GRB2

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.[1][2]

The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the sem-5 gene of Caenorhabditis elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.[3]

Function and expression

Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that targeted gene disruption of Grb2 in mice is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain. Grb2 has two closely related proteins with similar domain organizations, Gads and Grap. Gads and Grap are expressed specifically in hematopoietic cells and function in the coordination of tyrosine kinase mediated signal transduction.

Domains

The SH2 domain of Grb2 binds to phosphorylated tyrosine-containing peptides on receptors or scaffold proteins with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine (see [2]).

The N-terminal SH3 domain binds to proline-rich peptides and can bind to the Ras-guanine exchange factor SOS.

The C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1.[4]

Interactions

Grb2 has been shown to interact with:

See also

References

  1. ↑ Matuoka K, Shibata M, Yamakawa A, Takenawa T (Oct 1992). "Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries". Proceedings of the National Academy of Sciences of the United States of America. 89 (19): 9015–9. doi:10.1073/pnas.89.19.9015. PMC 50055. PMID 1384039.
  2. ↑ 2.0 2.1 Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J (Aug 1992). "The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling". Cell. 70 (3): 431–42. doi:10.1016/0092-8674(92)90167-B. PMID 1322798.
  3. ↑ "Entrez Gene: GRB2 growth factor receptor-bound protein 2".
  4. ↑ Berry DM, Nash P, Liu SK, Pawson T, McGlade CJ (Aug 2002). "A high-affinity Arg-X-X-Lys SH3 binding motif confers specificity for the interaction between Gads and SLP-76 in T cell signaling". Current Biology. 12 (15): 1336–41. doi:10.1016/S0960-9822(02)01038-2. PMID 12176364.
  5. ↑ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (Feb 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.
  6. ↑ Warmuth M, Bergmann M, Priess A, Häuslmann K, Emmerich B, Hallek M (Dec 1997). "The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr". The Journal of Biological Chemistry. 272 (52): 33260–70. doi:10.1074/jbc.272.52.33260. PMID 9407116.
  7. ↑ Ren R, Ye ZS, Baltimore D (Apr 1994). "Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites". Genes & Development. 8 (7): 783–95. doi:10.1101/gad.8.7.783. PMID 7926767.
  8. ↑ VanderNoot VA, Fitzpatrick FA (Sep 1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Analytical Biochemistry. 230 (1): 108–14. doi:10.1006/abio.1995.1444. PMID 8585605.
  9. ↑ Lepley RA, Fitzpatrick FA (Sep 1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". The Journal of Biological Chemistry. 269 (39): 24163–8. PMID 7929073.
  10. ↑ Fu C, Turck CW, Kurosaki T, Chan AC (Jul 1998). "BLNK: a central linker protein in B cell activation". Immunity. 9 (1): 93–103. doi:10.1016/S1074-7613(00)80591-9. PMID 9697839.
  11. ↑ Engels N, Wollscheid B, Wienands J (Jul 2001). "Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha". European Journal of Immunology. 31 (7): 2126–34. doi:10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o. PMID 11449366.
  12. ↑ Fusaki N, Tomita S, Wu Y, Okamoto N, Goitsuka R, Kitamura D, Hozumi N (May 2000). "BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking". European Journal of Immunology. 30 (5): 1326–30. doi:10.1002/(sici)1521-4141(200005)30:5<1326::aid-immu1326>3.0.co;2-q. PMID 10820378.
  13. ↑ Wienands J, Schweikert J, Wollscheid B, Jumaa H, Nielsen PJ, Reth M (Aug 1998). "SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation". The Journal of Experimental Medicine. 188 (4): 791–5. doi:10.1084/jem.188.4.791. PMC 2213353. PMID 9705962.
  14. ↑ 14.0 14.1 Angers-Loustau A, Côté JF, Charest A, Dowbenko D, Spencer S, Lasky LA, Tremblay ML (Mar 1999). "Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts". The Journal of Cell Biology. 144 (5): 1019–31. doi:10.1083/jcb.144.5.1019. PMC 2148201. PMID 10085298.
  15. ↑ Wang X, Weng LP, Yu Q (May 2000). "Specific inhibition of FGF-induced MAPK activation by the receptor-like protein tyrosine phosphatase LAR". Oncogene. 19 (19): 2346–53. doi:10.1038/sj.onc.1203558. PMID 10822386.
  16. ↑ 16.0 16.1 16.2 Million RP, Harakawa N, Roumiantsev S, Varticovski L, Van Etten RA (Jun 2004). "A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase". Molecular and Cellular Biology. 24 (11): 4685–95. doi:10.1128/MCB.24.11.4685-4695.2004. PMC 416425. PMID 15143164.
  17. ↑ 17.0 17.1 17.2 Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T (Feb 1994). "Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway". The EMBO Journal. 13 (4): 764–73. PMC 394874. PMID 8112292.
  18. ↑ Million RP, Van Etten RA (Jul 2000). "The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase". Blood. 96 (2): 664–70. PMID 10887132.
  19. ↑ Bai RY, Jahn T, Schrem S, Munzert G, Weidner KM, Wang JY, Duyster J (Aug 1998). "The SH2-containing adapter protein GRB10 interacts with BCR-ABL". Oncogene. 17 (8): 941–8. doi:10.1038/sj.onc.1202024. PMID 9747873.
  20. ↑ Ma G, Lu D, Wu Y, Liu J, Arlinghaus RB (May 1997). "Bcr phosphorylated on tyrosine 177 binds Grb2". Oncogene. 14 (19): 2367–72. doi:10.1038/sj.onc.1201053. PMID 9178913.
  21. ↑ Maru Y, Peters KL, Afar DE, Shibuya M, Witte ON, Smithgall TE (Feb 1995). "Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS". Molecular and Cellular Biology. 15 (2): 835–42. PMC 231961. PMID 7529874.
  22. ↑ Karoor V, Wang L, Wang HY, Malbon CC (Dec 1998). "Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350". The Journal of Biological Chemistry. 273 (49): 33035–41. doi:10.1074/jbc.273.49.33035. PMID 9830057.
  23. ↑ Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narsimhan R, Comoglio P (Jun 1996). "Specific uncoupling of GRB2 from the Met receptor. Differential effects on transformation and motility". The Journal of Biological Chemistry. 271 (24): 14119–23. doi:10.1074/jbc.271.24.14119. PMID 8662889.
  24. ↑ Liang Q, Mohan RR, Chen L, Wilson SE (Jul 1998). "Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways". Investigative Ophthalmology & Visual Science. 39 (8): 1329–38. PMID 9660480.
  25. ↑ 25.0 25.1 Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S (Mar 1999). "cbl-b inhibits epidermal growth factor receptor signaling". Oncogene. 18 (10): 1855–66. doi:10.1038/sj.onc.1202499. PMID 10086340.
  26. ↑ Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O (Jun 1998). "The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells". The Journal of Biological Chemistry. 273 (24): 14962–7. doi:10.1074/jbc.273.24.14962. PMID 9614102.
  27. ↑ Elly C, Witte S, Zhang Z, Rosnet O, Lipkowitz S, Altman A, Liu YC (Feb 1999). "Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation". Oncogene. 18 (5): 1147–56. doi:10.1038/sj.onc.1202411. PMID 10022120.
  28. ↑ 28.0 28.1 Feng GS, Ouyang YB, Hu DP, Shi ZQ, Gentz R, Ni J (May 1996). "Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway". The Journal of Biological Chemistry. 271 (21): 12129–32. doi:10.1074/jbc.271.21.12129. PMID 8647802.
  29. ↑ De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R (Feb 1999). "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". The EMBO Journal. 18 (4): 904–15. doi:10.1093/emboj/18.4.904. PMC 1171183. PMID 10022833.
  30. ↑ Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L (Jul 1999). "Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor". The Biochemical Journal. 341 (1): 211–6. doi:10.1042/0264-6021:3410211. PMC 1220349. PMID 10377264.
  31. ↑ Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF (Jun 2000). "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry. 275 (23): 17420–7. doi:10.1074/jbc.M001892200. PMID 10748054.
  32. ↑ Otipoby KL, Draves KE, Clark EA (Nov 2001). "CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1". The Journal of Biological Chemistry. 276 (47): 44315–22. doi:10.1074/jbc.M105446200. PMID 11551923.
  33. ↑ Okkenhaug K, Rottapel R (Aug 1998). "Grb2 forms an inducible protein complex with CD28 through a Src homology 3 domain-proline interaction". The Journal of Biological Chemistry. 273 (33): 21194–202. doi:10.1074/jbc.273.33.21194. PMID 9694876.
  34. ↑ Nunès JA, Truneh A, Olive D, Cantrell DA (Jan 1996). "Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules". The Journal of Biological Chemistry. 271 (3): 1591–8. doi:10.1074/jbc.271.3.1591. PMID 8576157.
  35. ↑ Sugiyama Y, Tomoda K, Tanaka T, Arata Y, Yoneda-Kato N, Kato J (Apr 2001). "Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1". The Journal of Biological Chemistry. 276 (15): 12084–90. doi:10.1074/jbc.M010811200. PMID 11278754.
  36. ↑ Riordan SM, Lidder S, Williams R, Skouteris GG (Sep 2000). "The beta-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis". The Biochemical Journal. 350 (3): 925–32. doi:10.1042/0264-6021:3500925. PMC 1221328. PMID 10970810.
  37. ↑ Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T (Jun 1996). "Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins". The Journal of Biological Chemistry. 271 (24): 14468–72. doi:10.1074/jbc.271.24.14468. PMID 8662907.
  38. ↑ 38.0 38.1 Okada S, Pessin JE (Oct 1996). "Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor". The Journal of Biological Chemistry. 271 (41): 25533–8. doi:10.1074/jbc.271.41.25533. PMID 8810325.
  39. ↑ 39.0 39.1 Erdreich-Epstein A, Liu M, Kant AM, Izadi KD, Nolta JA, Durden DL (Apr 1999). "Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages". Journal of Leukocyte Biology. 65 (4): 523–34. PMID 10204582.
  40. ↑ 40.0 40.1 40.2 Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A (May 2002). "FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl". Proceedings of the National Academy of Sciences of the United States of America. 99 (10): 6684–9. doi:10.1073/pnas.052138899. PMC 124463. PMID 11997436.
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C (May 2002). "Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement". The Biochemical Journal. 363 (Pt 3): 717–25. doi:10.1042/0264-6021:3630717. PMC 1222524. PMID 11964172.
  42. ↑ 42.0 42.1 42.2 Liu SK, McGlade CJ (Dec 1998). "Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc". Oncogene. 17 (24): 3073–82. doi:10.1038/sj.onc.1202337. PMID 9872323.
  43. ↑ 43.0 43.1 43.2 Park RK, Erdreich-Epstein A, Liu M, Izadi KD, Durden DL (Dec 1999). "High affinity IgG receptor activation of Src family kinases is required for modulation of the Shc-Grb2-Sos complex and the downstream activation of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase". Journal of Immunology. 163 (11): 6023–34. PMID 10570290.
  44. ↑ Jain SK, Langdon WY, Varticovski L (May 1997). "Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase". Oncogene. 14 (18): 2217–28. doi:10.1038/sj.onc.1201049. PMID 9174058.
  45. ↑ Robertson H, Langdon WY, Thien CB, Bowtell DD (Nov 1997). "A c-Cbl yeast two hybrid screen reveals interactions with 14-3-3 isoforms and cytoskeletal components". Biochemical and Biophysical Research Communications. 240 (1): 46–50. doi:10.1006/bbrc.1997.7608. PMID 9367879.
  46. ↑ Donovan JA, Wange RL, Langdon WY, Samelson LE (Sep 1994). "The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor". The Journal of Biological Chemistry. 269 (37): 22921–4. PMID 8083187.
  47. ↑ Gesbert F, Garbay C, Bertoglio J (Feb 1998). "Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells". The Journal of Biological Chemistry. 273 (7): 3986–93. doi:10.1074/jbc.273.7.3986. PMID 9461587.
  48. ↑ Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B (May 1997). "CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2". Oncogene. 14 (19): 2331–8. doi:10.1038/sj.onc.1201074. PMID 9178909.
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  67. ↑ 67.0 67.1 Braverman LE, Quilliam LA (Feb 1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". The Journal of Biological Chemistry. 274 (9): 5542–9. doi:10.1074/jbc.274.9.5542. PMID 10026169.
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  69. ↑ Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR (Aug 1996). "Suc1-associated neurotrophic factor target (SNT) protein is a major FGF-stimulated tyrosine phosphorylated 90-kDa protein which binds to the SH2 domain of GRB2". Biochemical and Biophysical Research Communications. 225 (3): 1021–6. doi:10.1006/bbrc.1996.1288. PMID 8780727.
  70. ↑ Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (Apr 1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". The Journal of Biological Chemistry. 274 (14): 9861–70. doi:10.1074/jbc.274.14.9861. PMID 10092678.
  71. ↑ Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J (May 1997). "A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway". Cell. 89 (5): 693–702. doi:10.1016/s0092-8674(00)80252-4. PMID 9182757.
  72. ↑ Ghadimi MP, Sanzenbacher R, Thiede B, Wenzel J, Jing Q, Plomann M, Borkhardt A, Kabelitz D, Janssen O (May 2002). "Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)". FEBS Letters. 519 (1–3): 50–8. doi:10.1016/s0014-5793(02)02709-6. PMID 12023017.
  73. ↑ Wenzel J, Sanzenbacher R, Ghadimi M, Lewitzky M, Zhou Q, Kaplan DR, Kabelitz D, Feller SM, Janssen O (Dec 2001). "Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor". FEBS Letters. 509 (2): 255–62. doi:10.1016/s0014-5793(01)03174-x. PMID 11741599.
  74. ↑ 74.0 74.1 Lewitzky M, Kardinal C, Gehring NH, Schmidt EK, Konkol B, Eulitz M, Birchmeier W, Schaeper U, Feller SM (Mar 2001). "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". Oncogene. 20 (9): 1052–62. doi:10.1038/sj.onc.1204202. PMID 11314042.
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Further reading

  • Colledge M, Froehner SC (May 1998). "Interaction between the nicotinic acetylcholine receptor and Grb2. Implications for signaling at the neuromuscular junction". Annals of the New York Academy of Sciences. 841: 17–27. doi:10.1111/j.1749-6632.1998.tb10907.x. PMID 9668219.
  • Ramesh N, Antón IM, Martínez-Quiles N, Geha RS (Jan 1999). "Waltzing with WASP". Trends in Cell Biology. 9 (1): 15–9. doi:10.1016/S0962-8924(98)01411-1. PMID 10087612.
  • O'Sullivan E, Kinnon C, Brickell P (1999). "Wiskott-Aldrich syndrome protein, WASP". The International Journal of Biochemistry & Cell Biology. 31 (3–4): 383–7. doi:10.1016/S1357-2725(98)00118-6. PMID 10224664.
  • Schlaepfer DD, Hauck CR, Sieg DJ (1999). "Signaling through focal adhesion kinase". Progress in Biophysics and Molecular Biology. 71 (3–4): 435–78. doi:10.1016/S0079-6107(98)00052-2. PMID 10354709.
  • Vidal M, Liu WQ, Gril B, Assayag F, Poupon MF, Garbay C (2004). "[Design of new anti-tumor agents interrupting deregulated signaling pathways induced by tyrosine kinase proteins. Inhibition of protein-protein interaction involving Grb2]". Journal De La Société De Biologie. 198 (2): 133–7. PMID 15368963.

External links

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