GAB2 Protein

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GAB2 Protein

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GAB2 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GAB2 Protein</th>
</tr>
<tr> [@bettens2012]
<td class="label">Gene</td> [@lamb2005]
<td><a href="/genes/gab2">GAB2</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UQC2" target="_blank">Q9UQC2</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~74 kDa (676 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, plasma membrane (recruited upon receptor activation)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>GAB/DOS scaffolding adaptor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/alzheimers">Alzheimer's Disease</a> (LOAD risk)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

GAB2 Protein

Overview

...

GAB2 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GAB2 Protein</th>
</tr>
<tr> [@bettens2012]
<td class="label">Gene</td> [@lamb2005]
<td><a href="/genes/gab2">GAB2</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UQC2" target="_blank">Q9UQC2</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~74 kDa (676 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, plasma membrane (recruited upon receptor activation)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>GAB/DOS scaffolding adaptor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/alzheimers">Alzheimer's Disease</a> (LOAD risk)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

GAB2 Protein

Overview

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.

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

4. MET-binding domain (MBD): Direct interaction site for the c-MET receptor tyrosine kinase

Post-translational Modifications

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

PI3K/AKT Pathway Amplification

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](/genes/akt1) activation leads to:

[GSK3β](/genes/gsk3b) inhibition (Ser9 phosphorylation) → reduced [tau](/proteins/tau) phosphorylation
BAD phosphorylation → anti-apoptotic signaling
[mTOR](/genes/mtor) activation → protein synthesis and neuronal growth
[FOXO](/genes/foxo3) inactivation → cell survival

SHP2/ERK Pathway

GAB2-recruited SHP2 activates Ras/ERK signaling:

SHP2 dephosphorylates negative regulators of Ras
Sustained ERK activation promotes synaptic plasticity and [long-term potentiation](/mechanisms/long-term-potentiation)
ERK phosphorylates CREB, driving expression of neuroprotective genes (BDNF, Bcl-2)
ERK also provides negative feedback by serine-phosphorylating GAB2

Neuronal Survival

In hippocampal and cortical [neurons](/entities/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

Role in Alzheimer's Disease

Tau Phosphorylation Regulation

GAB2 directly controls [tau](/proteins/tau) phosphorylation levels:

Normal function: GAB2 → PI3K → AKT → GSK3β inhibition → low [tau](/proteins/tau) phosphorylation
Impaired GAB2: Reduced PI3K/AKT → active GSK3β → hyperphosphorylated tau → [neurofibrillary tangles](/mechanisms/neurofibrillary-tangles)
GAB2 knockdown in primary neurons increases phospho-tau at Thr181, Ser199, Thr231, and Ser396
The effect is potentiated in [APOE](/proteins/apoe) ε4 background, explaining the gene-gene interaction

APOE ε4 Interaction

The synergy between GAB2 risk variants and [APOE](/genes/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

Amyloid Processing

GAB2 may also influence [amyloid-β](/proteins/amyloid-beta-protein) production:

PI3K/AKT signaling modulates [BACE1](/genes/bace1) expression and activity
GAB2-dependent ERK activation regulates [APP](/genes/app) processing through α-secretase pathway
Microglial GAB2 signaling downstream of [TREM2](/genes/trem2) affects amyloid phagocytosis

Protein-Protein Interactions

| Partner | Domain/Site | Function |
|---|---|---|
| [GRB2](/genes/grb2) | Proline-rich motifs | Receptor recruitment |
| PI3K (p85) | pY452, pY476 | AKT activation |
| [SHP2](/proteins/shp2-protein) | pY614 | ERK activation |
| CRK | pY643 | Cell migration |
| c-MET | MBD | Hepatocyte growth factor signaling |
| CBL | Multiple sites | Ubiquitin-mediated degradation |
| [AKT](/proteins/akt1-protein) | Indirect via PI3K | Survival signaling |

Brain Atlas Resources

[Allen Human Brain Atlas: GAB2 Expression](https://human.brain-map.org/microarray/search/show?search_term=GAB2) — Gene expression data across brain regions
[BrainSpan: GAB2 Transcriptome](https://www.brainspan.org/gene?gene=GAB2) — Developmental expression patterns
[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)

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Related Entities

GAB2PROTEIN

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slug	proteins-gab2-protein
kg_node_id	GAB2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-693684ab3a2c
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-gab2-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

200

Outgoing

219

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GAB2 Protein

GAB2 Protein

GAB2 Protein

Overview

GAB2 Protein

GAB2 Protein

Overview

Structure

Domain Architecture

Post-translational Modifications

Function and Signaling

PI3K/AKT Pathway Amplification

SHP2/ERK Pathway

Neuronal Survival

Role in Alzheimer's Disease

Tau Phosphorylation Regulation

APOE ε4 Interaction

Amyloid Processing

Protein-Protein Interactions

See Also

Brain Atlas Resources

External Links

References

💬 Discussion