect epigenetic modifications of Grb10 in adult fibroblast cells. ..
  42. Li L, Li X, Zhu Y, Zhang M, Yin D, Lu J, et al. Growth receptor binding protein 10 inhibits glucose-stimulated insulin release from pancreatic ?-cells associated with suppression of the insulin/insulin-like growth factor-1 signalling pathway. Clin Exp Pharmacol Physiol. 2013;40:841-7 pubmed publisher
    ..The results of the present study demonstrate that Grb10 is an important negative regulator of insulin/IGF-1 signalling in pancreatic ?-cells and a potential target to improve ?-cell function. ..
  43. Desbuquois B, Carré N, Burnol A. Regulation of insulin and type 1 insulin-like growth factor signaling and action by the Grb10/14 and SH2B1/B2 adaptor proteins. FEBS J. 2013;280:794-816 pubmed publisher
  44. Murdaca J, Treins C, Monthouël Kartmann M, Pontier Bres R, Kumar S, Van Obberghen E, et al. Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem. 2004;279:26754-61 pubmed
    ..In this study, we show that Grb10 acts as a positive regulator in VEGF-R2 signaling and protects VEGF-R2 from degradation by interacting with Nedd4, a component of the endocytic machinery. ..
  45. Liu Q, Wang Y, Chen Y, Zhang F, Gu T, Qu Y, et al. [The expression analysis of Grb10 during mouse embryonic development]. Yi Chuan. 2009;31:732-40 pubmed
    ..5 sections by using in situ hybridization analysis. Strong signals of Grb10 were detected in brain, spine, kidney, and muscle tissues. These results suggest that Grb10 may play an important role during the development process in mouse. ..
  46. Duselis A, Vrana P. Assessment and disease comparisons of hybrid developmental defects. Hum Mol Genet. 2007;16:808-19 pubmed
    ..We propose that such interactions and their resulting epimutations may similarly underlie the phenotypic and causal heterogeneity seen in many human diseases. ..
  47. Mirmohammadsadegh A, Baer A, Nambiar S, Bardenheuer W, Hengge U. Rapid identification of dysregulated genes in cutaneous malignant melanoma metastases using cDNA technology. Cells Tissues Organs. 2004;177:119-23 pubmed
    ..Ultimately, the identification of melanoma-associated genes may provide a potential therapeutic strategy for identifying and targeting malignant melanoma. ..
  48. Hitchins M, Bentley L, Monk D, Beechey C, Peters J, Kelsey G, et al. DDC and COBL, flanking the imprinted GRB10 gene on 7p12, are biallelically expressed. Mamm Genome. 2002;13:686-91 pubmed
    ..This may be a further example of over-expression of maternally derived transcripts in inter-specific mouse crosses. GRB10 remains the only imprinted gene identified within 7p11.2-p13. ..
  49. Guidoboni M, Doglioni C, Laurino L, Boiocchi M, Dolcetti R. Activation of infiltrating cytotoxic T lymphocytes and lymphoma cell apoptotic rates in gastric MALT lymphomas. Differences between high-grade and low-grade cases. Am J Pathol. 1999;155:823-9 pubmed
    ..Moreover, the finding of stronger cytotoxic responses in high- than in low-grade cases is of potential usefulness in the design of more effective therapeutic strategies for the management of these disorders. ..
  50. Schwemmle C, Luerssen K, Tolloczko R, Ptok M. [Child language development delay in craniofacial dysplasia]. HNO. 2004;52:150-2 pubmed
  51. Wick K, Werner E, Langlais P, Ramos F, Dong L, Shoelson S, et al. Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. J Biol Chem. 2003;278:8460-7 pubmed
    ..We conclude that binding of hGrb10gamma to IR decreases signaling through the IRS/PI 3-kinase/AKT pathway by physically blocking IRS access to IR. ..
  52. D Angelo G, Martini J, Iiri T, Fantl W, Martial J, Weiner R. 16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells. Mol Endocrinol. 1999;13:692-704 pubmed
    ..Taken together, these findings show that 16K hPRL inhibits the VEGF-induced Ras activation; this antagonism represents a novel and potentially important mechanism for the control of angiogenesis. ..
  53. Wilkins J, Ubeda F, Van Cleve J. The evolving landscape of imprinted genes in humans and mice: Conflict among alleles, genes, tissues, and kin. Bioessays. 2016;38:482-9 pubmed publisher
    ..Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression. ..