GAB2 gene

GRB2-associated binding protein 2; GAB gene family; pleckstrin homology domain; osteoclast differentiation; Growth Factor Receptor Bound Protein 2-associated protein 2; 

The GAB2 gene (GAB2 stands for GRB2-associated binding protein 2) is a protein-coding gene located on chromosome 11q13.4–q13.5. GAB2 encodes GRB2-associated binding protein 2, an adapter protein that transmits signals from cytokine and growth factor receptors as well as from T- and B-cell antigen receptors. It belongs to the GAB gene family(Abbeyquaye T et al. 2003) and contains a pleckstrin homology (PH) domain.

Gab/DOS proteins integrate and amplify signals from growth factor, cytokine, and antigen receptors, as well as from cell adhesion molecules. In addition, they diversify signals by directing the information originating from activated receptors into signaling pathways with different biological functions. Gab proteins are subject to complex regulation through forward and feedback phosphorylation processes, as well as through protein-protein interactions. GAB/DOS docking proteins organize entire signaling subsystems and thereby play an important, if not essential, role in many physiological processes. GAB2 is involved in various differentiation processes in the hematopoietic and nervous systems. In particular, GAB2-deficient mice exhibit impaired osteoclast development and, consequently, osteopetrosis. GAB2 is also essential for FceRI-mediated degranulation of mouse mast cells.

Mast cell degranulation: GAB2 binds to the SHP2 tyrosine phosphatase and the GRB2 adapter protein and acts as the primary activator of phosphatidylinositol 3-kinase in response to activation of the high-affinity IgE receptor. It is involved in protein tyrosine kinase signaling at the cell surface, phosphatidylinositol-3-kinase/protein kinase B signaling, the positive regulation of cell proliferation, the positive regulation of mast cell degranulation, and osteoclast differentiation.

Osteoclast differentiation: GAB2 has been found to play a role in osteoclast differentiation. GAB2 interacted with the C-terminal domain of RANK (603499) and mediated differentiation via a signaling pathway involving NF-κB (see 164011), AKT (see AKT1; 164730), and JNK (see MAPK8; 601158).

GAB2 is localized to 11q13.4–q13.5, a region that is frequently amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors. Co-expression of GAB2 with anti-apoptotic oncogenes led to a luminal phenotype, whereas co-expression 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 signaling pathway. GAB2 is amplified in some GAB2-overexpressing human breast tumors. It is hypothesized that drugs targeting GAB2 or GAB2-dependent signaling pathways could be useful for the treatment of breast tumors that overexpress GAB2 or HER2 or both.

1. Abbeyquaye T et al. (2003) Evolution of Gab family adaptor proteins. Gene 311:43–50.
2. Kramer MH et al. (2025) Overexpression of the signaling coordinator GAB2 can play an important role in the progression of acute myeloid leukemia. J Clin Invest 135:e195929.
3. Sármay G et al. (2006) The multiple functions of the Grb2-associated binder (Gab) adaptor/scaffolding protein in immune cell signaling. Immunol Lett 104:76–82.
4. Zhang Y et al. (2023) Association of the GAB1 gene with asthma susceptibility and the efficacy of inhaled corticosteroids in children. BMC Pulm Med 23:493.