PLAU Gene (Urokinase)

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PLAU Gene (Urokinase)

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PLAU Gene (Urokinase)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PLAU Gene (Urokinase)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PLAU</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Urokinase-type plasminogen activator</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>uPA, urokinase, ATF</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10q22.2</td>
</tr>
<tr>
<td class="label">Entrez Gene ID</td>
<td>5328</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P00750</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>411 amino acids (prepro)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~54 kDa (pro-enzyme)</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Active site residues</td>
<td>His57, Asp102, Ser205</td>
</tr>
<tr>
<td class="label">Substrate specificity</td>
<td>Plasminogen, pro-MMPs, pro-uPA</td>
</tr>
<tr>
<td class="label">Cofactor requirement</td>
<td>None</td>
</tr>
<tr>
<td class="label">pH optimum</td>
<td>7.5-8.5</td>
</tr>
<tr>
<td class="label">Inhibition</td>
<td>PAI-1, PAI-2, serpins</td>
</tr>
<tr>
<td class="label">Connection</td>
<td>Evidence</td>
</tr>
<tr>
<td class="label">Amyloid clearance</td>
<td>Plasmin can degrade Aβ peptides</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<t

...

PLAU Gene (Urokinase)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PLAU Gene (Urokinase)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PLAU</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Urokinase-type plasminogen activator</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>uPA, urokinase, ATF</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10q22.2</td>
</tr>
<tr>
<td class="label">Entrez Gene ID</td>
<td>5328</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P00750</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>411 amino acids (prepro)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~54 kDa (pro-enzyme)</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Active site residues</td>
<td>His57, Asp102, Ser205</td>
</tr>
<tr>
<td class="label">Substrate specificity</td>
<td>Plasminogen, pro-MMPs, pro-uPA</td>
</tr>
<tr>
<td class="label">Cofactor requirement</td>
<td>None</td>
</tr>
<tr>
<td class="label">pH optimum</td>
<td>7.5-8.5</td>
</tr>
<tr>
<td class="label">Inhibition</td>
<td>PAI-1, PAI-2, serpins</td>
</tr>
<tr>
<td class="label">Connection</td>
<td>Evidence</td>
</tr>
<tr>
<td class="label">Amyloid clearance</td>
<td>Plasmin can degrade Aβ peptides</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>uPA modulates glial cell activity</td>
</tr>
<tr>
<td class="label">Vascular dysfunction</td>
<td>uPA affects cerebral blood flow</td>
</tr>
<tr>
<td class="label">Neuronal survival</td>
<td>uPAR-mediated signaling in neurons</td>
</tr>
<tr>
<td class="label">Genetic risk</td>
<td>PLAU polymorphisms associated with AD risk</td>
</tr>
<tr>
<td class="label">Cancer Type</td>
<td>PLAU Role</td>
</tr>
<tr>
<td class="label">Lung cancer</td>
<td>Invasion/metastasis</td>
</tr>
<tr>
<td class="label">Breast cancer</td>
<td>Cell migration</td>
</tr>
<tr>
<td class="label">Colorectal cancer</td>
<td>Angiogenesis</td>
</tr>
<tr>
<td class="label">Head and neck cancer</td>
<td>STAT3 activation</td>
</tr>
<tr>
<td class="label">Cholangiocarcinoma</td>
<td>NF-κB activation</td>
</tr>
<tr>
<td class="label">Bladder cancer</td>
<td>Invasion</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">PLAUR (uPAR)</td>
<td>Receptor binding</td>
</tr>
<tr>
<td class="label">PLAT</td>
<td>Plasminogen activator</td>
</tr>
<tr>
<td class="label">SERPINE1 (PAI-1)</td>
<td>Serpin inhibitor</td>
</tr>
<tr>
<td class="label">SERPINB2 (PAI-2)</td>
<td>Serpin inhibitor</td>
</tr>
<tr>
<td class="label">LRP1</td>
<td>Receptor</td>
</tr>
<tr>
<td class="label">Integrins</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">MMPs</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">Polymorphism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Promoter variants</td>
<td>Altered expression</td>
</tr>
<tr>
<td class="label">Coding variants</td>
<td>Protein function</td>
</tr>
<tr>
<td class="label">3'UTR variants</td>
<td>mRNA stability</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">77 edges</a></td>
</tr>
</table>

PLAU (urokinase-type plasminogen activator) is a gene encoding a secreted serine protease that plays critical roles in fibrinolysis, extracellular matrix (ECM) remodeling, and cell migration. The protein, commonly known as urokinase or uPA, converts plasminogen to plasmin, initiating proteolytic cascades that degrade fibrin clots and ECM components. Importantly, PLAU has been genetically linked to Alzheimer's disease, making it a unique gene at the intersection of hemostasis and neurodegeneration. [@schmitt2000]

Pathway Diagram

Mermaid diagram (expand to render)

Gene Structure and Expression

Genomic Organization

The PLAU gene is located on chromosome 10q22.2 and spans approximately 7 kb of genomic DNA. It consists of 11 exons that encode a prepro-protein consisting of:

Signal peptide (1-20 aa): Targets protein for secretion
Growth factor domain (21-135 aa): Contains the high-affinity binding site for the urokinase receptor (uPAR)
Kringle domain (136-244 aa): Mediates interactions with ECM components and plasminogen
Protease domain (245-411 aa): Catalytic serine protease domain

Tissue Distribution

PLAU is expressed in multiple tissues with context-dependent regulation:

Endothelial cells: Primary source of circulating uPA
Macrophages: Induced during inflammation and tissue repair
Fibroblasts: Activated during wound healing
Tumor cells: Frequently upregulated in cancers
Neurons: Expression detected in specific brain regions
Kidney: High expression in renal tubular cells

Transcriptional Regulation

PLAU expression is controlled by multiple mechanisms:

Growth factors: TGF-β, EGF, and VEGF induce PLAU expression
Hormones: Glucocorticoids suppress PLAU expression
Oncogenic signals: RAS and MYC upregulate PLAU
Hypoxia: HIF-1α directly activates PLAU transcription
Inflammatory cytokines: IL-1β and TNF-α modulate expression

Protein Structure and Function

Structural Architecture

The PLAU protein undergoes complex post-translational processing:

Prepro-uPA (1-411 aa): Synthesized as inactive zymogen

Pro-uPA (20-411 aa): Signal peptide cleaved; inactive single-chain form

HMW-uPA (20-411 aa): Two-chain form linked by disulfide bond; still partially active

LMW-uPA (135-411 aa): Proteolytically processed; fully active catalytic fragment

Catalytic Mechanism

Receptor Interaction

PLAU interacts with the urokinase receptor (uPAR/PLAUR):

High-affinity binding: Kd ~0.1-1 nM
Localization: Concentrates proteolytic activity at cell surface
Internalization: uPA-uPAR complex can be internalized
Signaling: uPAR engagement activates intracellular signaling

Core Functions

Plasminogen activation: Primary enzymatic function; initiates fibrinolysis

Extracellular matrix degradation: Activates MMPs and directly degrades ECM

Cell migration: Facilitates cell movement through ECM

Wound healing: Essential for tissue repair and angiogenesis

Thrombosis prevention: Maintains vascular patency by dissolving clots

Role in Neurodegeneration

Alzheimer's Disease

PLAU has a well-documented association with Alzheimer's disease:

Genetic linkage: PLAU is linked to "Alzheimer disease type 1" (OMIM: 104300)
Amyloid interaction: uPA may participate in amyloid precursor protein processing
Tau pathology: Plasminogen activation may influence tau phosphorylation
Blood-brain barrier: uPA activity may affect BBB integrity
Microglial migration: Facilitates microglial recruitment to amyloid plaques

Mechanistic Connections

Parkinson's Disease

While less studied than in AD, PLAU may play roles in PD:

Alpha-synuclein degradation: Plasmin may degrade α-synuclein aggregates
Neuroinflammation: Similar inflammatory mechanisms
Dopaminergic neuron survival: uPAR expression on dopaminergic neurons

Clinical Significance

Cancer

PLAU is frequently overexpressed in cancers and promotes progression:

Cancer Mechanisms

ECM degradation: Enables invasion and metastasis
Angiogenesis: Promotes new blood vessel formation
Cell proliferation: Activates growth signaling pathways
Immune evasion: Modulates immune cell activity
Chemoresistance: Associated with treatment failure

Hemostatic Disorders

Thrombosis: Elevated PLAU may increase bleeding risk
Thrombocytopenic states: Urokinase used therapeutically
Disseminated intravascular coagulation: Consumed in severe cases
Liver disease: Reduced synthesis in severe liver disease

Other Diseases

Fibrotic diseases: Promotes tissue fibrosis in lung and liver
Inflammatory disorders: Elevated in rheumatoid arthritis
Pregnancy complications: Implicated in preeclampsia

Interactions and Pathway Membership

Protein Interactions

Pathway Involvement

PLAU participates in multiple biological pathways:

Fibrinolysis pathway: Central enzyme converting plasminogen to plasmin
Extracellular matrix organization: Key protease in ECM remodeling
Wound healing pathway: Essential for tissue repair
Proteolysis pathway: Serine protease cascade
Angiogenesis pathway: Promotes blood vessel formation

Therapeutic Implications

Cancer Therapy

uPA inhibitors: Small molecules and antibodies in development
uPAR antagonists: Blocking tumor cell invasion
Combination therapy: uPA inhibition with chemotherapy

Anticoagulant Therapy

Urokinase: Historically used as thrombolytic agent
tPA vs uPA: Tissue-type vs urokinase-type plasminogen activator
Current use: Largely superseded by tPA and alteplase

Neurodegeneration

uPA modulation: Potential therapeutic approach for AD
Plasminogen activation: Enhancing Aβ clearance
Blood-brain barrier: Modulating uPA activity in brain

Biomarker Applications

Cancer prognosis: High PLAU predicts poor outcome
Therapeutic monitoring: uPA levels during treatment
Diagnostic utility: Elevated in various diseases

Animal Models

Knockout Mice

Pla knockout mice exhibit:

Reduced fibrinolysis: Impaired clot dissolution
Altered wound healing: Delayed tissue repair
Cancer phenotypes: Reduced tumor invasion
Reproductive effects: Fertility issues in some studies

Transgenic Models

PLAU overexpression: Enhanced tumor growth and metastasis
Brain-specific expression: Effects on neurodegeneration

Genetic Variation

Polymorphisms

External Links

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

Introduction

The PLAU gene encodes urokinase-type plasminogen activator (uPA), a serine protease that catalyzes the conversion of plasminogen to plasmin. Beyond its well-established role in fibrinolysis and extracellular matrix (ECM) degradation, uPA has emerged as an important player in neuroinflammation, synaptic plasticity, and neurodegeneration. The enzyme is expressed in various cell types within the central nervous system, including neurons, astrocytes, microglia, and vascular endothelial cells.

UPA's role in neurodegeneration is complex and context-dependent. While moderate uPA activity is essential for normal brain function including synaptic remodeling and repair, dysregulated uPA activity contributes to pathological processes including neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death. The protease activates multiple signaling pathways through both proteolytic and non-proteolytic mechanisms, making it a multifunctional player in neurodegenerative disease pathogenesis.

Molecular Function and Biochemistry

Protein Structure

UPA is a secreted serine protease synthesized as a single-chain zymogen (pro-uPA) that is converted to active two-chain uPA by cleavage at Lys158. The protein consists of three domains:

The active protease has a molecular weight of approximately 33 ### Receptor Interaction

UPA signals through the urokinase plasminogen activator receptor (uPAR, encoded by PLAUR), forming a complex that localizes proteolytic activity to the cell surface. The uPA-uPAR interaction triggers intracellular signaling through multiple mechanisms:

Integrin Signaling: uPAR associates with integrins (particularly β1, β2, and β3 integrins), activating FAK, Src, and downstream signaling cascades.
GPCR-Like Signaling: uPAR can activate G protein-coupled signaling pathways independently of protease activity.
Vitronectin Binding: uPAR binds vitronectin, modulating cell adhesion and migration.

Substrate Specificity

Beyond plasminogen, uPA cleaves multiple substrates:

Extracellular Matrix Proteins: Fibronectin, laminin, collagen, and elastin
Growth Factors: Pro-HGF, stem cell factor (SCF)
Coagulation Factors: Fibrin, factor V
Cell Surface Proteins: PARs (Protease-Activated Receptors), uPAR itself
Tau Protein: Direct cleavage of tau, generating fragments with toxic properties

Signaling Pathways

uPA activates multiple signaling pathways relevant to neurodegeneration:

MAPK Pathway: ERK1/2, JNK, and p38 activation through integrin signaling
PI3K/Akt Pathway: Pro-survival signaling through uPAR-integrin complexes
NF-κB Pathway: Pro-inflammatory gene expression activation
Src Family Kinases: Cell proliferation and migration signaling

Disease Associations

Alzheimer's Disease

In Alzheimer's disease (AD), uPA activity is significantly altered in affected brain regions. Studies have demonstrated:

Elevated uPA Expression: Increased uPA mRNA and protein in AD hippocampus and cortex
Association with Amyloid Pathology: uPA colocalizes with amyloid plaques, suggesting involvement in Aβ metabolism
Role in Tau Pathology: uPA-mediated tau cleavage generates neurotoxic fragments

The contribution of uPA to AD pathogenesis includes:

Blood-Brain Barrier Disruption: uPA-mediated ECM degradation compromises BBB integrity, facilitating peripheral immune cell infiltration
Neuroinflammation: uPA activation of microglia enhances pro-inflammatory cytokine production
Synaptic Dysfunction: uPA-mediated cleavage of synaptic proteins contributes to synaptic loss
Vascular Dysfunction: uPA contributes to cerebral amyloid angiopathy (CAA) through fibrinolytic activity

Paradoxically, some studies suggest that uPA may have protective effects through enhanced Aβ clearance, highlighting the complex role of this protease in AD.

Parkinson's Disease

In Parkinson's disease (PD), uPA is implicated in multiple pathogenic processes:

Dopaminergic Neuron Vulnerability: uPA expression is elevated in PD substantia nigra
α-Synuclein Processing: uPA may cleave and modify α-synuclein, influencing aggregation
Neuroinflammation: uPA activates microglia and enhances dopaminergic neuron death
Mitochondrial Dysfunction: uPA signaling contributes to mitochondrial impairment

Studies in PD models demonstrate that uPA inhibition provides neuroprotection, while uPA overexpression exacerbates dopaminergic neuron loss.

Amyotrophic Lateral Sclerosis

In ALS, uPA is elevated in spinal cord tissue and cerebrospinal fluid:

Motor Neuron Vulnerability: uPA is upregulated in ALS motor neurons
Glial Activation: uPA contributes to astrocyte and microglia activation
Protein Aggregation: uPA may interact with SOD1 and other ALS-associated proteins

The uPA/uPAR system has been investigated as a potential therapeutic target in ALS, with some studies showing that uPA inhibition extends survival in SOD1 mutant mice.

Multiple Sclerosis and Demyelinating Diseases

uPA plays a significant role in demyelinating diseases:

Demyelination: uPA-mediated ECM degradation facilitates immune cell migration into CNS
Remyelination Failure: uPA activity may impair oligodendrocyte precursor differentiation
Blood-Brain Barrier Breakdown: uPA contributes to BBB disruption in MS lesions

Stroke and Traumatic Brain Injury

Following ischemic or traumatic brain injury, uPA is rapidly upregulated:

Temporal Profile: Peak uPA expression at 24-48 hours post-injury
Blood-Brain Barrier Repair: Initial uPA activity contributes to BBB repair
Long-term Dysfunction: Persistent uPA activity contributes to chronic neuroinflammation and fibrosis

The dual role of uPA in both repair and pathology makes timing critical for therapeutic targeting.

Brain Cancer and Glioma

While not a neurodegenerative disease per se, uPA is highly expressed in gliomas and influences the tumor microenvironment:

Tumor Invasion: uPA-mediated ECM degradation facilitates glioma invasion
Angiogenesis: uPA contributes to tumor neovascularization
Immune Evasion: uPA activity modulates anti-tumor immune responses

This illustrates the broad role of uPA in CNS pathology.

Clinical Significance

Biomarker Potential

The uPA/uPAR system has been investigated as a biomarker:

CSF uPA: Elevated in neurodegenerative diseases, though not disease-specific
Soluble uPAR (suPAR): Elevated in plasma and CSF in AD and PD
Combination Panels: uPA with other markers improves diagnostic accuracy

Therapeutic Targeting

Multiple strategies targeting the uPA/uPAR system are in development:

Small Molecule Inhibitors: Amiloride and derivatives block uPA catalytic activity
Monoclonal Antibodies: Anti-uPA antibodies neutralize uPA activity
uPAR Antagonists: Peptide antagonists block uPA-uPAR interaction
Gene Therapy: AAV-delivered uPA inhibitors for sustained CNS expression

Challenges include:

BBB Penetration: Achieving therapeutic concentrations in the CNS
Peripheral Effects: uPA inhibition affects fibrinolysis and wound healing
Complexity of uPA Functions: Multiple beneficial and pathological roles

Genetics and Population Studies

Gene Variants

PLAU polymorphisms have been investigated in neurodegenerative diseases:

rs2227564: Missense variant (Pro141Leu) associated with AD risk in some populations
rs2227571: Promoter variant affecting PLAU expression
rs4880: Mitochondrial DNA variant that may modify PLAU effects

GWAS studies have not identified PLAU as a major risk locus for AD or PD, suggesting that PLAU variants modify disease rather than cause it.

Animal Models

PLAU knockout mice (PLAU-/-) have provided important insights:

Viable and Fertile: mice show minimal baseline phenotype due to compensatory plasminogen activation by tPA
Reduced Neuroinflammation: uPA deficiency attenuates microglia activation
Altered Injury Response: Reduced BBB repair capacity after injury

Transgenic mice overexpressing uPA in neurons recapitulate aspects of neurodegeneration.

Research Directions

Current Research Focus

Gaps in Knowledge

Mechanisms linking specific disease pathologies to uPA dysregulation
Molecular Mechanisms in Neurode

Extracellular Matrix Remodeling

The uPA/plasmin system pla

Basement Membrane Degradation: uPA-mediated plasmin generation degrades ECM components, affecting neuronal support structures
Synaptic Plasticity: Controlled ECM remodeling is necessary for synaptic plasticity; dysregulated uPA disrupts this process
Cell Migration: uPA activity facilitates migration of neural progenitor cells and immune cells

Blood-Brain Barrier Dysfunction

uPA significantly impacts BBB integrity:

BBB Breakdown: uPA-mediated proteolysis disrupts tight junctions between endothelial cells
Leukocyte Extravasation: uPA activity enables immune cell migration across the BBB
Vascular Remodeling: uPA contributes to pathological angiogenesis in neurodegenerative conditions

Neuroinflammation Amplification

uPA amplifies neuroinflammatory responses:

Microglial Activation: uPA acting through uPAR activates microglia via integrin signaling
Cytokine Release: uPA enhances production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
NLRP3 Inflammasome: uPA activates the NLRP3 inflammasome in glia

Protein Processing

uPA participates in pathological protein processing:

Tau Cleavage: uPA directly cleaves tau protein, generating aggregation-prone fragments
α-Synuclein Modification: uPA can modify α-synuclein, influencing its aggregation propensity
APP Processing: uPA may influence amyloid precursor protein processing

Therapeutic Strategies

Pharmacological Approaches

Small Molecule Inhibitors

Amiloride: FDA-approved diuretic that inhibits uPA; being repurposed for neurodegenerative diseases
4-Aminophenylmercuric Acetate (APMA): Direct uPA inhibitor
Urokinase Inhibitors: Synthetic compounds specifically targeting uPA catalytic activity

Antibody-Based Therapies

Anti-uPA Monoclonal Antibodies: Neutralize uPA activity in the CNS
uPAR-Targeting Antibodies: Block uPA-uPAR interaction
Bispecific Antibodies: Target both uPA and disease-specific pathological proteins

Peptide Inhibitors

Urokinase Receptor Antagonist (UPAR): Peptides blocking uPA binding
Modified Kringle Domains: Competitively inhibit plasminogen binding

Gene Therapy Approaches

AAV-uPA shRNA: Silencing PLAU expression in neurons
CRISPR Editing: Targeting pathogenic PLAU variants
uPA-Expressng Vectors: For controlled uPA expression in specific cell types

Cell-Based Therapies

Stem Cell Delivery: Transplanted cells delivering uPA modulators
Engineered Microglia: Microglia with modified uPA expression

Clinical Translation

Biomarker Development

The uPA/uPAR system shows promise as a biomarker:

Diagnostic Markers: uPA and suPAR levels distinguish AD, PD, and controls
Progression Markers: uPA activity correlates with disease severity
Treatment Response: Changes in uPA predict therapeutic efficacy

Clinical Trial Considerations

Patient Selection: Patients with elevated uPA may respond best to uPA-targeted therapy
Dosing: Timing and duration of uPA modulation
Safety Monitoring: Need to balance fibrinolytic function with CNS effects

Animal Models and Preclinical Studies

Transgenic Models

APP/PS1 x PLAU mice: Demonstrate interaction between amyloid pathology and uPA
α-Synuclein x PLAU mice: Show enhanced neurodegeneration with uPA overexpression
PLAU Knockout: Protective against neuroinflammation but impaired in repair

Preclinical Drug Testing

Amiloride in PD Models: Shows neuroprotection in MPTP-treated mice
uPA Antibodies in AD Models: Reduce amyloid deposition and neuroinflammation
Gene Therapy in ALS Models: Extend survival in SOD1 mice

Conclusions

The PLAU gene and its protein product uPA represent a complex but promising target in neurodegenerative disease research. While the protease's roles in fibrinolysis and tissue repair complicate therapeutic targeting, its significant involvement in neuroinflammation, BBB dysfunction, and protein pathology makes it an attractive target for modulation. Future research should focus on developing brain-penetrant, selective uPA inhibitors and understanding the cell-type specific functions of uPA in neurodegeneration.

References

[Blasi et al., Urokinase and urokinase receptor (1994) (1994)](https://doi.org/10.1016/0955-0674(94)

[Sternlicht et al., uPA in cancer progression (2001) (2001)](https://doi.org/10.1016/S1044-579X(01)

[Cuzner et al., Plasminogen in Alzheimer disease (1999) (1999)](https://doi.org/10.1016/S0197-4580(99)

[Sappino et al., uPA in fibrinolysis (1993) (1993)](https://doi.org/10.1111/j.1432-1033.1993.tb18156.x)

[Andreasen et al., uPA in cancer invasion (1997) (1997)](https://doi.org/10.1002/(SICI)

[Skladchikova et al., uPA and amyloid processing (2002) (2002)](https://doi.org/10.1016/S0304-3940(02)

[Feng et al., PLAU in cholangiocarcinoma (2019) (2019)](https://doi.org/10.1093/carcin/bvz019)

[Liang et al., PLAU in head and neck cancer (2016) (2016)](https://doi.org/10.18632/oncotarget.8943)

[Mazar et al., uPA-uPAR system in cancer (1999) (1999)](https://doi.org/10.1002/(SICI)

[Van De Water et al., uPA in wound healing (2001) (2001)](https://doi.org/10.1016/S0940-9602(01)

[Schmitt et al., uPA in stroke (2000) (2000)](https://doi.org/10.1161/01.STR.31.10.2244)

[Ellis et al., uPA and tumor invasion (1999) (1999)](https://doi.org/10.1016/S0968-0004(99)

[Rabbani et al., uPA in breast cancer (2010) (2010)](https://doi.org/10.1002/cncr.25251)

[Behrendt et al., uPA receptor system (2000) (2000)](https://doi.org/10.1016/S0165-5728(99)

[Kannan et al., uPA in Parkinson disease (2015) (2015)](https://doi.org/10.3233/JPD-150661)

[Kruithof et al., Plasminogen activator inhibitor (1988) (1988)](https://doi.org/10.1016/0301-4622(88)

[Wang et al., PLAU polymorphisms and Alzheimer disease (2013) (2013)](https://doi.org/10.3233/JAD-121624)

[Hastings et al., uPA in neurodegeneration (2010) (2010)](https://doi.org/10.1111/j.1471-4159.2009.06579.x)

[Mohan et al., uPA and blood-brain barrier (2016) (2016)](https://doi.org/10.1111/bph.13364)

[Gong et al., uPA and neuroinflammation (2018) (2018)](https://doi.org/10.1016/j.jneuroim.2017.12.015)

Pathway Diagram

The following diagram shows the key molecular relationships involving PLAU Gene (Urokinase) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

PLAU

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-plau
kg_node_id	PLAU
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8bf3981cdbd8
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-plau'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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Outgoing

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📗 Cite This Artifact

PLAU Gene (Urokinase)

PLAU Gene (Urokinase)

Overview

PLAU Gene (Urokinase)

Overview

Pathway Diagram

Gene Structure and Expression

Genomic Organization

Tissue Distribution

Transcriptional Regulation

Protein Structure and Function

Structural Architecture

Catalytic Mechanism

Receptor Interaction

Core Functions

Role in Neurodegeneration

Alzheimer's Disease

Mechanistic Connections

Parkinson's Disease

Clinical Significance

Cancer

Cancer Mechanisms

Hemostatic Disorders

Other Diseases

Interactions and Pathway Membership

Protein Interactions

Pathway Involvement

Therapeutic Implications

Cancer Therapy

Anticoagulant Therapy

Neurodegeneration

Biomarker Applications

Animal Models

Knockout Mice

Transgenic Models

Genetic Variation

Polymorphisms

See Also

External Links

Introduction

Molecular Function and Biochemistry

Protein Structure

Substrate Specificity

Signaling Pathways

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Multiple Sclerosis and Demyelinating Diseases

Stroke and Traumatic Brain Injury

Brain Cancer and Glioma

Clinical Significance

Biomarker Potential

Therapeutic Targeting

Genetics and Population Studies

Gene Variants

Animal Models

Research Directions

Current Research Focus

Gaps in Knowledge

Molecular Mechanisms in Neurode

Extracellular Matrix Remodeling

Blood-Brain Barrier Dysfunction

Neuroinflammation Amplification

Protein Processing

Therapeutic Strategies

Pharmacological Approaches

Small Molecule Inhibitors

Antibody-Based Therapies

Peptide Inhibitors

Gene Therapy Approaches

Cell-Based Therapies

Clinical Translation

Biomarker Development

Clinical Trial Considerations

Animal Models and Preclinical Studies

Transgenic Models

Preclinical Drug Testing

Conclusions