[^1]
[^2]
| Gene | GAB2 |
| UniProt |
Q9UQC2 |
| Mol. Weight |
~74 kDa (676 aa) |
| Localization |
Cytoplasm, plasma membrane (recruited upon receptor activation) |
| Family |
GAB/DOS scaffolding adaptor family |
| Diseases |
Alzheimer's Disease (LOAD risk) |
GAB2 (GRB2 Associated Binding Protein 2) is a 74 kDa scaffolding adaptor protein encoded by the GAB2 gene. It functions as a multisite docking platform that amplifies signaling from receptor tyrosine kinases into the PI3K/AKT and Ras/ERK cascades. GAB2 is recruited to activated receptors via its interaction with GRB2, whereupon it undergoes tyrosine phosphorylation and recruits PI3K, SHP2, and other effectors. In the brain, GAB2 is a critical modulator of neuronal survival signaling, and its impairment increases tau phosphorylation through disinhibition of GSK3β and CDK5.
¶ 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.
- Tyrosine phosphorylation sites (multiple): Key sites include:
- Y452: Recruits p85 regulatory subunit of PI3K
- Y476: Additional PI3K recruitment site
- Y614: Recruits SHP2 (PTPN11) phosphatase
- Y643: Recruits CRK adaptor protein
- MET-binding domain (MBD): Direct interaction site for the c-MET receptor tyrosine kinase
- Tyrosine phosphorylation: Multiple sites phosphorylated by receptor tyrosine kinases (EGFR, c-MET, c-Kit) and non-receptor kinases (Src family)
- Serine phosphorylation: ERK-mediated phosphorylation at multiple serines provides negative feedback regulation
- Ubiquitination: CBL-mediated ubiquitination promotes GAB2 degradation, limiting signaling duration
¶ Function and Signaling
GAB2 serves as a critical signal amplifier in the PI3K/AKT pathway:
- Growth factor receptor activation recruits GRB2-GAB2 to the membrane
- Receptor-mediated tyrosine phosphorylation of GAB2 creates docking sites for p85/PI3K
- Recruited PI3K generates PIP3, which further recruits GAB2 via its PH domain (positive feedback)
- Robust AKT activation leads to:
- GSK3β inhibition (Ser9 phosphorylation) → reduced tau phosphorylation
- BAD phosphorylation → anti-apoptotic signaling
- mTOR activation → protein synthesis and neuronal growth
- FOXO inactivation → cell survival
GAB2-recruited SHP2 activates Ras/ERK signaling:
- SHP2 dephosphorylates negative regulators of Ras
- Sustained ERK activation promotes synaptic plasticity and long-term potentiation
- ERK phosphorylates CREB, driving expression of neuroprotective genes (BDNF, Bcl-2)
- ERK also provides negative feedback by serine-phosphorylating GAB2
In hippocampal and cortical neurons, GAB2 integrates survival signals from:
- NGF/TrkA: Neurotrophin signaling for cholinergic neuron survival
- BDNF/TrkB: Critical for hippocampal neuron maintenance and synaptic plasticity
- Insulin/IGF-1: Metabolic survival signaling impaired in AD (brain insulin resistance)
- EGF/EGFR: Growth factor signaling for cortical neuron maintenance
GAB2 directly controls tau phosphorylation levels:
- Normal function: GAB2 → PI3K → AKT → GSK3β inhibition → low tau phosphorylation
- Impaired GAB2: Reduced PI3K/AKT → active GSK3β → hyperphosphorylated tau → neurofibrillary tangles
- GAB2 knockdown in primary neurons increases phospho-tau at Thr181, Ser199, Thr231, and Ser396
- The effect is potentiated in APOE ε4 background, explaining the gene-gene interaction
The synergy between GAB2 risk variants and APOE ε4 likely involves:
- ApoE4 impairs insulin/IGF-1 receptor signaling, reducing GAB2 activation
- GAB2 risk variants further weaken the already compromised PI3K/AKT pathway
- Combined effect: severe impairment of GSK3β inhibition and tau phosphorylation control
- This epistatic mechanism explains why GAB2 variants show strongest effects in APOE ε4 carriers
GAB2 may also influence amyloid-β production:
- PI3K/AKT signaling modulates BACE1 expression and activity
- GAB2-dependent ERK activation regulates APP processing through α-secretase pathway
- Microglial GAB2 signaling downstream of TREM2 affects amyloid phagocytosis
| Partner |
Domain/Site |
Function |
| GRB2 |
Proline-rich motifs |
Receptor recruitment |
| PI3K (p85) |
pY452, pY476 |
AKT activation |
| SHP2 |
pY614 |
ERK activation |
| CRK |
pY643 |
Cell migration |
| c-MET |
MBD |
Hepatocyte growth factor signaling |
| CBL |
Multiple sites |
Ubiquitin-mediated degradation |
| AKT |
Indirect via PI3K |
Survival signaling |