GAB2 (GRB2 Associated Binding Protein 2) is a 74 kDa scaffolding adaptor protein encoded by the [GAB2](/genes/gab2) gene. It functions as a multisite docking platform that amplifies signaling from receptor tyrosine kinases into the [PI3K](/genes/pik3ca)/[AKT](/genes/akt1) and Ras/ERK cascades. GAB2 is recruited to activated receptors via its interaction with [GRB2](/genes/grb2), whereupon it undergoes tyrosine phosphorylation and recruits PI3K, [SHP2](/proteins/shp2-protein), and other effectors. In the brain, GAB2 is a critical modulator of neuronal survival signaling, and its impairment increases [tau](/proteins/tau) phosphorylation through disinhibition of [GSK3β](/genes/gsk3b) and [CDK5](/genes/cdk5).
Structure
Domain Architecture
GAB2 contains:
Pleckstrin Homology (PH) domain (residues 1-116): Binds phosphatidylinositol-3,4,5-trisphosphate (PIP3), anchoring GAB2 at the plasma membrane after PI3K activation. This creates a positive feedback loop: PI3K generates PIP3, which recruits more GAB2, which recruits more PI3K.
Central proline-rich region (residues 117-530): Contains multiple PXXP motifs that bind GRB2 SH3 domains. The GRB2 interaction is constitutive and recruits GAB2 to activated receptor tyrosine kinases.
[Allen Human Brain Atlas: GAB2 Expression](https://human.brain-map.org/microarray/search/show?search_term=GAB2) — Gene expression data across brain regions
[Allen Mouse Brain Atlas: GAB2](https://mouse.brain-map.org/search/show?search_type=gene&search_term=GAB2) — Mouse brain expression data
[Allen Cell Type Atlas](https://celltype.brain-map.org/) — Cell type-specific expression
External Links
[GAB2 at UniProt (Q9UQC2)](https://www.uniprot.org/uniprot/Q9UQC2)
[GAB2 at Human Protein Atlas](https://www.proteinatlas.org/ENSG00000033327-GAB2)
[GAB2 at AlphaFold](https://alphafold.ebi.ac.uk/entry/Q9UQC2)
[GAB2 at GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=GAB2)
References
[Reiman et al., GAB2 alleles modify Alzheimer's risk in APOE ε4 carriers (2007) (2007)](https://doi.org/10.1016/j.neuron.2007.09.022)
[Nizzari et al., Role of the GAB2 signaling pathway in Alzheimer's disease (2012) (2012)](https://doi.org/10.2174/156720512801322654)
[Jiang et al., GAB2 has a protective role in Alzheimer's disease by inhibiting tau hyperphosphorylation (2016) (2016)](https://doi.org/10.1016/j.bbadis.2016.07.011)
[Wohrle et al., Function, regulation and pathological roles of the Gab/DOS docking proteins (2009) (2009)](https://doi.org/10.1016/j.cellsig.2008.11.009)
[Bettens et al., Reduced GAB2 expression is associated with Alzheimer's disease (2012) (2012)](https://doi.org/10.1016/j.neurobiolaging.2011.04.016)
[Lamb et al., Disruption of the PI3K-Akt signaling pathway in Alzheimer's disease (2005) (2005)](https://doi.org/10.1016/j.neurobiolaging.2005.04.002)