Alternative titles; symbols
HGNC Approved Gene Symbol: GAB2
Cytogenetic location: 11q14.1 Genomic coordinates (GRCh38) : 11:78,215,293-78,417,820 (from NCBI)
The GAB2 gene encodes an adaptor molecule that is the principal activator of phosphatidylinositol-3 kinase (PIK3; see 171833) in response to activation of the high-affinity IgE receptor (see 147140) (Gu et al., 2001).
Nishida et al. (1999) identified GAB2 as a 100-kD adaptor molecule (pp100) interacting with SHP2 (176876) and PI3 kinase in response to various stimuli. The human GAB2 gene encodes a 676-amino acid protein with a pleckstrin homology domain, proline-rich sequences, and tyrosine residues that bind to SH2 domains when they are phosphorylated.
Zhao et al. (1999) identified a human adaptor molecule containing a pleckstrin homology domain at the N terminus that is closely related to GAB1 (604439) and Drosophila 'daughter of sevenless' (Dos). Zhao et al. (1999) called this protein GAB2. Northern blot analysis indicated that GAB2 is widely expressed and has an overlapping but distinctive expression pattern as compared with that of GAB1, with high levels of GAB2 mRNA detected in the heart, brain, placenta, spleen, ovary, peripheral blood leukocytes, and spinal cord.
Nishida et al. (1999) and Zhao et al. (1999) identified cDNA KIAA0571 (Nagase et al., 1998) as GAB2. Nagase et al. (1998) reported the high homology of GAB2 with GAB1 (34.2% amino acid identity).
Nishida et al. (1999) showed that tyrosine phosphorylation of GAB2 is induced by stimulation through gp130 (IL6ST; 600694), IL2R (147730), IL3R (308385), TPOR (159530), SCFR (164920), and TCR (see 186880). The authors showed GAB1 and GAB2 to be substrates for SHP2 in vitro.
Zhao et al. (1999) demonstrated that upon tyrosine phosphorylation, GAB2 physically interacts with SHP2 tyrosine phosphatase and GRB2 adaptor protein (604330). GAB2 has an inhibitory effect on the activation of ELK1 (311040)-dependent transcription triggered by a dominant active Ras (190020) mutant or under growth factor stimulation, whereas GAB1 acts to potentiate slightly the ELK1 activity in the same system. In contrast to the reciprocal effects of GAB1 and GAB2 in mediating ELK1 induction, these 2 molecules have a similar function in extracellular signal-regulated kinase activation induced by either oncogenic Ras or growth factor stimulation. Zhao et al. (1999) concluded that GAB1 and GAB2 may have distinct roles in coupling cytoplasmic-nuclear signal transduction.
Wada et al. (2005) determined that GAB2 has a role in osteoclast differentiation. GAB2 interacted with the C-terminal domain of RANK (603499) and mediated differentiation through a signaling pathway that included NFKB (see 164011), AKT (see AKT1; 164730), and JNK (see MAPK8; 601158).
The scaffolding adaptor GAB2 maps to 11q13.4-q13.5, a region commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors. Bentires-Alj et al. (2006) found that overexpression of GAB2 increases proliferation of MCF10A mammary cells in 3-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes caused luminal filling, whereas coexpression with NEU (also known as ERBB2 and HER2; 164870) resulted in an invasive phenotype. These effects of GAB2 were mediated by hyperactivation of the SHP2-ERK pathway. Furthermore, overexpression of Gab2 potentiated, whereas deficiency of Gab2 ameliorated, Neu-evoked breast carcinogenesis in mice. Finally, Bentires-Alj et al. (2006) found that GAB2 is amplified in some GAB2-overexpressing human breast tumors. Their data suggested that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and proposed a role for overexpression of GAB2 in mammary carcinogenesis. The authors suggested that agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.
Nagase et al. (1998) mapped the GAB2 gene to chromosome 11 using a radiation hybrid panel. By FISH, Yamada et al. (2001) mapped the GAB2 gene to human chromosome 11q13.4-q13.5 and mouse chromosome 7E2.
Reiman et al. (2007) used a genomewide SNP survey to examine 1,411 individuals with late-onset Alzheimer disease (AD; 104300) and controls, including 644 carriers of the APOE (107741) E4 allele and 767 noncarriers. The authors found a significant association between AD and 6 SNPs in the GAB2 gene that are part of a common haplotype block. Maximal significance of the association was at rs2373115 with an odds ratio of 4.06 (uncorrected p value of 9 x 10(-11)). Carriers of the APOE4 alleles had an even higher disease risk when the SNP risk allele was present (odds ratio of 24.64) compared to noncarriers. Neuropathologic studies found that GAB2 was overexpressed in neurons from AD patients, and the protein was detected in neurons, tangle-bearing neurons, and dystrophic neurites.
In contrast to the findings of Reiman et al. (2007), both Chapuis et al. (2008) and Miyashita et al. (2009) failed to detect an association between rs2373115 and risk of developing AD in Caucasian and Japanese individuals, respectively. Chapuis et al. (2008) studied 3 European Caucasian populations totaling 1,749 AD cases and 1,406 controls, and Miyashita et al. (2009) studied 1,656 Japanese cases and 1,656 Japanese controls; they suggested that GAB2 is, at best, a minor disease susceptibility gene for AD.
Gu et al. (2001) generated mice deficient in Gab2 by homologous recombination. Gab2 -/- mice were viable and generally healthy; however, the response of Gab2 -/- mast cells to stimulation of the high affinity IgE receptor Fc-epsilon-RI (see 147140) was defective. Accordingly, allergic reactions, such as passive cutaneous and systemic anaphylaxis, were markedly impaired in Gab -/- mice. Biochemical analyses revealed that signaling pathways dependent on phosphatidylinositol-3 hydroxykinase (PI3K), a critical component of the Fc-epsilon-RI signaling, were defective in Gab2 -/- mast cells. Gu et al. (2001) concluded that GAB2 is the principal activator of PI3K in response to Fc-epsilon-RI activation, thereby providing genetic evidence that Dos/Gab family scaffolds regulate the PI3K pathway in vivo.
Wada et al. (2005) found that the bone marrow of Gab2 -/- mice showed reduced cellularity, and they observed a significant increase in bone mass in Gab2 -/- mice. Wada et al. (2005) determined that Gab2 deficiency led to decreased bone resorption due to defective osteoclast differentiation.
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. A role for the scaffolding adapter GAB2 in breast cancer. Nature Med. 12: 114-121, 2006. [PubMed: 16369543] [Full Text: https://doi.org/10.1038/nm1341]
Chapuis, J., Hannequin, D., Pasquier, F., Bentham, P., Brice, A., Leber, I., Frebourg, T., Deleuze, J.-F., Cousin, E., Thaker, U., Amouyel, P., Mann, D., Lendon, C., Campion, D., Lambert, J.-C. Association study of the GAB2 gene with the risk of developing Alzheimer's disease. Neurobiol. Dis. 30: 103-106, 2008. [PubMed: 18272374] [Full Text: https://doi.org/10.1016/j.nbd.2007.12.006]
Gu, H., Saito, K., Klaman, L. D., Shen, J., Fleming, T., Wang, Y.-P., Pratt, J. C., Lin, G., Lim, B., Kinet, J.-P., Neel, B. G. Essential role for Gab2 in the allergic response. Nature 412: 186-190, 2001. [PubMed: 11449275] [Full Text: https://doi.org/10.1038/35084076]
Miyashita, A., Arai, H., Asada, T., Imagawa, M., Shoji, M., Higuchi, S., Urakami, K., Toyabe, S., Akazawa, K., Kanazawa, I., Ihara, Y., Kuwano, R. GAB2 is not associated with late-onset Alzheimer's disease in Japanese. Europ. J. Hum. Genet. 17: 682-686, 2009. [PubMed: 18854865] [Full Text: https://doi.org/10.1038/ejhg.2008.181]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Nishida, K., Yoshida, Y., Itoh, M., Fukada, T., Ohtani, T., Shirogane, T., Atsumi, T., Takahashi-Tezuka, M., Ishihara, K., Hibi, M., Hirano, T. Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. Blood 93: 1809-1816, 1999. [PubMed: 10068651]
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., and 22 others. GAB2 alleles modify Alzheimer's risk in APOE epsilon-4 carriers. Neuron 54: 713-720, 2007. [PubMed: 17553421] [Full Text: https://doi.org/10.1016/j.neuron.2007.05.022]
Wada, T., Nakashima, T., Oliveira-dos-Santos, A. J., Gasser, J., Hara, H., Schett, G., Penninger, J. M. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nature Med. 11: 394-399, 2005. [PubMed: 15750601] [Full Text: https://doi.org/10.1038/nm1203]
Yamada, K., Nishida, K., Hibi, M., Hirano, T., Matsuda, Y. Comparative FISH mapping of Gab1 and Gab2 genes in human, mouse and rat. Cytogenet. Cell Genet. 94: 39-42, 2001. [PubMed: 11701952] [Full Text: https://doi.org/10.1159/000048780]
Zhao, C., Yu, D.-H., Shen, R., Feng, G.-S. Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1. J. Biol. Chem. 274: 19649-19654, 1999. [PubMed: 10391903] [Full Text: https://doi.org/10.1074/jbc.274.28.19649]