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Gene Review

GRAP2  -  GRB2-related adaptor protein 2

Homo sapiens

Synonyms: Adapter protein GRID, GADS, GRAP-2, GRB-2-like protein, GRB2-related adapter protein 2, ...
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Disease relevance of GRAP2

  • Here, we show that Grap-2 is also expressed in neuroendocrine tumors and cell lines known to bear mutated forms of RET [1].
  • We report the identification of a new simian immunodeficiency virus (SIV), designated SIVden, in a naturally infected Dent's Mona monkey (Cercopithecus mona denti), which was kept as pet in Kinshasa, capital of the Democratic Republic of Congo [2].
  • P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts [3].
  • The DNA encoding the C-terminal SH3 domain of GADS (GADS-cSH3) was assembled synthetically using a recursive PCR technique and the protein was overexpressed in Escherichia coli, refolded and purified [4].
  • In Borrelia burgdorferi B31MI, class I includes the outer surface protein E (OspE) paralogs, L39, N38, and P38, whereas the class II group includes A68 and additional proteins that have not yet been identified [5].

Psychiatry related information on GRAP2

  • The Illness Self-Concept Repertory Grid appears capable of predicting treatment outcome and shows promise as a prognostic tool [6].
  • P38 MAP kinase is activated at early stages in Alzheimer's disease brain [7].
  • OBJECTIVE: This study investigated the psychometric properties of the Threshold Assessment Grid (TAG), a new assessment of the severity of mental health problems [8].
  • Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old), completed the State-Trait Anger Expression Inventory, the Clinical Analysis Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and a Repertory Grid [9].
  • The assessments included Cattell's 16PF Personality Inventory, a Body-Esteem index, a computer administered version of the Repertory Grid technique and semi-structured interviews [10].

High impact information on GRAP2


Chemical compound and disease context of GRAP2


Biological context of GRAP2

  • Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2 [18].
  • We first confirmed that the -2000 to +150 genomic region relative to the Mona gene transcription start site is sufficient to direct specific reporter gene expression in T cell lines, Jurkat, and MOLT-4 and in the immature myeloid cell lines, KG1a and RC2A [19].
  • We report here that 1B mRNA expressing cells do not express detectable amounts of Mona protein, in contrast to 1A expressing cells, and we show that 1B 5'UTR contains upstream open reading frames (uORFs) [20].
  • Strikingly, platelet activation by thrombin resulted in the rapid induction of Mona protein expression, suggesting that translation inhibition of 1B mRNA may be relieved in activated platelets [20].
  • Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling [1].

Anatomical context of GRAP2


Associations of GRAP2 with chemical compounds

  • Taken together, these results suggest that besides being involved in tyrosine kinase signaling in hematopoietic cells, Grap-2 plays a tissue-specific role as an inhibitor of RET mitogenic signaling [1].
  • Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells [24].
  • Here we studied the functional roles of sub-domains within the SLP-76 proline-rich region, specifically the Gads binding domain and the recently defined P1 domain [25].
  • Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs [26].
  • However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains [23].

Physical interactions of GRAP2


Enzymatic interactions of GRAP2

  • Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain [18].

Regulatory relationships of GRAP2


Other interactions of GRAP2

  • Using Grap2 as bait protein, we identified a novel human protein, GCIP (Grap2 cyclin-D interacting protein) [27].
  • Characterization of promoter elements directing Mona/Gads molecular adapter expression in T and myelomonocytic cells: involvement of the AML-1 transcription factor [19].
  • We molecularly cloned a new Grb2 family member, named Grf40, containing the common SH3-SH2-SH3 motif [21].
  • Mona, also called Gads, is a molecular adapter that plays a key role in T-cell and platelet signalling by linking the adaptors Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (Slp-76) and linker for activation of T cells (LAT) upon T-cell receptor and collagen receptor activation [20].
  • BACKGROUND: The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc [18].

Analytical, diagnostic and therapeutic context of GRAP2


  1. Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling. Ludwig, L., Kessler, H., Hoang-Vu, C., Dralle, H., Adler, G., Boehm, B.O., Schmid, R.M. Oncogene (2003) [Pubmed]
  2. Characterization of a novel vpu-harboring simian immunodeficiency virus from a Dent's Mona monkey (Cercopithecus mona denti). Dazza, M.C., Ekwalanga, M., Nende, M., Shamamba, K.B., Bitshi, P., Paraskevis, D., Saragosti, S. J. Virol. (2005) [Pubmed]
  3. P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts. Xia, W., Longaker, M.T., Yang, G.P. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  4. Expression, refolding and crystallizations of the Grb2-like (GADS) C-terminal SH3 domain complexed with a SLP-76 motif peptide. Faravelli, A., Dimasi, N. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2006) [Pubmed]
  5. Demonstration of the involvement of outer surface protein E coiled coil structural domains and higher order structural elements in the binding of infection-induced antibody and the complement-regulatory protein, factor H. McDowell, J.V., Wolfgang, J., Senty, L., Sundy, C.M., Noto, M.J., Marconi, R.T. J. Immunol. (2004) [Pubmed]
  6. Prediction of treatment response in pain patients: the illness self-concept repertory grid and EMG feedback. Large, R.G. Pain (1985) [Pubmed]
  7. P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Sun, A., Liu, M., Nguyen, X.V., Bing, G. Exp. Neurol. (2003) [Pubmed]
  8. Threshold 2: the reliability, validity and sensitivity to change of the Threshold Assessment Grid (TAG). Slade, M., Cahill, S., Kelsey, W., Powell, R., Strathdee, G. Acta psychiatrica Scandinavica. (2002) [Pubmed]
  9. Oral contraceptive use: implications for cognitive and emotional functioning. Rubino-Watkins, M.F., Doster, J.A., Franks, S., Kelly, K.S., Sonnier, B.L., Goven, A.J., Moorefield, R. J. Nerv. Ment. Dis. (1999) [Pubmed]
  10. Psychological effects of aesthetic dental treatment. Davis, L.G., Ashworth, P.D., Spriggs, L.S. Journal of dentistry. (1998) [Pubmed]
  11. Proline isomerization of histone h3 regulates lysine methylation and gene expression. Nelson, C.J., Santos-Rosa, H., Kouzarides, T. Cell (2006) [Pubmed]
  12. Crystal structure of the mammalian Grb2 adaptor. Maignan, S., Guilloteau, J.P., Fromage, N., Arnoux, B., Becquart, J., Ducruix, A. Science (1995) [Pubmed]
  13. RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells. Mainiero, F., Soriani, A., Strippoli, R., Jacobelli, J., Gismondi, A., Piccoli, M., Frati, L., Santoni, A. Immunity (2000) [Pubmed]
  14. Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition. Liu, Q., Berry, D., Nash, P., Pawson, T., McGlade, C.J., Li, S.S. Mol. Cell (2003) [Pubmed]
  15. Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. Ishiai, M., Kurosaki, M., Inabe, K., Chan, A.C., Sugamura, K., Kurosaki, T. J. Exp. Med. (2000) [Pubmed]
  16. Role of stress-activated MAP kinase P38 in cisplatin- and DTT-induced apoptosis of the esophageal carcinoma cell line Eca109. Zhang, Q.X., Feng, R., Zhang, W., Ding, Y., Yang, J.Y., Liu, G.H. World J. Gastroenterol. (2005) [Pubmed]
  17. P38 MAPK, but not p42/p44 MAPK mediated inducible nitric oxide synthase expression in C6 glioma cells. Xu, X., Malave, A. Life Sci. (2000) [Pubmed]
  18. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Liu, S.K., Fang, N., Koretzky, G.A., McGlade, C.J. Curr. Biol. (1999) [Pubmed]
  19. Characterization of promoter elements directing Mona/Gads molecular adapter expression in T and myelomonocytic cells: involvement of the AML-1 transcription factor. Guyot, B., Mouchiroud, G. J. Leukoc. Biol. (2003) [Pubmed]
  20. Upstream open reading frames regulate translation of Mona/Gads adapter mRNA in the megakaryocytic lineage. Guyot, B., Arnaud, S., Phothirath, P., Rigal, D., Mouchiroud, G. Platelets (2002) [Pubmed]
  21. Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT. Asada, H., Ishii, N., Sasaki, Y., Endo, K., Kasai, H., Tanaka, N., Takeshita, T., Tsuchiya, S., Konno, T., Sugamura, K. J. Exp. Med. (1999) [Pubmed]
  22. Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc. Liu, S.K., McGlade, C.J. Oncogene (1998) [Pubmed]
  23. Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Ma, W., Xia, C., Ling, P., Qiu, M., Luo, Y., Tan, T.H., Liu, M. Oncogene (2001) [Pubmed]
  24. Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Abtahian, F., Bezman, N., Clemens, R., Sebzda, E., Cheng, L., Shattil, S.J., Kahn, M.L., Koretzky, G.A. Mol. Cell. Biol. (2006) [Pubmed]
  25. Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function. Singer, A.L., Bunnell, S.C., Obstfeld, A.E., Jordan, M.S., Wu, J.N., Myung, P.S., Samelson, L.E., Koretzky, G.A. J. Biol. Chem. (2004) [Pubmed]
  26. Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation. Matsuyama, W., Watanabe, M., Shirahama, Y., Hirano, R., Mitsuyama, H., Higashimoto, I., Osame, M., Arimura, K. J. Immunol. (2006) [Pubmed]
  27. GCIP, a novel human grap2 and cyclin D interacting protein, regulates E2F-mediated transcriptional activity. Xia, C., Bao, Z., Tabassam, F., Ma, W., Qiu, M., Hua, S., Liu, M. J. Biol. Chem. (2000) [Pubmed]
  28. Vascular endothelial growth factor is upregulated by interleukin-1 beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway. Jung, Y.D., Liu, W., Reinmuth, N., Ahmad, S.A., Fan, F., Gallick, G.E., Ellis, L.M. Angiogenesis (2001) [Pubmed]
  29. The role of Gads in hematopoietic cell signalling. Liu, S.K., Berry, D.M., McGlade, C.J. Oncogene (2001) [Pubmed]
  30. Molecular cloning and expression of human grap-2, a novel leukocyte-specific SH2- and SH3-containing adaptor-like protein that binds to gab-1. Qiu, M., Hua, S., Agrawal, M., Li, G., Cai, J., Chan, E., Zhou, H., Luo, Y., Liu, M. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  31. Activation and role of MAP kinase-dependent pathways in retinal pigment epithelium cells: JNK1, P38 kinase, and cell death. Hecquet, C., Lefevre, G., Valtink, M., Engelmann, K., Mascarelli, F. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
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