Fyn — Proto Oncogene Tyrosine Protein Kinase Fyn is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Fyn (Proto-Oncogene Tyrosine-Protein Kinase Fyn) is a member of the Src family of non-receptor tyrosine kinases (SFKs) with critical functions in the nervous system. It is a 59 kDa protein encoded by the FYN gene on chromosome 6q21. Fyn is highly expressed in [neurons](/entities/neurons), oligodendrocytes, and [astrocytes](/entities/astrocytes), where it regulates myelination, synaptic plasticity, and [NMDA](/entities/nmda-receptor) receptor signaling. Unlike c-Src, Fyn has specialized roles in central nervous system development and myelin formation, and it is particularly implicated in [tau](/proteins/tau) pathology in Alzheimer's disease (Nygaard et al., 2014)[@nygaard2014]. title: Proto-Oncogene Tyrosine-Protein Kinase Fyn (Fyn) <div class="infobox infobox-protein">
| | | |---|---| | Protein Name | Proto-Oncogene Tyrosine-Protein Kinase Fyn | | Gene | [FYN](/proteins/fyn-protein) | | UniProt ID | [P06241](https://www.uniprot.org/uniprot/P06241) | | Molecular Weight | 59 kDa | | Subcellular Localization | Plasma membrane, Cytoplasm, Myelin sheath | | Protein Family | Src family non-receptor tyrosine kinases |
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Structure
Fyn shares the canonical Src family kinase domain architecture:
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Fyn — Proto-Oncogene Tyrosine-Protein Kinase Fyn
Introduction
Fyn — Proto Oncogene Tyrosine Protein Kinase Fyn is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Fyn (Proto-Oncogene Tyrosine-Protein Kinase Fyn) is a member of the Src family of non-receptor tyrosine kinases (SFKs) with critical functions in the nervous system. It is a 59 kDa protein encoded by the FYN gene on chromosome 6q21. Fyn is highly expressed in [neurons](/entities/neurons), oligodendrocytes, and [astrocytes](/entities/astrocytes), where it regulates myelination, synaptic plasticity, and [NMDA](/entities/nmda-receptor) receptor signaling. Unlike c-Src, Fyn has specialized roles in central nervous system development and myelin formation, and it is particularly implicated in [tau](/proteins/tau) pathology in Alzheimer's disease (Nygaard et al., 2014)[@nygaard2014]. title: Proto-Oncogene Tyrosine-Protein Kinase Fyn (Fyn) <div class="infobox infobox-protein">
| | | |---|---| | Protein Name | Proto-Oncogene Tyrosine-Protein Kinase Fyn | | Gene | [FYN](/proteins/fyn-protein) | | UniProt ID | [P06241](https://www.uniprot.org/uniprot/P06241) | | Molecular Weight | 59 kDa | | Subcellular Localization | Plasma membrane, Cytoplasm, Myelin sheath | | Protein Family | Src family non-receptor tyrosine kinases |
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Structure
Fyn shares the canonical Src family kinase domain architecture:
N-terminal myristoylation and palmitoylation: Dual lipid modification enables robust membrane anchoring; palmitoylation distinguishes Fyn from c-Src
Unique domain (residues 1-85): Contains Fyn-specific sequences that mediate unique protein interactions, including binding to myelin proteins
C-terminal tail: Tyr531 (human) is phosphorylated by CSK for autoinhibition
Fyn undergoes dynamic subcellular localization through palmitoylation cycles, trafficking between the Golgi apparatus, plasma membrane, and endosomal compartments (Smotrys & Linder, 2004)[@smotrys2004].
Normal Function
Myelination and Oligodendrocyte Function
Fyn is the most abundant SFK in oligodendrocytes and is essential for central nervous system myelination:
Myelin basic protein (MBP) phosphorylation: Enhances MBP stability and myelin compaction
Process extension: Promotes oligodendrocyte process outgrowth and wrapping around axons
Fyn knockout phenotype: Mice lacking Fyn show hypomyelination, tremors, and motor coordination deficits (Umemori et al., 1994)[@umemori1994]
Oligodendrocyte differentiation: Activates downstream pathways including [Cdk5](/genes/cdk5) and Rho GTPases
Synaptic Plasticity
In neurons, Fyn is enriched at postsynaptic densities:
NMDA receptor regulation: Phosphorylates GluN2B at Tyr1472, preventing clathrin-mediated endocytosis and enhancing synaptic transmission
[LTP](/mechanisms/long-term-potentiation) induction: Fyn activity is required for [long-term potentiation](/mechanisms/long-term-potentiation) at hippocampal synapses
Fyn knockout mice: Display impaired spatial learning, reduced [LTP](/mechanisms/long-term-potentiation), and abnormal fear conditioning
L1-CAM signaling: Contributes to axon guidance and neuronal migration
Integrin signaling: Activates FAK and promotes cell spreading
Tau Kinase Activity
Fyn is one of the few tyrosine kinases that directly phosphorylates [tau protein](/proteins/tau):
[Tau](/proteins/tau) Tyr18 phosphorylation: A primary Fyn site that regulates tau localization and microtubule binding
Tau-Fyn complex formation: Phosphorylated tau recruits Fyn to neuronal dendrites, affecting NMDA receptor function
Pathological relevance: This interaction is particularly important in AD pathogenesis
Role in Disease
Alzheimer's Disease
Fyn is a key mediator of tau toxicity in AD (Ittner et al., 2010)[@ittner2010]:
Tau-Fyn-NMDA receptor axis: Pathological tau recruits Fyn to [dendritic spines](/cell-types/dendritic-spines), where it phosphorylates GluN2B and enhances NMDA receptor currents, leading to excitotoxicity
[Aβ](/proteins/amyloid-beta) amplification of Fyn signaling: Aβ oligomers activate Fyn through NMDA receptor-dependent calcium influx
Synaptic loss: Fyn-mediated excitotoxicity contributes to early synaptic dysfunction in AD
Fyn inhibition benefits: Genetic reduction of Fyn rescues cognitive deficits in AD mouse models
Multiple Sclerosis
Fyn contributes to demyelination and neurodegeneration in MS:
Remyelination failure: Excessive Fyn activation may interfere with oligodendrocyte precursor differentiation
Neuroinflammation: Fyn mediates inflammatory signaling in [microglia](/entities/microglia) and astrocytes
Axonal damage: Fyn contributes to excitotoxic damage in MS lesions
Parkinson's Disease
[α-synuclein](/proteins/alpha-synuclein) effects: Fyn phosphorylates α-synuclein at Tyr125, modulating aggregation
Dopaminergic neuron vulnerability: Fyn activation may contribute to inflammation-mediated neurodegeneration
Glioblastoma
Fyn is overexpressed in glioblastoma and contributes to tumor invasion and proliferation through multiple signaling pathways.
Therapeutic Targeting
Saracatinib (AZD0530)
The most extensively tested Fyn inhibitor in neurodegeneration:
[Blood-brain barrier](/entities/blood-brain-barrier) penetration: Good CNS exposure achieved
Phase II AD trial: 135 patients with mild AD; showed target engagement but no significant cognitive benefit over 6 months (Klein et al., 2019)[@van2019]
Ongoing studies: Combination approaches with anti-amyloid therapies being explored
Tolerability: Generally well-tolerated; mild gastrointestinal side effects
PP2: Research tool compound; not clinically suitable
Src/Fyn selective inhibitors: Several in preclinical development for AD
Future Directions
Biomarker-guided therapy: Selecting patients with elevated Fyn activity markers
Combination approaches: Fyn inhibition paired with anti-amyloid or anti-tau antibodies
Earlier intervention: Targeting synaptic dysfunction before irreversible neurodegeneration
Key Publications
Nygaard HB, van Dyck CH, Strittmatter SM. Fyn kinase inhibition as a novel therapy for Alzheimer's disease. Alzheimers Res Ther. 2014;6(1):8. [doi:10.1186/alzrt232](https://doi.org/10.1186/alzrt232)
Ittner A, Bertz J, Suh LS, et al. Fyn kinase is a downstream mediator of tau toxicity. Nat Cell Biol. 2016;18(1):70-80. [doi:10.1038/ncb3268](https://doi.org/10.1038/ncb3268)
Umemori H, Sato S, Yagi T, et al. Regulation of myelination by specific tyrosine phosphorylation of myelin basic protein. Nat Neurosci. 2003;6(7):711-7. [doi:10.1038/nn1070](https://doi.org/10.1038/nn1070)
[ClinicalTrials.gov: Saracatinib](https://clinicaltrials.gov/ct2/show/NCT01873066) - Clinical trial information
Background
The study of Fyn — Proto Oncogene Tyrosine Protein Kinase Fyn has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
References
[Nygaard HB, Wagner AF, Bowen GS, et al, Shared molecular pathways in neurodegeneration: a Fyn kinase perspective (2014)](https://doi.org/10.1074/jbc.O114.552879)
[Smotrys JE, Linder ME, Palmitoylation of intracellular signaling proteins: regulation and function (2004)](https://doi.org/10.1146/annurev.biochem.73.011303.073954)
[Umemori H, Kadowaki Y, Hirosawa K, et al, Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination (1994)](https://doi.org/10.1523/JNEUROSCI.14-05-02901.1994)
[Ittner LM, Ke YD, Delerue F, et al, Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models (2010)](https://doi.org/10.1016/j.cell.2010.06.036)
[van Dyck CH, Nygaard HB, Chen K, et al, Effect of AZD0530 on cerebral metabolic decline in Alzheimer's disease: the BLAZE randomized clinical trial (2019)](https://doi.org/10.3233/JAD-180780)