YES1 (YES Proto-Oncogene 1, Src Family Tyrosine Kinase) is a member of the Src family of non-receptor tyrosine kinases (SFKs). It is widely expressed in various tissues including the brain, where it participates in signaling pathways controlling cell proliferation, differentiation, and survival. YES1 is involved in neural development, synaptic function, and has emerging roles in neurodegenerative disease pathogenesis [1].
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YES1 — YES Proto-Oncogene 1, Src Family Tyrosine Kinase
Introduction
Mermaid diagram (expand to render)
YES1 (YES Proto-Oncogene 1, Src Family Tyrosine Kinase) is a member of the Src family of non-receptor tyrosine kinases (SFKs). It is widely expressed in various tissues including the brain, where it participates in signaling pathways controlling cell proliferation, differentiation, and survival. YES1 is involved in neural development, synaptic function, and has emerging roles in neurodegenerative disease pathogenesis [1]. <div class="infobox infobox-gene"> <table> <tr><th colspan="2" style="background:#f0f0f0;">YES1 Gene</th></tr> <tr><td><b>Official Symbol</b></td><td>YES1</td></tr> <tr><td><b>Full Name</b></td><td>YES Proto-Oncogene 1, Src Family Tyrosine Kinase</td></tr> <tr><td><b>Chromosomal Location</b></td><td>18p11.32</td></tr> <tr><td><b>NCBI Gene ID</b></td><td>https://www.ncbi.nlm.nih.gov/gene/7524 7524</td></tr> <tr><td><b>OMIM</b></td><td>https://www.omim.org/entry/164880 164880</td></tr> <tr><td><b>Ensembl ID</b></td><td>ENSG00000106105</td></tr> <tr><td><b>UniProt ID</b></td><td>https://www.uniprot.org/uniprot/P42681 P42681</td></tr> <tr><td><b>Associated Diseases</b></td><td>AD, PD, cancer, stroke</td></tr> </table> </div>
Protein Structure
YES1 encodes a 536-amino acid protein member of the Src family of non-receptor tyrosine kinases (SFKs). The protein structure includes:
N-terminal myristoylation site: Required for membrane association and localization
Unique domain: Variable region conferring specific protein interactions
SH3 domain: Proline-rich region for protein-protein interactions with adaptor proteins
SH2 domain: Phosphotyrosine-binding domain for regulatory interactions
Kinase domain (SH1): Catalytic domain with tyrosine kinase activity
The protein undergoes conformational regulation through intramolecular interactions between the SH3 domain and a polyproline region, and between the SH2 domain and a C-terminal regulatory tyrosine (Y527 in Src, Y536 in YES1).
Function
In the Nervous System
YES1 plays important roles in multiple neuronal processes:
Synaptic Plasticity: YES1 is enriched in synaptic fractions and regulates AMPA and NMDA receptor trafficking [4]. It phosphorylates PSD-95 and other scaffolding proteins at synapses, modulating synaptic strength and plasticity.
NMDA Receptor Signaling: YES1 phosphorylates NMDA receptor subunits (GluN2A/B), influencing receptor trafficking and downstream signaling pathways involved in synaptic plasticity and memory formation.
Tau Phosphorylation: YES1 can phosphorylate tau protein at multiple sites, including Y197, contributing to tau pathology in Alzheimer's disease [2].
Amyloid-β Processing: YES1 regulates amyloid precursor protein (APP) processing and Aβ production through modulation of α- and β-secretase activity [1].
Neuroinflammation: YES1 signaling in microglia modulates inflammatory responses and cytokine production in Parkinson's disease models [3].
Signaling Pathways
YES1 participates in multiple signaling cascades:
Receptor tyrosine kinase (RTK) signaling
Integrin-mediated adhesion signaling
Cytokine receptor signaling
G-protein coupled receptor (GCP) signaling
Disease Associations
Alzheimer's Disease
YES1 contributes to AD pathogenesis through multiple mechanisms:
Amyloid-β production: YES1 activity promotes APP processing by β- and γ-secretases
Tau pathology: YES1-mediated tau phosphorylation contributes to neurofibrillary tangle formation
Synaptic dysfunction: YES1 dysregulation impairs synaptic plasticity and memory
Therapeutic target: YES1 inhibitors show promise in preclinical AD models [2]
Parkinson's Disease
YES1 is upregulated in dopaminergic neurons of PD patients
Promotes neuroinflammation through microglial activation [3]
Contributes to mitochondrial dysfunction
YES1 inhibition provides neuroprotection in PD models
Stroke and Brain Injury
YES1 is rapidly activated following ischemic injury
Mediates excitotoxic cell death through NMDA receptor regulation
Contributes to blood-brain barrier disruption
Expression Pattern
YES1 is expressed throughout the brain:
Neurons: High expression in cortex, hippocampus, and cerebellum
Glia: Moderate expression in astrocytes and microglia
Synapses: Enriched in pre- and post-synaptic compartments
Expression is activity-dependent, regulated by neuronal firing
Therapeutic Implications
Drug Development
Several strategies targeting YES1 are under investigation:
| Agent | Type | Status | Notes | |-------|------|--------|-------| | Dasatinib | Multi-kinase inhibitor | Preclinical | FDA-approved for CML, being repurposed | | Bosutinib | SFK inhibitor | Preclinical | Shows neuroprotection | | YES1-selective | Under development | Discovery | Higher specificity |
Therapeutic Approaches
Repurposed cancer drugs: FDA-approved Src inhibitors being tested in neurodegeneration
Combination therapy: YES1 inhibitors with Aβ-targeting or tau-targeting agents
Gene therapy: AAV-mediated delivery of dominant-negative YES1
[Zhang et al., YES1 regulates amyloid-beta production and neuronal survival (2018)](https://pubmed.ncbi.nlm.nih.gov/30552131/)
[Liu et al., Src family kinase inhibition reduces tau pathology in Alzheimer's models (2019)](https://pubmed.ncbi.nlm.nih.gov/31768059/)
[Chen et al., YES1-mediated neuroinflammation in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32857012/)
[Martinez et al., YES1 in synaptic plasticity and memory formation (2021)](https://pubmed.ncbi.nlm.nih.gov/34254478/)
Pathway Diagram
The following diagram shows the key molecular relationships involving YES1 — YES Proto-Oncogene 1, Src Family Tyrosine Kinase discovered through SciDEX knowledge graph analysis: