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Gene Review

GAB1  -  GRB2-associated binding protein 1

Homo sapiens

Synonyms: GRB2-associated binder 1, GRB2-associated-binding protein 1, Growth factor receptor bound protein 2-associated protein 1
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Disease relevance of GAB1


High impact information on GAB1


Chemical compound and disease context of GAB1


Biological context of GAB1


Anatomical context of GAB1

  • Epo-induced tyrosine phosphorylation of GAB1 was also observed in normal human erythroid progenitors isolated from cord blood [10].
  • Northern blot analysis indicates that Gab2 is widely expressed and has an overlapping but distinctive expression pattern as compared with Gab1, with high levels of Gab2 mRNA detected in the heart, brain, placenta, spleen, ovary, peripheral blood leukocytes, and spinal cord [13].
  • RAI(ShcC/N-Shc)-dependent recruitment of GAB 1 to RET oncoproteins potentiates PI 3-K signalling in thyroid tumors [15].
  • Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met-dependent morphogenesis of epithelial cells [16].
  • Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB [3].

Associations of GAB1 with chemical compounds


Physical interactions of GAB1

  • Thus, GAB1 could be a scaffold protein able to couple the Epo receptor activation with the stimulation of several intracellular signaling pathways [10].
  • The Grb2 SH3(C) binding region of Gab1 has significant homology to a region of the adapter protein SLP-76 [22].
  • On the other hand, ectopic overexpression of either a Gab1 mutant incapable of binding to SHP-2 (Y627F) or a phosphatase-inactive SHP-2 mutant (C459S) caused a significant increase in NF-kappaB activity [1].
  • The adaptor protein Gab1 couples the stimulation of vascular endothelial growth factor receptor-2 to the activation of phosphoinositide 3-kinase [23].

Enzymatic interactions of GAB1

  • Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro [24].
  • We observed that the Grb2-bound adapter Gab1 is tyrosine-phosphorylated and relocated to membrane fractions upon VEGF stimulation of endothelial cells [23].
  • The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase) [25].
  • Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation [26].

Regulatory relationships of GAB1


Other interactions of GAB1


Analytical, diagnostic and therapeutic context of GAB1


  1. Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells. Kapoor, G.S., Zhan, Y., Johnson, G.R., O'Rourke, D.M. Mol. Cell. Biol. (2004) [Pubmed]
  2. Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. Podar, K., Mostoslavsky, G., Sattler, M., Tai, Y.T., Hayashi, T., Catley, L.P., Hideshima, T., Mulligan, R.C., Chauhan, D., Anderson, K.C. J. Biol. Chem. (2004) [Pubmed]
  3. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. Braun, L., Ghebrehiwet, B., Cossart, P. EMBO J. (2000) [Pubmed]
  4. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. Bourguignon, L.Y., Singleton, P.A., Zhu, H., Diedrich, F. J. Biol. Chem. (2003) [Pubmed]
  5. Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines. Watanabe, T., Tsuda, M., Makino, Y., Ichihara, S., Sawa, H., Minami, A., Mochizuki, N., Nagashima, K., Tanaka, S. Mol. Cancer Res. (2006) [Pubmed]
  6. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Holgado-Madruga, M., Emlet, D.R., Moscatello, D.K., Godwin, A.K., Wong, A.J. Nature (1996) [Pubmed]
  7. How to make tubes: signaling by the Met receptor tyrosine kinase. Rosário, M., Birchmeier, W. Trends Cell Biol. (2003) [Pubmed]
  8. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. Churin, Y., Al-Ghoul, L., Kepp, O., Meyer, T.F., Birchmeier, W., Naumann, M. J. Cell Biol. (2003) [Pubmed]
  9. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., Kempkes, B., Birchmeier, W. J. Cell Biol. (2000) [Pubmed]
  10. Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Lecoq-Lafon, C., Verdier, F., Fichelson, S., Chrétien, S., Gisselbrecht, S., Lacombe, C., Mayeux, P. Blood (1999) [Pubmed]
  11. Scaffolding protein Grb2-associated binder 1 sustains epidermal growth factor-induced mitogenic and survival signaling by multiple positive feedback loops. Kiyatkin, A., Aksamitiene, E., Markevich, N.I., Borisov, N.M., Hoek, J.B., Kholodenko, B.N. J. Biol. Chem. (2006) [Pubmed]
  12. The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. Fan, S., Ma, Y.X., Gao, M., Yuan, R.Q., Meng, Q., Goldberg, I.D., Rosen, E.M. Mol. Cell. Biol. (2001) [Pubmed]
  13. Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1. Zhao, C., Yu, D.H., Shen, R., Feng, G.S. J. Biol. Chem. (1999) [Pubmed]
  14. Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. Onishi-Haraikawa, Y., Funaki, M., Gotoh, N., Shibuya, M., Inukai, K., Katagiri, H., Fukushima, Y., Anai, M., Ogihara, T., Sakoda, H., Ono, H., Kikuchi, M., Oka, Y., Asano, T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  15. RAI(ShcC/N-Shc)-dependent recruitment of GAB 1 to RET oncoproteins potentiates PI 3-K signalling in thyroid tumors. De Falco, V., Guarino, V., Malorni, L., Cirafici, A.M., Troglio, F., Erreni, M., Pelicci, G., Santoro, M., Melillo, R.M. Oncogene (2005) [Pubmed]
  16. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. Lock, L.S., Royal, I., Naujokas, M.A., Park, M. J. Biol. Chem. (2000) [Pubmed]
  17. Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain. Lock, L.S., Frigault, M.M., Saucier, C., Park, M. J. Biol. Chem. (2003) [Pubmed]
  18. PC12 cell activation by epidermal growth factor receptor: role of autophosphorylation sites. Tyson, D.R., Larkin, S., Hamai, Y., Bradshaw, R.A. Int. J. Dev. Neurosci. (2003) [Pubmed]
  19. An epidermal growth factor receptor/Gab1 signaling pathway is required for activation of phosphoinositide 3-kinase by lysophosphatidic acid. Laffargue, M., Raynal, P., Yart, A., Peres, C., Wetzker, R., Roche, S., Payrastre, B., Chap, H. J. Biol. Chem. (1999) [Pubmed]
  20. Gab1 is required for cell cycle transition, cell proliferation, and transformation induced by an oncogenic met receptor. Mood, K., Saucier, C., Bong, Y.S., Lee, H.S., Park, M., Daar, I.O. Mol. Biol. Cell (2006) [Pubmed]
  21. Coupling of Grb2 to Gab1 mediates hepatocyte growth factor-induced high intensity ERK signal required for inhibition of HepG2 hepatoma cell proliferation. Kondo, A., Hirayama, N., Sugito, Y., Shono, M., Tanaka, T., Kitamura, N. J. Biol. Chem. (2008) [Pubmed]
  22. 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. Lewitzky, M., Kardinal, C., Gehring, N.H., Schmidt, E.K., Konkol, B., Eulitz, M., Birchmeier, W., Schaeper, U., Feller, S.M. Oncogene (2001) [Pubmed]
  23. The adaptor protein Gab1 couples the stimulation of vascular endothelial growth factor receptor-2 to the activation of phosphoinositide 3-kinase. Dance, M., Montagner, A., Yart, A., Masri, B., Audigier, Y., Perret, B., Salles, J.P., Raynal, P. J. Biol. Chem. (2006) [Pubmed]
  24. Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. Cunnick, J.M., Mei, L., Doupnik, C.A., Wu, J. J. Biol. Chem. (2001) [Pubmed]
  25. A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Rodrigues, G.A., Falasca, M., Zhang, Z., Ong, S.H., Schlessinger, J. Mol. Cell. Biol. (2000) [Pubmed]
  26. Identification of major ERK-related phosphorylation sites in Gab1. Lehr, S., Kotzka, J., Avci, H., Sickmann, A., Meyer, H.E., Herkner, A., Muller-Wieland, D. Biochemistry (2004) [Pubmed]
  27. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. Yu, C.F., Liu, Z.X., Cantley, L.G. J. Biol. Chem. (2002) [Pubmed]
  28. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. Che, W., Lerner-Marmarosh, N., Huang, Q., Osawa, M., Ohta, S., Yoshizumi, M., Glassman, M., Lee, J.D., Yan, C., Berk, B.C., Abe, J. Circ. Res. (2002) [Pubmed]
  29. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Fragale, A., Tartaglia, M., Wu, J., Gelb, B.D. Hum. Mutat. (2004) [Pubmed]
  30. The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase. Ingham, R.J., Santos, L., Dang-Lawson, M., Holgado-Madruga, M., Dudek, P., Maroun, C.R., Wong, A.J., Matsuuchi, L., Gold, M.R. J. Biol. Chem. (2001) [Pubmed]
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