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Gene Review

GAB2  -  GRB2-associated binding protein 2

Homo sapiens

Synonyms: GRB2-associated binder 2, GRB2-associated-binding protein 2, Growth factor receptor bound protein 2-associated protein 2, KIAA0571, pp100
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Disease relevance of GAB2


High impact information on GAB2

  • These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway [1].
  • We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts [5].
  • We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis [5].
  • In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcepsilonRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2-PI3K pathway that is known to be essential for both degranulation and adhesion [6].
  • The simultaneous crosslinking of CD28 and CD45, a tyrosine phosphatase, could prevent tyrosine phosphorylation of pp100 [7].

Chemical compound and disease context of GAB2

  • In hormone-responsive breast cancer cells, GAB2 mRNA and protein expression were induced by estradiol in a manner sensitive to the pure anti-estrogen ICI 182780, indicating that this regulation is mediated via the ER [8].
  • Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma [2].
  • Gab2 therefore represents a novel link between steroid and growth factor signaling in breast cancer, and when overexpressed, may modulate the sensitivity of breast cancer cells to these important growth regulators [8].

Biological context of GAB2


Anatomical context of GAB2

  • The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored [1].
  • Furthermore, the inhibitory capacity of Gab2 is strictly dependent upon the integrity of its PH domain, suggesting phosphoinositide-mediated membrane recruitment is important to Gab2 function in T cells [14].
  • The impact of this negative regulation was further emphasized by a potent transforming activity for S159A Gab2, but not wild-type Gab2, in fibroblasts [10].
  • Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein [12].
  • Overexpression of Gab2 in Jurkat cells or antigen-specific T cell hybridomas resulted in the inhibition of NF-AT activation, interleukin-2 production, and tyrosine phosphorylation [11].

Associations of GAB2 with chemical compounds

  • Analysis of the rate of proliferation of cells expressing these mutants of Gab2 demonstrated that tyrosine 614F mutation enhanced proliferation whereas serine 623A diminished it [9].
  • Finally, higher levels of Gab2 expression led to the formation of large disorganized structures with defective luminal clearance [12].
  • A prominent tyrosine-phosphorylated protein of approximately 100 kDa (designated pp100) in epidermal growth factor (EGF)-stimulated A431 cells was found to be a main interaction partner of the protein-tyrosine phosphatase SHP-1 in pull-down experiments with a glutathione S-transferase-SHP-1 fusion protein [15].
  • However, the sole mutation of Tyr-614 into phenylalanine is sufficient to prevent Gab2 from recruiting SHP-2 [16].
  • We report here an important regulatory role for Gab2 in beta(1) integrin signaling pathway that mediates hematopoietic cell adhesion and migration [17].

Physical interactions of GAB2

  • Our findings provide the first evidence of a negative function for a scaffolding adapter in T cells and identify Gab2/PI3K-containing complexes as novel regulators of TCR signaling [18].
  • The individual SH2 domains of SHP2 can independently bind Gab2, potentially important for the adapter function of SHP2 [19].
  • Introduction of constitutive 14-3-3-binding sites into Gab2 renders it refractory to receptor activation, demonstrating that site-selective binding of 14-3-3 proteins is sufficient to terminate Gab2 signalling [20].

Regulatory relationships of GAB2


Other interactions of GAB2

  • Overexpression of wild-type Gab2 revealed a negative role in regulation of CD3/CD28 induction of the transcription factors NF-kappaB and AP-1 [14].
  • To characterize this inhibitory function further, we used Gab2 mutants unable to bind either PI3K or SHP-2 and a PH domain deletion mutant [14].
  • The altered expression of GAB2, an intracellular adaptor molecule involved in regulating phosphatase function, is of particular interest given the recent identification of the intracellular phosphatase PTPN22 as a risk gene for RA [24].
  • These results demonstrate that ERK-mediated phosphorylation of Gab2 serine 623 is involved in fine tuning the proliferative response of T lymphocytes to IL-2 [9].
  • This migration shift was strongly diminished by treating cells with the MEK inhibitor U0126, indicating a possible role for ERK in Gab2 phosphorylation [9].
  • Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology [25].

Analytical, diagnostic and therapeutic context of GAB2

  • At the earliest stages of oncogenesis, FTKs can mimic mitogenic cytokine signalling pathways involving the GAB-2 adaptor protein and signal transducers and activators of transcription (STAT) factors, generating replicative stress and thereby promoting a mutator phenotype [26].
  • Through this association, Gab2 is recruited to the lipid raft after TCR ligation and exerts inhibitory function [27].


  1. A role for the scaffolding adapter GAB2 in breast cancer. Bentires-Alj, M., Gil, S.G., Chan, R., Wang, Z.C., Wang, Y., Imanaka, N., Harris, L.N., Richardson, A., Neel, B.G., Gu, H. Nat. Med. (2006) [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. Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML). Scherr, M., Chaturvedi, A., Battmer, K., Dallmann, I., Schultheis, B., Ganser, A., Eder, M. Blood (2006) [Pubmed]
  4. Dual phosphorylation of phosphoinositide 3-kinase adaptor Grb2-associated binder 2 is responsible for superoxide formation synergistically stimulated by Fc gamma and formyl-methionyl-leucyl-phenylalanine receptors in differentiated THP-1 cells. Momose, H., Kurosu, H., Tsujimoto, N., Kontani, K., Tsujita, K., Nishina, H., Katada, T. J. Immunol. (2003) [Pubmed]
  5. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Wada, T., Nakashima, T., Oliveira-dos-Santos, A.J., Gasser, J., Hara, H., Schett, G., Penninger, J.M. Nat. Med. (2005) [Pubmed]
  6. Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo. Kraft, S., Fleming, T., Billingsley, J.M., Lin, S.Y., Jouvin, M.H., Storz, P., Kinet, J.P. J. Exp. Med. (2005) [Pubmed]
  7. Antibody and B7/BB1-mediated ligation of the CD28 receptor induces tyrosine phosphorylation in human T cells. Vandenberghe, P., Freeman, G.J., Nadler, L.M., Fletcher, M.C., Kamoun, M., Turka, L.A., Ledbetter, J.A., Thompson, C.B., June, C.H. J. Exp. Med. (1992) [Pubmed]
  8. The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. Daly, R.J., Gu, H., Parmar, J., Malaney, S., Lyons, R.J., Kairouz, R., Head, D.R., Henshall, S.M., Neel, B.G., Sutherland, R.L. Oncogene (2002) [Pubmed]
  9. Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation. Arnaud, M., Crouin, C., Deon, C., Loyaux, D., Bertoglio, J. J. Immunol. (2004) [Pubmed]
  10. PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2. Lynch, D.K., Daly, R.J. EMBO J. (2002) [Pubmed]
  11. Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell receptor signaling by recruitment of inhibitory molecules. Yamasaki, S., Nishida, K., Hibi, M., Sakuma, M., Shiina, R., Takeuchi, A., Ohnishi, H., Hirano, T., Saito, T. J. Biol. Chem. (2001) [Pubmed]
  12. Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein. Brummer, T., Schramek, D., Hayes, V.M., Bennett, H.L., Caldon, C.E., Musgrove, E.A., Daly, R.J. J. Biol. Chem. (2006) [Pubmed]
  13. GAB2 is a novel target of 11q amplification in AML/MDS. Zatkova, A., Schoch, C., Speleman, F., Poppe, B., Mannhalter, C., Fonatsch, C., Wimmer, K. Genes Chromosomes Cancer (2006) [Pubmed]
  14. Ligation of CD28 stimulates the formation of a multimeric signaling complex involving grb-2-associated binder 2 (gab2), SRC homology phosphatase-2, and phosphatidylinositol 3-kinase: evidence that negative regulation of CD28 signaling requires the gab2 pleckstrin homology domain. Parry, R.V., Whittaker, G.C., Sims, M., Edmead, C.E., Welham, M.J., Ward, S.G. J. Immunol. (2006) [Pubmed]
  15. The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin. Keilhack, H., Hellman, U., van Hengel, J., van Roy, F., Godovac-Zimmermann, J., Böhmer, F.D. J. Biol. Chem. (2000) [Pubmed]
  16. Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2. Arnaud, M., Mzali, R., Gesbert, F., Crouin, C., Guenzi, C., Vermot-Desroches, C., Wijdenes, J., Courtois, G., Bernard, O., Bertoglio, J. Biochem. J. (2004) [Pubmed]
  17. Role of the docking protein Gab2 in beta(1)-integrin signaling pathway-mediated hematopoietic cell adhesion and migration. Yu, W.M., Hawley, T.S., Hawley, R.G., Qu, C.K. Blood (2002) [Pubmed]
  18. Cutting edge: gab2 mediates an inhibitory phosphatidylinositol 3'-kinase pathway in T cell antigen receptor signaling. Pratt, J.C., Igras, V.E., Maeda, H., Baksh, S., Gelfand, E.W., Burakoff, S.J., Neel, B.G., Gu, H. J. Immunol. (2000) [Pubmed]
  19. Molecular interactions of SHP1 and SHP2 in IL-3-signalling. Wheadon, H., Paling, N.R., Welham, M.J. Cell. Signal. (2002) [Pubmed]
  20. Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein. Brummer, T., Larance, M., Herrera Abreu, M.T., Lyons, R.J., Timpson, P., Emmerich, C.H., Fleuren, E.D., Lehrbach, G.M., Schramek, D., Guilhaus, M., James, D.E., Daly, R.J. EMBO J. (2008) [Pubmed]
  21. 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]
  22. The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines. Gadina, M., Sudarshan, C., Visconti, R., Zhou, Y.J., Gu, H., Neel, B.G., O'Shea, J.J. J. Biol. Chem. (2000) [Pubmed]
  23. Deferential regulation of placenta growth factor (PlGF)-mediated signal transduction in human primary term trophoblast and endothelial cells. Arroyo, J., Torry, R.J., Torry, D.S. Placenta (2004) [Pubmed]
  24. Peripheral blood gene expression profiling in rheumatoid arthritis. Batliwalla, F.M., Baechler, E.C., Xiao, X., Li, W., Balasubramanian, S., Khalili, H., Damle, A., Ortmann, W.A., Perrone, A., Kantor, A.B., Gulko, P.S., Kern, M., Furie, R., Behrens, T.W., Gregersen, P.K. Genes Immun. (2005) [Pubmed]
  25. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Reiman, E.M., Webster, J.A., Myers, A.J., Hardy, J., Dunckley, T., Zismann, V.L., Joshipura, K.D., Pearson, J.V., Hu-Lince, D., Huentelman, M.J., Craig, D.W., Coon, K.D., Liang, W.S., Herbert, R.H., Beach, T., Rohrer, K.C., Zhao, A.S., Leung, D., Bryden, L., Marlowe, L., Kaleem, M., Mastroeni, D., Grover, A., Heward, C.B., Ravid, R., Rogers, J., Hutton, M.L., Melquist, S., Petersen, R.C., Alexander, G.E., Caselli, R.J., Kukull, W., Papassotiropoulos, A., Stephan, D.A. Neuron (2007) [Pubmed]
  26. Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells. Turner, S.D., Alexander, D.R. Leukemia (2006) [Pubmed]
  27. Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells. Yamasaki, S., Nishida, K., Sakuma, M., Berry, D., McGlade, C.J., Hirano, T., Saito, T. Mol. Cell. Biol. (2003) [Pubmed]
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