FYN (Fyn Tyrosine Kinase) is a member of the Src family of non-receptor tyrosine kinases, expressed prominently in the brain where it plays critical roles in synaptic plasticity, signal transduction, and neuronal function. Originally identified as a viral oncogene, Fyn is involved in numerous cellular processes including myelination, immune signaling, and learning and memory formation.
In the context of neurodegenerative diseases, FYN has emerged as a key signaling molecule that promotes amyloid-beta (Aβ) toxicity, contributes to tau pathology, and modulates NMDA receptor function leading to excitotoxicity. The kinase is therefore considered a potential therapeutic target for Alzheimer's disease and related disorders.
| Property |
Value |
| Gene |
FYN |
| UniProt |
P06241 |
| PDB Structures |
1AZZ, 2D4Q, 4K2J, 5NPE |
| Molecular Weight |
~59 kDa |
| Subcellular Localization |
Membrane, cytoskeleton, postsynaptic densities |
| Protein Family |
Src Family Tyrosine Kinase |
| Expression |
Neurons, microglia, astrocytes, oligodendrocytes |
Fyn is a member of the Src family of non-receptor tyrosine kinases with characteristic domain architecture:
- Myristoylation site: Covalent attachment of myristic acid for membrane anchoring
- Unique domain: Mediates protein-protein interactions specific to Fyn
¶ Src Homology Domains
- SH3 domain: Proline-rich region binding, involved in signaling complexes
- SH2 domain: Phosphotyrosine binding, regulates kinase activity
- Kinase domain (SH1): Catalytic domain with tyrosine kinase activity
- C-terminal tail: Contains Tyr527 (inhibitory phosphorylation site)
- Activation loop: Contains Tyr420 (autophosphorylation site, activating)
- Linker region: Connects SH2 domain to kinase domain
Fyn shares high structural homology with other Src family kinases:
- SRC: Ubiquitously expressed, critical for cell growth
- LCK: T-cell specific, immune function
- YES: Widely expressed, redundant with Fyn
- LYN: Myeloid cell expression
Fyn plays essential roles in synaptic transmission and plasticity:
- Phosphorylates NMDA receptor subunits (GluN2A/B)
- Regulates channel trafficking to the plasma membrane
- Modulates synaptic plasticity (LTP, LTD)
- Controls calcium influx through NMDA receptors
- Phosphorylates AMPA receptor subunits
- Modulates receptor trafficking and function
- Regulates synaptic strength
- Localizes to postsynaptic densities
- Interacts with PSD-95 and other scaffolding proteins
- Forms signaling complexes with glutamate receptors
Fyn is essential for proper myelination in the CNS:
- Promotes oligodendrocyte differentiation
- Regulates myelin gene expression
- Supports myelin maintenance
Fyn participates in immune signaling:
- T-cell receptor signaling (via LCK redundancy)
- Microglial activation
- Neuroinflammatory responses
¶ Learning and Memory
Fyn is required for cognitive function:
- LTP induction in hippocampal neurons
- Memory consolidation
- Synaptic plasticity mechanisms
Fyn is strongly implicated in AD pathogenesis through multiple mechanisms:
- Amyloid-beta (Aβ) oligomers activate Fyn
- Aβ binds to cellular prion protein (PrP^c), triggering Fyn activation
- Fyn activation is an early event in Aβ toxicity
- Fyn knockout mice are protected from Aβ toxicity
- Fyn phosphorylates NMDA receptor subunits
- Leads to enhanced calcium influx (excitotoxicity)
- Contributes to synaptic dysfunction
- Links Aβ to glutamate excitotoxicity
Fyn phosphorylates tau protein:
- Tyrosine phosphorylation of tau (Tyr18, Tyr394)
- Promotes tau aggregation into neurofibrillary tangles
- Mediates Aβ-induced tau pathology
- Therapeutic target for breaking Aβ-tau interaction
- Fyn inhibitors protect against Aβ toxicity
- Saracatinib (AZD0530) tested in clinical trials
- Challenges: achieving CNS penetration and avoiding toxicity
Fyn is implicated in Parkinson's disease:
- Fyn expression altered in PD substantia nigra
- Contributes to dopaminergic neuron vulnerability
- May regulate α-synuclein toxicity
- Fyn in microglial activation
- Contributes to neuroinflammation in PD
- May exacerbate dopaminergic neuron loss
¶ Multiple Sclerosis and Demyelination
Fyn plays complex roles in demyelinating diseases:
- Required for proper oligodendrocyte maturation
- Fyn deficiency leads to hypomyelination
- Role in demyelination and remyelination
- Fyn modulators being investigated for MS
- Balancing remyelination with immune function
- Huntington's Disease: Altered Fyn signaling
- Amyotrophic Lateral Sclerosis (ALS): Motor neuron vulnerability
- Frontotemporal Dementia: Tau pathology connections
Several approaches are being developed:
¶ Clinical Candidates
- Saracatinib (AZD0530): Advanced to clinical trials for AD
- Dasatinib (Sprycel): FDA-approved for leukemia, tested in CNS
- Bosutinib: Another SFK inhibitor in development
- CNS penetration: Many inhibitors don't cross the blood-brain barrier
- Toxicity: Off-target effects due to ubiquitous Src family expression
- Selectivity: Developing Fyn-selective vs. pan-SFK inhibitors
¶ Antibody-Based Therapy
- Targeting Aβ-Fyn interaction
- Blocking upstream activators
- Reducing Fyn expression
- Modulating downstream effectors
- Fyn inhibitors with Aβ immunotherapy
- Combined with tau-targeted approaches
- El Yaouti K, et al, Fyn kinase in Alzheimer's disease (2019)
- Lee CY, et al, Fyn and tau pathology in Alzheimer's disease (2019)
- Zhou Y, et al, Fyn in Parkinson's disease (2018)
- Salter MW, et al, Fyn and NMDA receptor signaling (2011)
- Kaufman AC, et al, Fyn inhibitors for neuroprotection (2015)
- Nassar K, et al, Fyn and amyloid-beta toxicity (2015)
- Tejeda GS, et al, Fyn in synaptic plasticity and cognitive function (2019)
- Combs CK, et al, Fyn and neuroinflammation in neurodegenerative disease (2016)
- Molokanova E, et al, Src family kinase inhibitors in clinical trials for Alzheimer's disease (2019)
- Tessier-Lavigne M, et al, Fyn in demyelination and multiple sclerosis (2019)