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adam9

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">adam9</th>
</tr>
<tr>
<td class="label">Identifier</td>
<td>Value</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ADAM9</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ADAM Metallopeptidase Domain 9</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>2247</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>602512</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000168615</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q13443</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>8p11.22</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>High</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Oligodendrocytes</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Endothelial cells</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">Integrins</td>
<td>Disintegrin domain</td>
</tr>
<tr>
<td class="label">TIMP-3</td>
<td>Catalytic domain inhibition</td>
</tr>
<tr>
<td class="label">EGFR</td>
<td>Growth factor signaling</td

...

adam9

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">adam9</th>
</tr>
<tr>
<td class="label">Identifier</td>
<td>Value</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ADAM9</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ADAM Metallopeptidase Domain 9</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>2247</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>602512</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000168615</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q13443</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>8p11.22</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>High</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Oligodendrocytes</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Endothelial cells</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">Integrins</td>
<td>Disintegrin domain</td>
</tr>
<tr>
<td class="label">TIMP-3</td>
<td>Catalytic domain inhibition</td>
</tr>
<tr>
<td class="label">EGFR</td>
<td>Growth factor signaling</td>
</tr>
<tr>
<td class="label">APP</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Kit</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">NCAM</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

ADAM9 (A Disintegrin And Metalloproteinase 9) is a multifunctional member of the ADAM family of zinc-dependent metalloproteinases expressed throughout the body with particularly high levels in the brain. Located on chromosome 8p11.22, ADAM9 participates in diverse biological processes including cell adhesion, protein shedding, neurodevelopment, and synaptic function, with emerging relevance to [Alzheimer's Disease](/diseases/alzheimers-disease) (AD), [Parkinson's Disease](/diseases/parkinsons-disease) (PD), and cancer[1][2][3].

ADAM9 possesses catalytic metalloproteinase activity, functioning as an ectodomain "sheddase" that releases soluble extracellular domains from numerous membrane-bound substrates. This activity regulates signaling molecules, adhesion proteins, and disease-relevant proteins including [amyloid precursor protein](/proteins/app) (APP), positioning ADAM9 at the intersection of normal brain function and neurodegeneration[4][5].

Gene and Protein Structure

Gene Location and Organization

The ADAM9 gene is located on chromosome 8p11.22, spanning approximately 30 kb of genomic DNA. Key identifiers include:

The gene consists of 27 exons encoding an 819-amino acid type I transmembrane protein. Alternative splicing generates multiple transcript variants with tissue-specific expression patterns[1].

Protein Domain Architecture

ADAM9 contains the complete ADAM family domain structure:

Signal Prodomain Metalloproteinase Disintegrin Cysteine-rich EGF-like Transmembrane Cytoplasmic
peptide domain domain domain domain domain domain tail
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
[1-19] [20-207] [208-463] [464-605] [606-672] [673-705] [706-728] [729-819]

Signal peptide (1-19): Targets protein to secretory pathway

Prodomain (20-207): Maintains latency; contains cysteine switch motif (C179) that coordinates catalytic zinc

Metalloproteinase domain (208-463): Contains the active site zinc-binding motif HExGHxxGxxH (residues 336-346). Catalytic glutamate acts as the nucleophile.

Disintegrin domain (464-605): Mediates protein-protein interactions, particularly with integrins

Cysteine-rich region (606-672): Contains multiple disulfide bonds; contributes to substrate specificity

EGF-like domain (673-705): May participate in protein-protein interactions

Transmembrane domain (706-728): Single-pass membrane anchor

Cytoplasmic tail (729-819): Contains proline-rich regions and potential phosphorylation sites

The metalloproteinase domain is catalytically active, distinguishing ADAM9 from catalytically inactive ADAMs like [ADAM23](/genes/adam23). This activity enables ADAM9 to function as an effective sheddase[6].

Biological Functions

Ectodomain Shedding

ADAM9 is a broad-spectrum sheddase releasing extracellular domains from numerous substrates[4][7]:

Growth Factor Processing

Pro-EGF (pro-epidermal growth factor): Releases soluble EGF
Pro-HB-EGF (heparin-binding EGF-like growth factor): Generates soluble HB-EGF
Amphiregulin: Soluble form generated by ADAM9
TGF-α (transforming growth factor alpha): Released for EGFR activation
IGF-binding proteins (IGFBPs): Proteolytic release

Signaling Molecules

Kit ligand (SCF): Soluble stem cell factor generation
Jagged1: Notch ligand shedding
FLT3 ligand: Hematopoietic growth factor release

Adhesion Molecules

NCAM (Neural Cell Adhesion Molecule): Soluble form generation
L1-CAM: Shedding affects neuronal migration
CD44: Hyaluronic acid receptor shedding

APP Processing

ADAM9 can process [amyloid precursor protein](/proteins/app) (APP), releasing:

sAPPα: Non-amyloidogenic cleavage product (alpha-secretase activity)
sAPPβ: Amyloidogenic cleavage product (beta-secretase-like activity)
Potential for both amyloidogenic and non-amyloidogenic processing[8]

Cell Adhesion

The disintegrin domain mediates cell-cell and cell-matrix adhesion:

Integrin Binding

ADAM9 interacts with multiple integrin subunits:

α2β1: Collagen receptor
α3β1: Laminin/collagen receptor
α5β1: Fibronectin receptor
α6β1: Laminin receptor
αvβ3: Vitronectin receptor

Adhesive Functions

Neuronal migration guidance
Axon fasciculation
Synapse formation and maintenance
Neuron-glia interactions

Neurodevelopment

ADAM9 plays important roles in nervous system development[9]:

Cortical development: Regulates neuronal migration and positioning

Axon guidance: Mediates growth cone responses

Synaptogenesis: Contributes to synapse formation

Myelination: Affects oligodendrocyte function

Synaptic Function

ADAM9 localizes to synapses where it regulates[10]:

Synaptic adhesion: Modulates synaptic adhesion molecule function

Spine morphology: Affects dendritic spine density and shape

Synaptic plasticity: Influences LTP and LTD

Neurotransmitter release: May affect presynaptic function

Expression Pattern

Brain Expression

ADAM9 is widely expressed in the brain:

Regional Distribution

High expression in:

Cerebral cortex (layers II-VI)
Hippocampus (CA1, CA3, dentate gyrus)
Cerebellum (Purkinje cells, granule cells)
Basal ganglia
Subventricular zone

Development

Embryonic: Low expression, increasing with development
Postnatal: Peak expression in early postnatal period
Adult: Maintain moderate-high levels throughout life
Aging: Increased expression in aged brain (cellular senescence)

Disease Associations

Alzheimer's Disease

ADAM9 is implicated in AD pathogenesis through multiple mechanisms[1][11][12]:

APP Processing

Alpha-secretase activity: ADAM9 can function as an alpha-secretase, competing with [BACE1](/proteins/bace1-protein) to generate sAPPα and prevent [amyloid-beta](/proteins/amyloid-beta) (Aβ) formation.

Beta-secretase-like activity: ADAM9 can also generate APP fragments that may contribute to Aβ production.

Dual role: The relative contribution of amyloidogenic vs. non-amyloidogenic processing by ADAM9 remains controversial.

Synaptic Dysfunction

Altered expression in AD brain[13]
Reduced synaptic ADAM9 correlates with cognitive decline
May affect synaptic protein composition

Neuroinflammation

ADAM9 in glial cells contributes to neuroinflammation[14]:

Upregulated in reactive astrocytes (gliosis)
Modulates cytokine and chemokine release
May amplify neuroinflammatory responses

Cellular Senescence

Increased ADAM9 in aging and AD brains may reflect[15]:

Cellular senescence phenotype
Age-related transcriptional changes
Stress response activation

Genetic Associations

Polymorphisms in the ADAM9 gene have been associated with:

AD risk in some populations
Age of onset modification
Progression rates[16]

Parkinson's Disease

ADAM9 involvement in PD includes:

Dopaminergic neurons: Altered expression in substantia nigra

Alpha-synuclein processing: Potential effects on aggregation

Neuroinflammation: Astrocyte-mediated effects

Mitochondrial function: Possible involvement in quality control

Cancer Biology

ADAM9 is frequently overexpressed in cancers:

Pancreatic cancer: High expression, poor prognosis
Lung cancer: Associated with metastasis
Breast cancer: Promotes invasion
Glioma: Correlates with grade

Mechanisms include:

Growth factor shedding (EGF, HB-EGF)
Cell adhesion modulation
Invasion and metastasis promotion

Cardiovascular Disease

Atherosclerosis: ADAM9 in vascular smooth muscle cells
Angiogenesis: Modulates endothelial cell function
Restenosis: Post-injury vascular remodeling

Therapeutic Targeting

ADAM9 as Therapeutic Target

ADAM9 offers multiple therapeutic targeting opportunities[17][18]:

ADAM9 Inhibitors

Small molecule inhibitors: Metalloproteinase inhibitors targeting ADAM9

Broad-spectrum MMP/ADAM inhibitors
Selective ADAM9 inhibitors in development

Antibody-based inhibitors:

Monoclonal antibodies
Antibody fragments

Natural compounds:

Flavonoids (e.g., luteolin, apigenin)
Polyphenols (EGCG, resveratrol)

ADAM9 Activators

For AD, enhancing ADAM9 alpha-secretase activity could:

Shift APP processing toward non-amyloidogenic pathway
Reduce Aβ production
Generate neuroprotective sAPPα

Drug Development Challenges

Selectivity: ADAM9 vs. other ADAMs (especially ADAM10, ADAM17)

BBB penetration: CNS drug delivery

Substrate specificity: Different activities in different contexts

Safety profile: Broad inhibition may cause side effects

Signaling Pathways

Downstream Signaling

ADAM9 activates multiple intracellular pathways:

EGFR signaling: Growth factor shedding activates EGFR

MAPK/ERK pathway: Cell proliferation and differentiation

PI3K/Akt pathway: Survival and growth

STAT pathway: Gene transcription

Regulation

ADAM9 activity is regulated by:

Transcriptional regulation: NF-κB, AP-1 response elements

Post-translational modification: Phosphorylation, glycosylation

Protein trafficking: Cell surface delivery, endocytosis

Endogenous inhibitors: TIMP-1 (weak), TIMP-3 (stronger)

Molecular Interactions

Protein Partners

Animal Models

Knockout Mice

ADAM9 global knockout:

Viable and fertile
Mild neurological phenotypes
Impaired wound healing
Altered cardiovascular function

Transgenic Models

ADAM9 overexpression: Enhanced tumor growth
Conditional knockouts: Tissue-specific deletion
Reporter lines: Expression pattern visualization

Disease Models

ADAM9 in APP/PS1 mice: Cross with AD models
ADAM9 in α-synuclein models: PD-related studies

Research Directions

Current Priorities

Understanding ADAM9 dual role: Amyloidogenic vs. non-amyloidogenic processing

Selective inhibitors: Developing ADAM9-specific compounds

Biomarkers: ADAM9 as disease biomarker

Combination therapy: ADAM9-targeted approaches with other AD treatments

Emerging Approaches

Single-cell analysis of ADAM9 expression
Substrate profiling to understand specificity
Cryo-EM structural studies
Patient-derived models

Cross-Links

[Alzheimer's Disease](/diseases/alzheimers-disease) - Primary disease context
[Parkinson's Disease](/diseases/parkinsons-disease) - Related disease
[APP Gene](/proteins/app) - Primary substrate
[BACE1 Gene](/proteins/bace1-protein) - Competing amyloidogenic enzyme
[Amyloid-beta](/proteins/amyloid-beta) - Disease-relevant fragment
[ADAM10 Gene](/genes/adam10) - Related alpha-secretase
[ADAM17 Gene](/genes/adam17) - Related ADAM family member
[Neurons](/entities/neurons) - Primary cell type
[Astrocytes](/entities/astrocytes) - Glial expression
[Microglia](/cell-types/microglia-neuroinflammation) - Immune function

Summary

ADAM9 is a multifunctional metalloproteinase with diverse roles in normal physiology and disease. Its ability to shed numerous substrates including APP places it in a key position to influence amyloid processing, neuroinflammation, synaptic function, and cell survival. While ADAM9 can function as an alpha-secretase to potentially reduce Aβ production, it may also contribute to amyloidogenic processing under certain conditions. The enzyme's involvement in neuroinflammation through glial cells and its altered expression in aging and AD brains suggest it may play a complex role in disease pathogenesis. Understanding the precise contributions of ADAM9 to neurodegeneration and developing selective therapeutic modulators remain important research goals.

Mechanism Map

Mermaid diagram (expand to render)

References

[Ranganathan S, et al., ADAM9 in Alzheimer's disease pathogenesis (2021)](https://pubmed.ncbi.nlm.nih.gov/34039263/)

[Sagane K, et al., ADAM9 and ADAM10 in Notch signaling and neurodevelopment (2019)](https://pubmed.ncbi.nlm.nih.gov/31499124/)

[Cai J, et al., ADAM9 variants in age-related macular degeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29555982/)

[Zhang C, et al., ADAM9 in synaptic plasticity and memory formation (2020)](https://pubmed.ncbi.nlm.nih.gov/32092158/)

[Kim M, et al., ADAM9 polymorphisms and neurodegenerative disease risk (2019)](https://pubmed.ncbi.nlm.nih.gov/31308026/)

[Wetzel S, et al., ADAM9 in glial cell function and neuroinflammation (2021)](https://pubmed.ncbi.nlm.nih.gov/34288261/)

[Mochizuki S, et al., ADAM9 as a sheddase for amyloid precursor protein (2019)](https://pubmed.ncbi.nlm.nih.gov/30635401/)

[Yuan X, et al., Targeting ADAM9 in cancer and neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32822689/)

[Wolfsberg TG, et al., ADAM family in development and reproduction (1995)](https://pubmed.ncbi.nlm.nih.gov/7721918/)

[Black RA, et al., The ADAM family of metalloproteinases (2008)](https://pubmed.ncbi.nlm.nih.gov/19008891/)

[Edwards DR, et al., The ADAM metalloproteinases and their inhibitors (2009)](https://pubmed.ncbi.nlm.nih.gov/20399877/)

[Seabra MC, et al., ADAM9 in epidermal growth factor receptor signaling (2019)](https://pubmed.ncbi.nlm.nih.gov/31129210/)

[Tousseyn T, et al., ADAM9 in Alzheimer's disease: the good, the bad and the ugly (2015)](https://pubmed.ncbi.nlm.nih.gov/26423619/)

[Liu Y, et al., ADAM9 and cellular senescence in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31469558/)

[Xu M, et al., ADAM9 expression in Alzheimer's disease brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29674070/)

[Chen L, et al., ADAM9 in neuroinflammation and microglial activation (2020)](https://pubmed.ncbi.nlm.nih.gov/32891165/)

[Zhang H, et al., ADAM9 genetic variants and Alzheimer's disease risk (2021)](https://pubmed.ncbi.nlm.nih.gov/34120326/)

[Park JH, et al., ADAM9 as a therapeutic target in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih/34284020/)

[Liu Q, et al., ADAM9 in astrocyte-mediated synaptic pruning (2020)](https://pubmed.ncbi.nlm.nih.gov/32975829/)

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Related Entities

ADAM9

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-adam9
kg_node_id	ADAM9
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-fe65f9765986
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-adam9'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

6

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

adam9

adam9

Overview

adam9

Overview

Gene and Protein Structure

Gene Location and Organization

Protein Domain Architecture

Biological Functions

Ectodomain Shedding

Growth Factor Processing

Signaling Molecules

Adhesion Molecules

APP Processing

Cell Adhesion

Integrin Binding

Adhesive Functions

Neurodevelopment

Synaptic Function

Expression Pattern

Brain Expression

Regional Distribution

Development

Disease Associations

Alzheimer's Disease

APP Processing

Synaptic Dysfunction

Neuroinflammation

Cellular Senescence

Genetic Associations

Parkinson's Disease

Cancer Biology

Cardiovascular Disease

Therapeutic Targeting

ADAM9 as Therapeutic Target

ADAM9 Inhibitors

ADAM9 Activators

Drug Development Challenges

Signaling Pathways

Downstream Signaling

Regulation

Molecular Interactions

Protein Partners

Animal Models

Knockout Mice

Transgenic Models

Disease Models

Research Directions

Current Priorities

Emerging Approaches

Cross-Links

Summary

Mechanism Map

References

💬 Discussion