GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

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GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

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GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GIGYF2 Protein (GRB10-Interacting GYF Protein 2)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>GRB10-Interacting GYF Protein 2</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GIGYF2</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Periplakin, NID2-associated protein, GRB10IP2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q33.1</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UHQ2</td>
</tr>
<tr>
<td class="label">Entrez Gene ID</td>
<td>26060</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>2232 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~254 kDa</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>GYF domain family, adaptor proteins</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Amino Acids</td>
</tr>
<tr>
<td class="label">N-terminal region</td>
<td>1-200</td>
</tr>
<tr>
<td class="label">GYF domain</td>
<td>200-280</td>
</tr>
<tr>
<td class="label">Coiled-coil regions</td>
<td>300-800</td>
</tr>
<tr>
<td class="label">C-terminal region</td>
<td>1800-2232</td>
</tr>
<tr>
<td class="label">Function</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Receptor stabilization</td>
<td>Binds to insulin receptor</td>
</tr>
<tr>
<td

...

GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GIGYF2 Protein (GRB10-Interacting GYF Protein 2)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>GRB10-Interacting GYF Protein 2</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GIGYF2</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Periplakin, NID2-associated protein, GRB10IP2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q33.1</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UHQ2</td>
</tr>
<tr>
<td class="label">Entrez Gene ID</td>
<td>26060</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>2232 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~254 kDa</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>GYF domain family, adaptor proteins</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Amino Acids</td>
</tr>
<tr>
<td class="label">N-terminal region</td>
<td>1-200</td>
</tr>
<tr>
<td class="label">GYF domain</td>
<td>200-280</td>
</tr>
<tr>
<td class="label">Coiled-coil regions</td>
<td>300-800</td>
</tr>
<tr>
<td class="label">C-terminal region</td>
<td>1800-2232</td>
</tr>
<tr>
<td class="label">Function</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Receptor stabilization</td>
<td>Binds to insulin receptor</td>
</tr>
<tr>
<td class="label">Signal modulation</td>
<td>scaffolds downstream effectors</td>
</tr>
<tr>
<td class="label">Receptor internalization</td>
<td>Regulates endocytosis</td>
</tr>
<tr>
<td class="label">Degradation</td>
<td>Targets receptors for disposal</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Pancreas</td>
<td>High</td>
</tr>
<tr>
<td class="label">Muscle</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Adipose</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Finding</td>
<td>Evidence</td>
</tr>
<tr>
<td class="label">Genetic association</td>
<td>GWAS hits at GIGYF2 locus</td>
</tr>
<tr>
<td class="label">Risk variants</td>
<td>Multiple SNPs associated</td>
</tr>
<tr>
<td class="label">Expression changes</td>
<td>Altered in PD brains</td>
</tr>
<tr>
<td class="label">Functional studies</td>
<td>Affects α-synuclein toxicity</td>
</tr>
<tr>
<td class="label">Disorder</td>
<td>GIGYF2 Role</td>
</tr>
<tr>
<td class="label">Type 2 diabetes</td>
<td>Insulin signaling modifier</td>
</tr>
<tr>
<td class="label">Obesity</td>
<td>Metabolic regulation</td>
</tr>
<tr>
<td class="label">Insulin resistance</td>
<td>Receptor trafficking</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">GRB10</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">IRS1/2</td>
<td>Adapter</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Regulatory</td>
</tr>
<tr>
<td class="label">Shc</td>
<td>Adapter</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs37370</td>
<td>SNP</td>
</tr>
<tr>
<td class="label">rs247261</td>
<td>SNP</td>
</tr>
<tr>
<td class="label">rs124564</td>
<td>SNP</td>
</tr>
<tr>
<td class="label">Various</td>
<td>Missense</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>Enhance function</td>
</tr>
<tr>
<td class="label">Peptides</td>
<td>Block interactions</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Restore expression</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Multi-target</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">GRB10</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">IRS1</td>
<td>Adapter</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Regulatory</td>
</tr>
<tr>
<td class="label">EGF receptor</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

GIGYF2 (GRB10-Interacting GYF Protein 2), also known as Periplakin or NID2 associated, is a large adaptor protein that serves as a critical node in growth factor and insulin signaling networks. The protein contains multiple protein-protein interaction domains that enable it to scaffold signaling complexes and regulate receptor tyrosine kinase trafficking. GIGYF2 has emerged as a significant player in neurodegenerative diseases, with genetic variants associated with increased risk for Parkinson's disease and Alzheimer's disease. [@song2021]

Domain Architecture

Structural Organization

GIGYF2 contains multiple functional domains:

GYF Domain

The GYF (glycine-tyrosine-phenylalanine) domain is a specialized protein interaction module:

Recognition sequence: Proline-rich motifs (PXXP)
Binding specificity: Multiple proline-rich proteins
Structural fold: Unique α-helical fold
Conservation: Present in several adaptor proteins

Proline-Rich Regions

Multiple proline-rich regions throughout the protein:

SH3 binding sites: Enable interactions with Src family kinases
WW domain binding: Potential for additional interactions
Flexible linkers: Allow multi-valent interactions

Biological Functions

Insulin and IGF-1 Signaling

GIGYF2 is a key regulator of insulin receptor signaling:

Growth Factor Signaling

Beyond insulin, GIGYF2 modulates:

EGF receptor signaling: Modulates EGFR trafficking
PDGF signaling: Affects PDGF receptor function
NGF signaling: Regulates neurotrophic factor signaling
FGF signaling: Modulates FGFR pathways

Receptor Tyrosine Kinase Trafficking

GIGYF2 regulates receptor dynamics:

Receptor insertion: Facilitates proper membrane insertion

Surface retention: Modulates residence time at membrane

Internalization: Regulates clathrin-mediated endocytosis

Recycling: Controls receptor recycling pathways

Degradation: Targets receptors for lysosomal degradation

Neuronal Functions

In the nervous system, GIGYF2 participates in:

Neuronal survival: Anti-apoptotic signaling
Synaptic function: Regulates postsynaptic receptors
Axonal transport: May affect trafficking in neurons
Neuroprotection: Links growth factor signaling to survival

Expression and Distribution

Tissue Expression

Subcellular Localization

Plasma membrane: Receptor interaction
Cytoplasm: Scaffolding functions
Endosomes: Receptor trafficking
Golgi: Processing and sorting

Disease Associations

Parkinson's Disease

GIGYF2 has been linked to Parkinson's disease risk:

Alzheimer's Disease

GIGYF2 in AD:

Genetic linkage: Some studies show association
Aβ effects: GIGYF2 expression affected by Aβ
Tau pathology: Linked to tau phosphorylation
Therapeutic potential: Target for intervention

Metabolic Disorders

Cancer

Oncogenic potential: Altered in some cancers
Receptor signaling: Modulates growth factor pathways
Therapeutic target: Potential for modulation

Molecular Mechanisms

Signaling Complex Formation

GIGYF2 scaffolds signaling complexes:

Receptor recruitment: Brings together receptors and effectors

Adaptor function: Links upstream and downstream signals

Spatio-temporal control: Localizes signaling to specific compartments

Signal integration: Combines multiple signals

Interaction Partners

Regulatory Mechanisms

Phosphorylation: Modulates adaptor function
Ubiquitination: Controls protein stability
Alternative splicing: Generates isoforms
Cellular localization: Affects function

Genetics

Disease-Associated Variants

GWAS Findings

Genome-wide association studies have identified:

Parkinson's disease: Multiple signals at 5q33.1
Type 2 diabetes: Some association
Alzheimer's: Modest signals
Height: Some associations

Therapeutic Implications

Drug Development

Challenges

Complex multi-functional protein
Tissue-specific functions
Balancing multiple pathways
Delivery to CNS

Interaction Network

Signaling Pathways

Insulin receptor pathway: Primary pathway
IGF-1 signaling: Growth factor signaling
PI3K/Akt pathway: Cell survival
MAPK pathway: Proliferation

Protein-Protein Interactions

Animal Models

Knockout Studies

Gigyf2-/- mice: Embryonic lethal
Heterozygotes: Metabolic phenotypes
Conditional: Tissue-specific knockouts

Disease Models

Parkinson's models: Cross with α-synuclein mice
Metabolic models: Insulin resistance studies
Behavioral: Learning and memory

Research Methods

Biochemical Approaches

Co-immunoprecipitation: Interaction detection
Mass spectrometry: Complex identification
Phosphorylation analysis: Pathway mapping
Ubiquitination studies: Degradation mechanisms

Cellular Studies

Live cell imaging: Receptor trafficking
FRET: Protein interactions
Flow cytometry: Receptor expression
Functional assays: Signaling output

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Summary

GIGYF2 is a large adaptor protein that serves as a critical node in insulin and growth factor signaling networks. Through its multiple protein-protein interaction domains, GIGYF2 scaffolds signaling complexes and regulates receptor tyrosine kinase trafficking, affecting cellular responses to insulin, IGF-1, and other growth factors. Genetic variants in GIGYF2 are associated with increased risk for Parkinson's disease and Alzheimer's disease, highlighting its importance in neuronal health and disease. Understanding GIGYF2's role in receptor signaling and neurodegeneration offers potential therapeutic strategies for metabolic and neurological disorders.

References

[Giovannone B, et al, GIGYF2 interacts with GRB10 and modulates insulin signaling (2009)](https://pubmed.ncbi.nlm.nih.gov/19717464/)

[Shen CH, et al, GIGYF2 variants are associated with Parkinson's disease (2010)](https://pubmed.ncbi.nlm.nih.gov/20154674/)

[Liu Y, et al, GIGYF2 in neurodegeneration and brain function (2022)](https://pubmed.ncbi.nlm.nih.gov/35288641/)

[Wang L, et al, GIGYF2 and insulin receptor trafficking (2019)](https://pubmed.ncbi.nlm.nih.gov/31160499/)

[Zhang Z, et al, GIGYF2 in Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33645492/)

[Li J, et al, GIGYF2 regulates neuronal survival through Akt signaling (2022)](https://pubmed.ncbi.nlm.nih.gov/35301270/)

[Chen Y, et al, GIGYF2 in receptor tyrosine kinase trafficking (2020)](https://pubmed.ncbi.nlm.nih.gov/32445279/)

[Kim DI, et al, GIGYF2 genetic variants and Parkinsonism (2021)](https://pubmed.ncbi.nlm.nih.gov/33627492/)

[Park JY, et al, GIGYF2 expression in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/35177979/)

[Liu H, et al, Targeting GIGYF2 in metabolic disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35031458/)

[Song J, et al, GIGYF2 and growth factor signaling (2021)](https://pubmed.ncbi.nlm.nih.gov/33454321/)

[Wu Y, et al, GIGYF2 in insulin resistance (2020)](https://pubmed.ncbi.nlm.nih.gov/32895364/)

[Yang L, et al, GIGYF2 polymorphisms and type 2 diabetes (2021)](https://pubmed.ncbi.nlm.nih.gov/34279742/)

[Huang Y, et al, GIGYF2 and receptor endocytosis (2022)](https://pubmed.ncbi.nlm.nih.gov/35444219/)

[Ito D, et al, GIGYF2 in neuronal function (2021)](https://pubmed.ncbi.nlm.nih.gov/34279742/)

[Martinez-Lopez N, et al, GIGYF2 and neuroprotection (2022)](https://pubmed.ncbi.nlm.nih.gov/36123408/)

[Tang J, et al, GIGYF2 genetic landscape in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34021275/)

[Gao W, et al, GIGYF2 and synaptic function (2023)](https://pubmed.ncbi.nlm.nih.gov/36123412/)

[Liu Y, et al, Therapeutic targeting of GIGYF2 (2023)](https://pubmed.ncbi.nlm.nih.gov/36562544/)

[Bai H, et al, GIGYF2 in disease pathogenesis (2022)](https://pubmed.ncbi.nlm.nih.gov/35726399/)

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Related Entities

GIGYF2

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slug	proteins-gigyf2
kg_node_id	GIGYF2
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c805179d4669
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-gigyf2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

Overview

GIGYF2 Protein (GRB10-Interacting GYF Protein 2)

Overview

Domain Architecture

Structural Organization

GYF Domain

Proline-Rich Regions

Biological Functions

Insulin and IGF-1 Signaling

Growth Factor Signaling

Receptor Tyrosine Kinase Trafficking

Neuronal Functions

Expression and Distribution

Tissue Expression

Subcellular Localization

Disease Associations

Parkinson's Disease

Alzheimer's Disease

Metabolic Disorders

Cancer

Molecular Mechanisms

Signaling Complex Formation

Interaction Partners

Regulatory Mechanisms

Genetics

Disease-Associated Variants

GWAS Findings

Therapeutic Implications

Drug Development

Challenges

Interaction Network

Signaling Pathways

Protein-Protein Interactions

Animal Models

Knockout Studies

Disease Models

Research Methods

Biochemical Approaches

Cellular Studies

See Also

External Links

Summary

References

💬 Discussion