grb2 adaptor protein


Summary: A signal transducing adaptor protein that links extracellular signals to the MAP KINASE SIGNALING SYSTEM. Grb2 associates with activated EPIDERMAL GROWTH FACTOR RECEPTOR and PLATELET-DERIVED GROWTH FACTOR RECEPTORS via its SH2 DOMAIN. It also binds to and translocates the SON OF SEVENLESS PROTEINS through its SH3 DOMAINS to activate PROTO-ONCOGENE PROTEIN P21(RAS).

Top Publications

  1. Grandal M, Grøvdal L, Henriksen L, Andersen M, Holst M, Madshus I, et al. Differential roles of Grb2 and AP-2 in p38 MAPK- and EGF-induced EGFR internalization. Traffic. 2012;13:576-85 pubmed publisher
    ..Thus, it seems that EGFR in the two situations uses different sets of internalization mechanisms. ..
  2. Dharmawardana P, Peruzzi B, Giubellino A, Burke T, Bottaro D. Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy. Anticancer Drugs. 2006;17:13-20 pubmed
    ..These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics. ..
  3. McLaughlin W, Hou T, Wang W. Prediction of binding sites of peptide recognition domains: an application on Grb2 and SAP SH2 domains. J Mol Biol. 2006;357:1322-34 pubmed
    ..We also suggested novel roles for the proteins by reviewing their top interaction candidates. ..
  4. Tossidou I, Kardinal C, Peters I, Kriz W, Shaw A, Dikic I, et al. CD2AP/CIN85 balance determines receptor tyrosine kinase signaling response in podocytes. J Biol Chem. 2007;282:7457-64 pubmed
    ..Because repression of CIN85 protein leads to a restored RTK signaling response, our results support an important role of CD2AP/CIN85 protein balance in the normal signaling response of podocytes. ..
  5. Giubellino A, Burke T, Bottaro D. Grb2 signaling in cell motility and cancer. Expert Opin Ther Targets. 2008;12:1021-33 pubmed
    ..These functions make Grb2 a therapeutic target for strategies designed to prevent the spread of solid tumors through local invasion and metastasis. ..
  6. Harkiolaki M, Tsirka T, Lewitzky M, Simister P, Joshi D, Bird L, et al. Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2. Structure. 2009;17:809-22 pubmed publisher
    ..In summary, our study reveals interaction types of SH3 domains, highlighting their great versatility. ..
  7. Zhang J, Koenig A, Young C, Billadeau D. GRB2 couples RhoU to epidermal growth factor receptor signaling and cell migration. Mol Biol Cell. 2011;22:2119-30 pubmed publisher
    ..Taken together, the data suggest a unique regulatory mechanism by which RhoU interaction with SH3 adaptor proteins might serve to integrate growth factor receptor signaling with RhoU activation. ..
  8. Jiang X, Sorkin A. Epidermal growth factor receptor internalization through clathrin-coated pits requires Cbl RING finger and proline-rich domains but not receptor polyubiquitylation. Traffic. 2003;4:529-43 pubmed
    ..We propose that the RING domain of Cbl facilitates endocytosis either by epidermal growth factor receptor monoubiquitylation or by ubiquitylation of proteins associated with the receptor...
  9. Gaston I, Johnson K, Oda T, Bhat A, Reis M, Langdon W, et al. Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl. Exp Hematol. 2004;32:113-21 pubmed
    ..Following this initial interaction, Cbl can then become tyrosine phosphorylated and interact with the SH2 domain of Bcr-Abl, further stabilizing the complex. ..

More Information


  1. Hamazaki T, Kehoe S, Nakano T, Terada N. The Grb2/Mek pathway represses Nanog in murine embryonic stem cells. Mol Cell Biol. 2006;26:7539-49 pubmed
    ..These data indicate that the Grb2/Mek pathway primarily mediates Nanog gene repression upon ES cell differentiation into primitive endoderm. ..
  2. Schulze W, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol. 2005;1:2005.0008 pubmed
    ..Our results demonstrate that system-wide mapping of peptide-protein interactions sites is possible, and suggest shared and unique roles of ErbB-receptor family members in downstream signaling. ..
  3. Chazaud C, Yamanaka Y, Pawson T, Rossant J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell. 2006;10:615-24 pubmed
    ..We propose a model in which the ICM develops as a mosaic of EPI and PE progenitors at E3.5, dependent on Grb2-Ras-MAP kinase signaling, followed by later segregation of the progenitors into the appropriate cell layers...
  4. Upshaw J, Arneson L, Schoon R, Dick C, Billadeau D, Leibson P. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006;7:524-32 pubmed
    ..These findings identify a previously unknown mechanism by which NKG2D-DAP10 mediates cytotoxicity and provides a framework for evaluating activation by other receptor complexes that lack immunoreceptor tyrosine-based activation motifs. ..
  5. Bisson N, James D, Ivosev G, Tate S, Bonner R, Taylor L, et al. Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor. Nat Biotechnol. 2011;29:653-8 pubmed publisher
    ..Capturing a key hub protein and dissecting its interactions by SRM should be equally applicable to quantifying signaling dynamics for a range of hubs in protein interaction networks. ..
  6. Ahmed Z, George R, Lin C, Suen K, Levitt J, Suhling K, et al. Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function. Cell Signal. 2010;22:23-33 pubmed publisher
    ..Synthetic peptides based on the C-terminus of FGFR2 bind to full length Grb2 with low micromolar affinity. The function of this novel mode of Grb2 binding provides resistance to site-specific Shp2-mediated receptor dephosphorylation. ..
  7. Siegel A, Herskowitz J, Speck S. The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog. 2008;4:e1000039 pubmed publisher
    ..Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis-identifying a strategy that appears to be conserved between at least EBV and MHV68. ..
  8. Giubellino A, Gao Y, Lee S, Lee M, Vasselli J, Medepalli S, et al. Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist. Cancer Res. 2007;67:6012-6 pubmed
    ..These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process. ..
  9. Jeong S, Kim S, Yoo J, Han M, Park J, Kim H, et al. Increased association of dynamin II with myosin II in ras transformed NIH3T3 cells. Acta Biochim Biophys Sin (Shanghai). 2006;38:556-62 pubmed
    ..These results suggest that dynamin II acts as an intermediate messenger in the Ras signal transduction pathway leading to membrane ruffling and cell migration. ..
  10. Sigismund S, Algisi V, Nappo G, Conte A, Pascolutti R, Cuomo A, et al. Threshold-controlled ubiquitination of the EGFR directs receptor fate. EMBO J. 2013;32:2140-57 pubmed publisher
    ..Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation. ..
  11. Schulze W, Mann M. A novel proteomic screen for peptide-protein interactions. J Biol Chem. 2004;279:10756-64 pubmed
    ..Our data are consistent with a change in the role of Sos from Ras-dependent signaling to actin remodeling/endocytic signaling events by a proline-SH3 domain switch. ..
  12. Huang F, Sorkin A. Growth factor receptor binding protein 2-mediated recruitment of the RING domain of Cbl to the epidermal growth factor receptor is essential and sufficient to support receptor endocytosis. Mol Biol Cell. 2005;16:1268-81 pubmed
    ..We concluded that Grb2-mediated recruitment of the functional RING domain of Cbl to the EGFR is essential and sufficient to support receptor endocytosis. ..
  13. Raychaudhuri M, Mukhopadhyay D. Grb2-mediated alteration in the trafficking of AbetaPP: insights from Grb2-AICD interaction. J Alzheimers Dis. 2010;20:275-92 pubmed publisher
    ..Having established the Grb2-mediated trafficking of AICD and its impairment, the significance of its consequence has now become apparent in the downstream events of AD pathogenesis. ..
  14. Sorkin A, Goh L. Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res. 2008;314:3093-106 pubmed publisher
    ..The role of EGFR interaction with the Grb2 adaptor protein and Cbl ubiquitin ligase, and receptor ubiquitination in the clathrin-dependent internalization and sorting ..
  15. Jang I, Zhang J, Gu H. Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling. Immunol Rev. 2009;232:150-9 pubmed publisher
  16. Million R, Harakawa N, Roumiantsev S, Varticovski L, Van Etten R. A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase. Mol Cell Biol. 2004;24:4685-95 pubmed
    ..These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins. ..
  17. Cho S, Velikovsky C, Swaminathan C, Houtman J, Samelson L, Mariuzza R. Structural basis for differential recognition of tyrosine-phosphorylated sites in the linker for activation of T cells (LAT) by the adaptor Gads. EMBO J. 2004;23:1441-51 pubmed
  18. McDonald C, Seldeen K, Deegan B, Farooq A. Structural basis of the differential binding of the SH3 domains of Grb2 adaptor to the guanine nucleotide exchange factor Sos1. Arch Biochem Biophys. 2008;479:52-62 pubmed publisher
    ..Taken together, our study provides structural basis of the differential binding of SH3 domains of Grb2 to Sos1 and a detailed thermodynamic profile of this key protein-protein interaction pertinent to cellular signaling and cancer. ..
  19. Garg P, Verma R, Nihalani D, Johnstone D, Holzman L. Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol. 2007;27:8698-712 pubmed
  20. Nag A, Monine M, Faeder J, Goldstein B. Aggregation of membrane proteins by cytosolic cross-linkers: theory and simulation of the LAT-Grb2-SOS1 system. Biophys J. 2009;96:2604-23 pubmed publisher
    ..We discuss the model predictions in light of recent experiments on RBL-2H3 and Jurkat E6.1 cells and suggest that the gel phase has been observed in activated mast cells. ..
  21. Oak S, Zhou Y, Jarrett H. Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1. J Biol Chem. 2003;278:39287-95 pubmed
    ..In the presence of laminin, c-Jun is activated in both skeletal muscle microsomes and in C2C12 myoblasts, and proliferation increases in C2C12 myoblasts. We postulate that this pathway signals muscle homeostasis and hypertrophy. ..
  22. Goh L, Huang F, Kim W, Gygi S, Sorkin A. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J Cell Biol. 2010;189:871-83 pubmed publisher
    ..mechanisms involve ubiquitination of the receptor kinase domain, the clathrin adaptor complex AP-2, the Grb2 adaptor protein, and three C-terminal lysine residues (K1155, K1158, and K1164), which are acetylated, a novel ..
  23. Sato T, Shimazaki T, Naka H, Fukami S, Satoh Y, Okano H, et al. FRS2? regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells. Stem Cells. 2010;28:1661-73 pubmed publisher
    ..Thus, FRS2? fine-tunes the FGF-signaling to control qualitatively different biological activities, self-renewal at least partly through Hes1 versus proliferation of NSPCs. ..
  24. Sun J, Pedersen M, Bengtsson S, Ronnstrand L. Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl. Exp Cell Res. 2007;313:3935-42 pubmed
  25. Riera L, Lasorsa E, Ambrogio C, Surrenti N, Voena C, Chiarle R. Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated signaling and anaplastic large cell lymphoma growth. J Biol Chem. 2010;285:26441-50 pubmed publisher
    ..Finally, shRNA knockdown experiments showed that Grb2 regulates primarily the NPM-ALK-mediated phosphorylation of SHP2 and plays a key role in ALCL cell growth. ..
  26. Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y, et al. Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proc Natl Acad Sci U S A. 2004;101:17144-9 pubmed
    ..These experiments demonstrate that intracellular signals that depend on specific tyrosine residues in FRS2alpha lie upstream of gene products critical for induction of lens and retina. ..
  27. Houtman J, Higashimoto Y, Dimasi N, Cho S, Yamaguchi H, Bowden B, et al. Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences. Biochemistry. 2004;43:4170-8 pubmed
    ..These studies provide quantitative information on how different binding parameters can determine in vivo binding site specificity observed for multiprotein signaling complexes. ..
  28. Stork B, Engelke M, Frey J, Horejsi V, Hamm Baarke A, Schraven B, et al. Grb2 and the non-T cell activation linker NTAL constitute a Ca(2+)-regulating signal circuit in B lymphocytes. Immunity. 2004;21:681-91 pubmed
  29. McDonald C, Seldeen K, Deegan B, Farooq A. SH3 domains of Grb2 adaptor bind to PXpsiPXR motifs within the Sos1 nucleotide exchange factor in a discriminate manner. Biochemistry. 2009;48:4074-85 pubmed publisher
    ..Taken together, this study furthers our understanding of the assembly of a key signaling complex central to cellular machinery. ..
  30. Dance M, Montagner A, Salles J, Yart A, Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal. 2008;20:453-9 pubmed
  31. Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, et al. Neph1, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2. J Biol Chem. 2008;283:9177-86 pubmed publisher
    ..Thus, SFK orchestrates a wide spectrum of protein-protein interactions and intracellular signaling networks at SD through tyrosine phosphorylation. ..
  32. Das S, Raychaudhuri M, Sen U, Mukhopadhyay D. Functional implications of the conformational switch in AICD peptide upon binding to Grb2-SH2 domain. J Mol Biol. 2011;414:217-30 pubmed publisher
    ..Our results reveal the significance of a specific interaction of the two molecules to optimize the rapid transport of AICD inside endosomal vesicles presumably to reduce the cytotoxic load. ..
  33. Shen X, Xi G, Radhakrishnan Y, Clemmons D. Recruitment of Pyk2 to SHPS-1 signaling complex is required for IGF-I-dependent mitogenic signaling in vascular smooth muscle cells. Cell Mol Life Sci. 2010;67:3893-903 pubmed publisher
    ..Thus, Pyk2 recruitment to SHPS-1 plays an important role in regulating the IGF-I-stimulated mitogenic response. ..
  34. Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, Mellman I. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature. 2010;464:783-7 pubmed publisher
    ..Interestingly, dimers were enriched in the cell periphery in an actin- and receptor-expression-dependent fashion, resulting in a peripheral enhancement of EGF-induced signalling that may enable polarized responses to growth factors. ..
  35. Weisswange I, Newsome T, Schleich S, Way M. The rate of N-WASP exchange limits the extent of ARP2/3-complex-dependent actin-based motility. Nature. 2009;458:87-91 pubmed publisher
    ..We suggest that the exchange rate of N-WASP controls the rate of ARP2/3-complex-dependent actin-based motility by regulating the extent of actin polymerization by antagonizing filament capping. ..
  36. Herskowitz J, Siegel A, Jacoby M, Speck S. Systematic mutagenesis of the murine gammaherpesvirus 68 M2 protein identifies domains important for chronic infection. J Virol. 2008;82:3295-310 pubmed publisher
    ..Taken together, these analyses will aide future studies for identifying M2 interacting partners and B-cell signaling pathways that are manipulated by the M2 protein...
  37. Huang F, Goh L, Sorkin A. EGF receptor ubiquitination is not necessary for its internalization. Proc Natl Acad Sci U S A. 2007;104:16904-9 pubmed
    ..Altogether these data emphasize the robustness of the EGFR internalization process, which can be controlled by multiple kinase- and ubiquitination-dependent and -independent mechanisms. ..
  38. Koonpaew S, Janssen E, Zhu M, Zhang W. The importance of three membrane-distal tyrosines in the adaptor protein NTAL/LAB. J Biol Chem. 2004;279:11229-35 pubmed
    ..Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function. ..
  39. Houtman J, Yamaguchi H, Barda Saad M, Braiman A, Bowden B, Appella E, et al. Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1. Nat Struct Mol Biol. 2006;13:798-805 pubmed
    ..These data suggest that multipoint binding of distal adaptor proteins mediates the formation of oligomeric signaling clusters vital for intracellular signaling. ..
  40. Shutes A, Berzat A, Cox A, Der C. Atypical mechanism of regulation of the Wrch-1 Rho family small GTPase. Curr Biol. 2004;14:2052-6 pubmed
    ..We propose that Grb2 overcomes N-terminal negative regulation to promote Wrch-1 effector interaction. Thus, Wrch-1 exhibits an atypical model of regulation not seen in other Rho family GTPases. ..
  41. Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006;21:737-48 pubmed
    ..Taken together, these data provide direct evidence for the role of EGFR ubiquitination in receptor targeting to the lysosome and implicate Lys63-linked polyubiquitin chains in this sorting process. ..
  42. Lin C, Melo F, Ghosh R, Suen K, Stagg L, Kirkpatrick J, et al. Inhibition of basal FGF receptor signaling by dimeric Grb2. Cell. 2012;149:1514-24 pubmed publisher
    ..These observations establish a role for Grb2 as an active regulator of RTK signaling. ..
  43. Araki T, Nawa H, Neel B. Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors. J Biol Chem. 2003;278:41677-84 pubmed
  44. Ogura K, Shiga T, Yokochi M, Yuzawa S, Burke T, Inagaki F. Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor. J Biomol NMR. 2008;42:197-207 pubmed publisher
    ..Based on the binding interactions between the inhibitor and the Grb2 SH2 domain in solution, we proposed a design of second-generation inhibitors that could be expected to have higher affinity. ..
  45. Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol. 2005;168:441-52 pubmed
    ..These results indicate that EGF receptor signaling regulates invadopodium formation through the N-WASP-Arp2/3 pathway and cofilin is necessary for the stabilization and maturation of invadopodia. ..
  46. Hinsby A, Olsen J, Mann M. Tyrosine phosphoproteomics of fibroblast growth factor signaling: a role for insulin receptor substrate-4. J Biol Chem. 2004;279:46438-47 pubmed
    ..Finally, we present evidence for a complex containing insulin receptor substrate-4 and ShcA in signaling by the fibroblast growth factor receptor. ..
  47. Khanday F, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Dericco J, et al. Sos-mediated activation of rac1 by p66shc. J Cell Biol. 2006;172:817-22 pubmed
    ..This relationship between p66shc, grb2, and sos1 provides a novel mechanism for the activation of rac1. ..
  48. Johannessen L, Pedersen N, Pedersen K, Madshus I, Stang E. Activation of the epidermal growth factor (EGF) receptor induces formation of EGF receptor- and Grb2-containing clathrin-coated pits. Mol Cell Biol. 2006;26:389-401 pubmed
    ..Our data demonstrate that EGFR-induced signaling and Grb2 are essential for formation of clathrin-coated pits accommodating the EGFR, while activation of MAPK and PI3K is not required. ..
  49. Hartgroves L, Lin J, Langen H, Zech T, Weiss A, Harder T. Synergistic assembly of linker for activation of T cells signaling protein complexes in T cell plasma membrane domains. J Biol Chem. 2003;278:20389-94 pubmed
    ..Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. ..
  50. Yamasaki S, Nishida K, Sakuma M, Berry D, McGlade C, Hirano T, et al. Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells. Mol Cell Biol. 2003;23:2515-29 pubmed
  51. Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, et al. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J. 2002;21:303-13 pubmed
    ..Thus, in addition to its well-characterized role in mediating positive signals, Grb2 can terminate signal transduction by accelerating c-Cbl-dependent sorting of active tyrosine kinases to destruction. ..
  52. Lu W, Gong D, Bar Sagi D, Cole P. Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol Cell. 2001;8:759-69 pubmed
    ..These studies support a novel mechanism explaining how tyrosine phosphorylation of a PTPase is important in signal transduction. ..
  53. Oak S, Russo K, Petrucci T, Jarrett H. Mouse alpha1-syntrophin binding to Grb2: further evidence of a role for syntrophin in cell signaling. Biochemistry. 2001;40:11270-8 pubmed
    ..Grb2-C-SH3 domain bound syntrophin with slightly higher affinity than Grb2-N-SH3 domain. Crk-L, an SH2/SH3 protein of similar domain structure but different specificity, does not bind these syntrophin sequences. ..