{"gene":"FYN","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2003,"finding":"Fyn is required for Reelin-induced tyrosine phosphorylation and downregulation of the adaptor protein Disabled-1 (Dab1) in neurons. Fyn directly phosphorylates Dab1, and genetic reduction of Fyn copy number reduces Dab1 phosphorylation stoichiometry in vivo; Src partially compensates when Fyn is reduced, but Yes does not.","method":"Pharmacological Src-family kinase inhibition, analysis of Dab1 phosphorylation in fyn/src/yes mutant mouse embryos, cultured neuron assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockouts combined with biochemical phosphorylation assays, replicated across multiple kinase-deficient backgrounds","pmids":["12526739"],"is_preprint":false},{"year":2005,"finding":"Combined absence of Src and Fyn nearly abolishes Dab1 tyrosine phosphorylation and phenocopies the reeler phenotype (inverted cortical layering, impaired Purkinje plate formation), demonstrating that Src and Fyn are the principal kinases mediating Reelin-dependent neuronal migration in vivo.","method":"Double Src/Fyn knockout mice, immunohistochemistry, Dab1 phosphorylation biochemistry","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockouts showing near-complete loss of signaling, replicated in multiple brain regions","pmids":["16162939"],"is_preprint":false},{"year":2002,"finding":"FcεRI activation of mast cells engages a Fyn kinase-dependent signaling pathway that is distinct from the Lyn/LAT pathway and is specifically required for mast cell degranulation. Fyn deficiency impairs degranulation while leaving the calcium response intact; Lyn deficiency enhances Fyn-dependent signals.","method":"Fyn-knockout and Lyn-knockout mast cells, degranulation assays, calcium measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout of Fyn and Lyn with distinct functional readouts (degranulation vs. calcium), multiple orthogonal assays","pmids":["12089510"],"is_preprint":false},{"year":2003,"finding":"Fyn directly binds Nephrin via its SH3 domain and phosphorylates Nephrin on tyrosine in podocyte lipid-raft membrane fractions. Genetic deletion of Fyn in mice causes coarsening of podocyte foot processes and markedly reduces Nephrin phosphorylation in glomerular detergent-resistant membrane fractions.","method":"Biochemical fractionation, direct binding assays (SH3-domain pulldown), in vitro kinase assay, Fyn/Yes knockout mice, glomerular morphology analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro direct binding and kinase assay combined with Fyn-KO mouse genetics and ultrastructural morphology","pmids":["12668668"],"is_preprint":false},{"year":2004,"finding":"Fyn phosphorylates the cytoplasmic domain of Nephrin on multiple tyrosine residues more potently than Src. This phosphorylation augments the interaction between Nephrin and Podocin and activates AP-1 promoter signaling downstream of Nephrin/Podocin.","method":"Co-transfection of Cos-1 cells, tyrosine-to-phenylalanine mutagenesis, co-immunoprecipitation, AP-1 reporter assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis, co-IP, and functional reporter assay in a single study","pmids":["15579503"],"is_preprint":false},{"year":2006,"finding":"Coxsackievirus attachment to DAF on the apical epithelial surface activates Fyn kinase, which is required for phosphorylation of caveolin and transport of the virus into the cell within caveolar vesicles.","method":"Inhibitor studies, siRNA, caveolar transport assays in polarized epithelial cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pharmacological inhibition, RNAi, caveolar fractionation) in a single rigorous study","pmids":["16413486"],"is_preprint":false},{"year":1995,"finding":"Fyn participates in regulation of focal adhesion kinase (FAK) and paxillin phosphorylation in the cytoskeleton downstream of Csk. Double-mutant genetic analysis shows Fyn and Src have overlapping but distinct roles: Src controls cortactin and tensin phosphorylation, while FAK/paxillin phosphorylation is partly dependent on both.","method":"Genetic epistasis in src/fyn/csk triple-mutant mouse embryos, tyrosine phosphorylation biochemistry, immunofluorescence of actin and cortactin","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double/triple mutant epistasis combined with biochemical substrate phosphorylation analysis","pmids":["7617039"],"is_preprint":false},{"year":1995,"finding":"Fyn kinase is activated in mouse keratinocytes during calcium- or TPA-induced differentiation, phosphorylates cortactin (p80-85), and is specifically required for keratinocyte differentiation; fyn-null keratinocytes show no p80-85 phosphorylation induction and are impaired in differentiation both in vitro and in vivo.","method":"Kinase activity immunoprecipitation assay, fyn/yes knockout keratinocytes, in vitro and in vivo differentiation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout compared with yes-null controls, biochemical kinase assay, dual in vitro/in vivo phenotype","pmids":["7557381"],"is_preprint":false},{"year":1999,"finding":"Fyn mediates reactive oxygen species (H2O2)-induced activation of JAK2, leading to Shc tyrosine phosphorylation and Ras activation. This pathway is Fyn-specific: H2O2-stimulated JAK2, Shc, and Ras activation are abolished in Fyn-/- fibroblasts but unaltered in Src-/- fibroblasts; re-expression of Fyn (but not Src) rescues JAK2 activation.","method":"Fyn-/- and Src-/- fibroblasts, kinase activity assays, Ras-GTP pull-down, rescue by transfection of Fyn vs. Src","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with isogenic rescue experiment, multiple downstream readouts, Src vs. Fyn specificity established","pmids":["10409649"],"is_preprint":false},{"year":2000,"finding":"PKC-eta directly associates with Fyn and directly activates Fyn kinase activity in vitro. PKC-eta-driven growth suppression of keratinocytes depends on Fyn, placing Fyn downstream of PKC-eta in the keratinocyte growth-arrest/differentiation pathway. Fyn activation alone suppresses keratinocyte (but not fibroblast) growth by downmodulating EGF receptor signaling.","method":"Co-immunoprecipitation of PKC-eta and Fyn, in vitro kinase assay with recombinant PKC-eta, fyn-KO keratinocytes, EGFR signaling analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of PKC-eta activation of Fyn, genetic KO cell phenotype, co-IP, multiple orthogonal methods in one study","pmids":["11106751"],"is_preprint":false},{"year":2009,"finding":"Fyn kinase regulates endocytosis of flotillin-1 and flotillin-2: EGF induces flotillin internalization via Fyn (but not Src or Yes) by directly phosphorylating Tyr160 on flotillin-1 and Tyr163 on flotillin-2; mutation of these residues to phenylalanine blocks Fyn-induced flotillin internalization and reduces uptake of the GPI-linked protein CD59.","method":"SYF cells (Src/Yes/Fyn-null) with individual kinase re-expression, rapamycin-inducible Fyn activation system, site-directed mutagenesis (Y→F), GPI-protein endocytosis assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in null cells, site-directed mutagenesis of phosphorylation sites, inducible kinase activation, functional endocytosis readout","pmids":["19258392"],"is_preprint":false},{"year":2006,"finding":"Cell rigidity response on fibronectin requires Fyn (but not endogenous c-Src) at the leading edge. Fyn recruitment depends on its palmitoylation site; adding that palmitoylation site to c-Src enables it to support the rigidity response. Fyn phosphorylates p130Cas at the leading edge in a rigidity-dependent manner.","method":"Live-cell imaging of GFP-tagged Src-family kinases, palmitoylation-site chimeras, p130Cas phosphorylation assay at leading edges","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — imaging and chimera experiments, single lab, two orthogonal methods","pmids":["16597701"],"is_preprint":false},{"year":2003,"finding":"Integrin αvβ6 ligation by fibronectin in oral squamous cell carcinoma forms a complex with Fyn, activates Fyn kinase, recruits and activates FAK, activates Shc, and couples to the Raf-ERK/MAPK pathway, leading to MMP-3 transcription and promoting cancer cell proliferation and experimental metastasis.","method":"Co-immunoprecipitation of β6/Fyn/FAK complex, kinase activity assays, MMP-3 reporter, in vivo metastasis model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP signaling complex, multiple downstream pathway readouts, in vivo validation; single lab","pmids":["12917446"],"is_preprint":false},{"year":2000,"finding":"TCR antagonist stimulation selectively activates Fyn kinase and induces Vav tyrosine phosphorylation in a Fyn-dependent manner, without activating Lck or ZAP-70. Fyn-deficient T cells fail to phosphorylate/activate Vav and cannot form APC-T cell conjugates (immunologic synapse) in response to either agonist or antagonist peptides.","method":"Fyn-/- TCR-transgenic mice, Jurkat cells with differential Lck/Fyn expression, kinase activity assays, Vav phosphorylation, conjugate formation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mice plus complementary cell-line experiments, multiple readouts, specificity established by Lck/Fyn differential expression","pmids":["11005864"],"is_preprint":false},{"year":1998,"finding":"Fyn is N-myristoylated on cytosolic polysomes and then targeted to the plasma membrane where it is palmitoylated. Dual acylation clusters Fyn in caveolae-like membrane microdomains.","method":"Biochemical acylation analysis, membrane fractionation, lipid raft/caveolae isolation (review with primary biochemical data cited)","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of acylation and membrane targeting reviewed with cited experimental data; review article","pmids":["9839441"],"is_preprint":false},{"year":1998,"finding":"CD73 ligation-mediated signal transduction in murine T lymphocytes requires Fyn kinase: fyn-/- mice are unresponsive to CD73-mediated signaling, demonstrating a necessary role for Fyn in this GPI-anchored protein signaling pathway.","method":"fyn-/- mice, anti-CD73 mAb stimulation, T cell proliferation and IL-2 secretion assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with functional readout, single lab, single method","pmids":["9808167"],"is_preprint":false},{"year":2005,"finding":"Receptor protein tyrosine phosphatase alpha (PTPα) suppresses Fyn activity in thymocyte lipid rafts. In PTPα-/- thymocytes, raft-associated Fyn is hyperactivated due to increased phosphorylation at its activating (Tyr417) and inhibitory (Tyr528) residues. Hyperactive Fyn then phosphorylates Cbp/PAG, promoting its association with C-terminal Src kinase (Csk).","method":"PTPα-knockout thymocytes, lipid raft fractionation, Fyn kinase activity assay, phospho-specific antibodies for Fyn Tyr417/528, Cbp/PAG co-IP with Csk","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with lipid raft fractionation, site-specific phosphorylation analysis, and co-IP; multiple orthogonal methods","pmids":["16339530"],"is_preprint":false},{"year":2015,"finding":"STEP (STriatal-Enriched protein tyrosine Phosphatase) dephosphorylates PTPα at Tyr789, preventing PTPα translocation to synaptic membranes and blocking its ability to activate Fyn. Upon ethanol exposure, PKA phosphorylates and inactivates STEP, allowing PTPα to translocate to lipid rafts and activate Fyn, which then upregulates GluN2B-containing NMDA receptor signaling.","method":"Primary neuronal cultures, STEP knockdown/pharmacological inhibition, phospho-specific antibodies, synaptosomal fractionation, in vitro phosphatase assay, in vivo ethanol treatment","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — identified STEP as PTPα phosphatase by in vitro assay, genetic and pharmacological manipulation, synaptic fractionation, in vivo validation","pmids":["25951993"],"is_preprint":false},{"year":2009,"finding":"Netrin-1 binding to DCC on mature oligodendrocytes recruits Fyn to a complex with the DCC intracellular domain that includes FAK and N-WASP, resulting in RhoA inhibition and induction of process remodeling. Fyn-/- oligodendrocytes fail to increase process branching in response to netrin-1.","method":"Fyn-knockout oligodendrocyte cultures, co-immunoprecipitation of DCC/Fyn/FAK/N-WASP complex, RhoA activity assay, in vitro process branching assay, in vivo netrin-1/DCC expression studies","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, complex co-IP, RhoA activity assay, and functional morphology readout in one study","pmids":["19141671"],"is_preprint":false},{"year":2016,"finding":"FYN interacts with the C-terminal domain of NOX4, colocalizes with NOX4 in perinuclear mitochondria/ER/nuclear fractions in cardiomyocytes, and directly phosphorylates NOX4 at Tyr566 to negatively regulate NOX4-induced superoxide production and apoptosis. FYN-deficient mice show exacerbated cardiac hypertrophy; Nox4 deletion rescues this phenotype.","method":"Co-immunoprecipitation, co-localization imaging, site-directed mutagenesis of Tyr566, in vitro kinase assay, Fyn-KO and Nox4-KO mice, transverse aortic constriction model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, co-IP, genetic rescue (Nox4 deletion in Fyn-KO), multiple in vivo models","pmids":["27525436"],"is_preprint":false},{"year":2017,"finding":"Fyn phosphorylates SHP-1 at Ser591 (inactivating the phosphatase), enabling activatory immunoreceptor (ITAM) signaling. By contrast, Lyn phosphorylates SHP-1 at Tyr536 (activating the phosphatase), promoting inhibitory signaling. Thus Fyn and Lyn have opposing roles in controlling immunoreceptor signaling status.","method":"Site-specific phosphorylation assays, SHP-1 mutagenesis, Fyn-/- and Lyn-/- mice, nephritis and arthritis in vivo models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — identification of specific phosphorylation sites with mutagenesis, opposing-kinase specificity established, validated in vivo in disease models","pmids":["28811476"],"is_preprint":false},{"year":2015,"finding":"Fyn inhibition (AZD0530) potently inhibits Fyn and prevents Aβ oligomer-induced signaling through Fyn to Pyk2 and NR2B NMDA receptors in brain slices. In APP/PS1 mice, AZD0530 fully rescues spatial memory, synaptic depletion, and reduces microglial activation without affecting Aβ metabolism; it also rescues Tau phosphorylation in APP/PS1/Tau mice.","method":"Brain slice signaling assays, pharmacokinetics, Morris water maze, novel object recognition, immunohistochemistry, immunoblotting in APP/PS1 and triple-transgenic mice","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological Fyn inhibition in ex vivo and in vivo models, multiple orthogonal behavioral and biochemical readouts, two transgenic models","pmids":["25707991"],"is_preprint":false},{"year":2019,"finding":"Fyn kinase, in conjunction with CD36, regulates microglial uptake of aggregated α-synuclein. Fyn mediates PKCδ-dependent NF-κB-p65 nuclear translocation leading to NLRP3 inflammasome priming, and facilitates αSyn import into microglia to generate mitochondrial ROS that activate the NLRP3 inflammasome.","method":"Fyn-KO mice, A53T and viral αSyn overexpression mouse models, siRNA knockdown, NF-κB reporter, NLRP3 inflammasome activation assays, human PD neuropathology","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, pharmacological inhibition, multiple mouse models, mechanistic pathway dissection with multiple readouts","pmids":["31036561"],"is_preprint":false},{"year":2018,"finding":"Fyn directly colocalizes with and phosphorylates β-catenin at Tyr142 in articular chondrocytes, stabilizing β-catenin and promoting its nuclear translocation, thereby upregulating catabolic enzymes and accelerating cartilage degradation and osteoarthritis development.","method":"Co-immunoprecipitation, phosphorylation assay with Tyr142 site-specific analysis, Fyn-KO mice with destabilization-of-medial-meniscus OA model, pharmacological Fyn inhibition (AZD0530, PP1)","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct phosphorylation assay of β-catenin Tyr142, co-IP, genetic KO mouse model, pharmacological validation","pmids":["29555825"],"is_preprint":false},{"year":2020,"finding":"Fyn kinase controls tau aggregation in vivo independently of Aβ. Fyn-knockout in a mutant-tau transgenic mouse (Tg/Fyn-/-) nearly abolishes neurofibrillary tangles, reduces tau hyperphosphorylation, alters tau solubility, diminishes synaptic tau accumulation, and reduces tau seeding capacity. Pseudophosphorylation of tau at the Fyn epitope Y18 boosts tau fibrillization in vitro.","method":"Fyn-KO crossed to tau-transgenic mice, tau seeding biosensor assay, in vitro fibrillization assay with phosphomimetic tau Y18E","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO in tauopathy model, in vitro reconstitution of fibrillization with phosphomimetic, tau seeding assay, multiple orthogonal readouts","pmids":["32814048"],"is_preprint":false},{"year":2018,"finding":"Pyk2 is a novel tau tyrosine kinase that colocalizes, interacts with, and phosphorylates tau in vivo and in vitro. Pyk2 activity is increased in Fyn-constitutively-active mice and decreased in Fyn-KO mice, placing Pyk2 as a direct tau kinase acting downstream of Fyn.","method":"Pyk2-transgenic and Pyk2/tau double-transgenic mice, in vitro kinase assay of Pyk2 phosphorylating tau, co-immunoprecipitation, FynCA and FynKO mice","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, co-IP, and in vivo genetic models in single lab","pmids":["29782321"],"is_preprint":false},{"year":2006,"finding":"Fyn mediates transactivation of Trk receptor tyrosine kinases by adenosine (a G-protein-coupled receptor ligand). Fyn and Trk colocalize in a juxtanuclear membrane compartment, adenosine activates Fyn, and Fyn directly phosphorylates Trk in vitro with kinetics matching Trk activation in cells.","method":"Co-localization imaging, in vitro Fyn phosphorylation of Trk assay, adenosine stimulation time-course, Fyn overexpression rescue","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, co-localization, and functional transactivation; single lab, single study","pmids":["16860569"],"is_preprint":false},{"year":2015,"finding":"BDNF activation of oligodendroglial TrkB receptors stimulates Fyn phosphorylation, which is necessary for subsequent phosphorylation of Erk1/2 and promotion of CNS myelination. A kinase-dead Fyn mutant inhibits BDNF-induced Erk1/2 activation and abrogates BDNF's promyelinating effect.","method":"Myelinating cocultures, PP2 inhibitor, kinase-dead Fyn overexpression, Fyn overexpression in oligodendrocytes, in vivo Fyn phosphorylation co-localization with mature oligodendrocytes","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead dominant-negative, pharmacological inhibition, in vivo localization; single lab, multiple methods","pmids":["26449489"],"is_preprint":false},{"year":2015,"finding":"Tyro3 receptor tyrosine kinase binds Fyn via affinity chromatography of the Tyro3 intracellular domain, and Fyn kinase activity is downregulated in Tyro3-KO mice. Fyn-KO mice exhibit reduced myelin thickness and decreased myelination in Schwann cell-neuron cocultures, identifying Tyro3-Fyn as a receptor-linked signaling mechanism controlling Schwann cell myelination.","method":"Affinity chromatography to identify Fyn as Tyro3 binding partner, Tyro3-KO and Fyn-KO mice, dorsal root ganglion cocultures, myelin thickness measurement","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography pulldown, genetic knockouts, functional myelination assay; single lab","pmids":["26224309"],"is_preprint":false},{"year":2011,"finding":"Fyn regulates apoptosis in pancreatic cancer by controlling HnRNPA2B1 and Sam68: Fyn activity maintains HnRNPA2B1 expression (which promotes anti-apoptotic Bcl-xL splicing via blocking Bcl-xS formation) and phosphorylates Sam68 (reducing its pro-Bcl-xL splicing activity). Loss of Fyn kinase activity reduces HnRNPA2B1 and decreases Sam68 phosphorylation, shifting Bcl-x splicing toward the pro-apoptotic Bcl-xS.","method":"Kinase-dead Fyn transfection, HnRNPA2B1 siRNA, Sam68 siRNA, Bcl-x splicing assay, apoptosis assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead Fyn, siRNA knockdowns, splicing assays, multiple pathway readouts; single lab","pmids":["21642356"],"is_preprint":false},{"year":2011,"finding":"Fyn mediates hyperosmolarity-induced retrieval of the bile canalicular transporters Mrp2 and Bsep from the canalicular membrane in rat liver. This is driven by NADPH oxidase-generated ROS activating Fyn. Fyn associates with cortactin and increases cortactin phosphorylation beneath the canalicular membrane, contributing to transporter retrieval.","method":"Perfused rat liver model, Fyn-specific inhibitor PP-2, Fyn siRNA knockdown, p47phox-KO mice, co-immunoprecipitation of Fyn-cortactin, cortactin phosphorylation assay, biliary excretion measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition, siRNA, genetic KO mice (p47phox), co-IP with cortactin; single lab, multiple methods","pmids":["22057277"],"is_preprint":false},{"year":2016,"finding":"FYN associates with FLT3 (both wild-type and oncogenic FLT3-ITD) via the FYN SH2 domain interacting with multiple FLT3 phosphotyrosine sites in a kinase-activity-dependent manner. FYN expression selectively potentiates FLT3-ITD-dependent STAT5 phosphorylation and colony formation.","method":"Co-immunoprecipitation, SH2-domain mutant FYN, FYN overexpression in FLT3-ITD cells, phospho-STAT5/AKT/ERK immunoblotting, colony formation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutant, overexpression with multiple pathway readouts; single lab","pmids":["26848862"],"is_preprint":false},{"year":2012,"finding":"IFNγ induces Fyn-dependent phosphorylation of E-cadherin and p120-catenin, leading to E-cadherin internalization, ubiquitinylation (via Hakai E3 ligase), and proteasomal degradation. Fyn siRNA or the Src-kinase inhibitor PP1 prevents IFNγ-induced E-cadherin internalization and subsequent epithelial barrier disruption.","method":"siRNA knockdown of Fyn, immunoprecipitation, immunofluorescence confocal microscopy, E-cadherin ubiquitinylation assay, barrier integrity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown, co-IP, imaging, and functional barrier assay; single lab, multiple methods","pmids":["22715382"],"is_preprint":false},{"year":2016,"finding":"Fyn deficiency attenuates renal fibrosis through a STAT3-dependent mechanism that is independent of the Smad pathway. STAT3 small interfering RNA in Fyn-deficient cells further suppresses α-SMA expression, and a STAT3 activator partially restores fibrotic markers, placing STAT3 downstream of Fyn in renal fibrogenesis.","method":"Fyn-KO mice with unilateral ureteral obstruction, pharmacological Fyn inhibition in kidney cell lines, STAT3 siRNA in Fyn-deficient cells, STAT3 activator rescue","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model, pharmacological inhibition, epistasis via siRNA rescue; single lab","pmids":["27616741"],"is_preprint":false},{"year":2016,"finding":"MOBP (myelin-associated oligodendrocytic basic protein) synthesis is stimulated by Fyn kinase activity in cultured primary oligodendrocytes, and MOBP promotes morphological differentiation of oligodendrocytes.","method":"Fyn kinase inhibition and activation in primary oligodendrocyte cultures, MOBP expression and morphology analysis","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological manipulation, morphological readout; limited mechanistic detail from abstract","pmids":["26801084"],"is_preprint":false},{"year":2015,"finding":"Fyn-phosphorylated PIKE-A binds to and inhibits AMPK's catalytic alpha subunit, impairing T172 phosphorylation and reducing AMPK kinase activity. Fyn depletion or pharmacological Fyn inhibition prevents PIKE-A/AMPK association, restoring AMPK tumor-suppressive activity.","method":"Co-immunoprecipitation of PIKE-A and AMPK, Fyn phosphorylation-site mutagenesis of PIKE-A, Fyn siRNA/inhibitor, AMPK substrate phosphorylation assay, cell proliferation assay, glioblastoma samples","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, site-directed mutagenesis, Fyn KD, kinase activity assay; single lab, multiple methods","pmids":["26001218"],"is_preprint":false},{"year":2013,"finding":"Fyn regulates adipogenesis by phosphorylating PIKE-A, which then enhances PIKE-A interaction with STAT5a, reducing STAT5a transcriptional activity. Fyn-null or pharmacologically inhibited adipocytes fail to fully differentiate, and PIKE-/- adipose tissue also shows reduced STAT5a activity.","method":"3T3-L1 adipogenesis model, Fyn-KO cells, Fyn pharmacological inhibition, co-IP of PIKE-A/STAT5a, STAT5a transcriptional reporter","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, co-IP, functional differentiation assay; single lab","pmids":["23438599"],"is_preprint":false},{"year":2008,"finding":"Lysophosphatidic acid (LPA) induces rapid Fyn activation and increased association of Fyn with p120-catenin at cell-cell junctions in ovarian cancer cells, driving junction dispersal and single-cell migration. This is the principal Src-family kinase recruited to p120-catenin in this context.","method":"Co-immunoprecipitation of Fyn and p120-catenin after LPA stimulation, PP2 inhibitor, immunofluorescence of junction dynamics","journal":"International journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP experiment, pharmacological inhibitor, single lab","pmids":["18506685"],"is_preprint":false},{"year":2014,"finding":"TLR4 physically interacts with Fyn upon LPS stimulation in astrocytes (shown by co-immunoprecipitation and co-localization), and this TLR4-Fyn interaction drives PI3K/Akt/NF-κB-dependent upregulation of PAI-1. Fyn siRNA or PP2 blocks TLR4 tyrosine phosphorylation and LPS-induced PAI-1 expression.","method":"Co-immunoprecipitation of TLR4-Fyn, immunofluorescence co-localization, Fyn siRNA, PP2 inhibitor, PAI-1 expression assay, neurite outgrowth assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA plus functional neurite assay; single lab, multiple methods","pmids":["25106729"],"is_preprint":false},{"year":2013,"finding":"Fyn kinase is required for dengue virus RNA replication. RNAi depletion of Fyn reduces DV2 RNA replication, and serial passaging of virus under dasatinib or AZD0530 selects a resistance mutation in the NS4B transmembrane domain 3, genetically linking Fyn to the viral RNA replication step.","method":"RNAi depletion of Src-family kinases, Northern blot and reporter replicon assays, resistance mutation mapping by serial passaging","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown combined with viral resistance mutation that bypasses Fyn RNAi, two orthogonal methods; single lab","pmids":["23616652"],"is_preprint":false},{"year":2021,"finding":"FYN-TRAF3IP2 is a recurrent oncogenic gene fusion in AITL and PTCL, NOS that drives aberrant NF-κB signaling downstream of T cell receptor activation. Expression of FYN-TRAF3IP2 in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with Tet2 loss in PTCL development; IκB kinase inhibitors suppress FYN-TRAF3IP2-induced lymphoma.","method":"Identification of fusion by sequencing, hematopoietic progenitor reconstitution mouse model, NF-κB reporter and signaling assays, IKK inhibitor treatment in vitro and in vivo","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transformation assay, NF-κB pathway mechanistic dissection, pharmacological IKK inhibition rescue, multiple mouse models","pmids":["33928261"],"is_preprint":false},{"year":2018,"finding":"Fyn is a modulator of erythropoietin signaling: Fyn-/- mice exhibit reduced tyrosine phosphorylation of EPO-R and decreased STAT5 activity. Fyn also acts as a physiologic repressor of Nrf2; absence of Fyn leads to persistent Nrf2 activation, ROS-induced Jak2-Akt-mTOR pathway overactivation, and impaired autophagy, which can be rescued by rapamycin.","method":"Fyn-/- mice, EPO-R tyrosine phosphorylation assay, STAT5 activity, Nrf2 target gene expression, mTOR pathway immunoblotting, rapamycin treatment","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple pathway readouts and pharmacological rescue; single lab","pmids":["30252956"],"is_preprint":false},{"year":2019,"finding":"Aβ oligomers promote oligodendrocyte differentiation and MBP translation via integrin β1 receptor and Fyn kinase, with Ca2+/CaMKII as downstream effectors. Pharmacological Fyn inhibition attenuates Aβ-induced oligodendrocyte differentiation and MBP upregulation in organotypic cerebellar slices.","method":"Integrin β1 blockade, Fyn pharmacological inhibition, MBP local translation assay, organotypic cerebellar slice model with lysolecithin demyelination","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of Fyn, integrin β1 blockade, ex vivo remyelination model; single lab","pmids":["31171765"],"is_preprint":false},{"year":2015,"finding":"P2X7 receptor physically interacts with Fyn kinase (co-immunoprecipitation), and P2X7 receptor agonist BzATP enhances Fyn kinase activity. Blocking Fyn activity or downregulating Fyn expression inhibits BzATP-induced oligodendrocyte progenitor cell migration.","method":"Co-immunoprecipitation of P2X7 and Fyn, Fyn kinase activity assay, Fyn inhibitor and siRNA knockdown, OPC migration assay","journal":"Purinergic signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and kinase assay, pharmacological and siRNA validation; single lab, limited mechanistic detail","pmids":["26099359"],"is_preprint":false},{"year":2023,"finding":"CD28-containing CAR-T cells signal through FYN kinase rather than LCK for their primary activation. FYN-dependent CAR signaling (requiring both FYN and CD28 intracellular domain) promotes T cell proliferation and memory formation, whereas LCK-dependent signaling leads to exhaustion. LCK-deficient CAR-T cells with intact FYN show superior in vivo anti-tumor efficacy.","method":"LCK-deficient CAR-T cells, in vivo CAR-T efficacy models, phenotypic analysis of exhaustion/memory markers, CD28 domain mutant CARs","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic LCK deficiency, CD28 domain requirement established, in vivo efficacy readout; single lab, multiple methods","pmids":["36696897"],"is_preprint":false},{"year":2010,"finding":"Fyn kinase localizes to the egg cortex, polar body, fertilizing cone, and meiotic/mitotic spindles of rat eggs. In mammalian oocytes, Fyn concentrates asymmetrically at the site of cleavage furrow ingression co-localizing with F-actin during meiosis and mitosis; dominant-negative Fyn prolongs furrow ingression duration and leads to larger polar bodies and longer spindles.","method":"Live-cell confocal imaging, microinjection of Fyn cRNA (wild-type and dominant-negative), SFK inhibitor SU6656, polar body extrusion timing and spindle length measurement","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging, dominant-negative microinjection, pharmacological inhibition, quantitative phenotypic readout; single lab","pmids":["20841362"],"is_preprint":false},{"year":2007,"finding":"Fyn phosphorylates APP at Tyr757 of the YENPTY motif and increases APP cell-surface expression. In the presence of Dab1, Fyn significantly increases sAPPα production and C-terminal fragment levels, and potentiates Dab1-dependent APP phosphorylation and surface trafficking. Fyn-KO mice show reduced sAPPα in vivo.","method":"Co-immunoprecipitation, co-immunostaining, FLIM (fluorescence lifetime imaging), Fyn overexpression with/without Dab1, Fyn-KO mouse brain analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, FLIM, overexpression, and in vivo KO; multiple methods; single lab","pmids":["18089558"],"is_preprint":false},{"year":2019,"finding":"Fyn kinase activity is regulated by submembrane localization: a FRET biosensor shows that Fyn outside its membrane microdomains is hyperactive, while microdomains provide a suppressive microenvironment. A relatively high Fyn activity is also observed at perinuclear regions.","method":"FRET biosensor for Fyn kinase activity in live cells, membrane microdomain-targeted biosensor variants (Fyn-tag vs. Lyn-tag), pharmacological perturbations of membrane domains","journal":"ACS sensors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET live-cell biosensor with targeted variants, pharmacological perturbation; single lab, novel tool paper","pmids":["30588803"],"is_preprint":false}],"current_model":"FYN is a dually acylated (N-myristoylated and palmitoylated) Src-family non-receptor tyrosine kinase that localizes to plasma membrane lipid-raft/caveolar microdomains where its activity is suppressed, and is activated downstream of diverse receptors (TCR, FcεRI, integrins, GPCRs, RTKs, TLR4, P2X7) to phosphorylate substrates including Dab1 (regulating Reelin-dependent neuronal migration), Nephrin (modulating podocyte slit-diaphragm integrity), GluN2B/NR2B NMDA receptor subunits (controlling synaptic plasticity and ethanol responses), tau (promoting tau hyperphosphorylation and aggregation in tauopathy), flotillin-1/2 Tyr160/163 (driving endocytosis), β-catenin Tyr142 (promoting osteoarthritis), NOX4 Tyr566 (negatively regulating ROS production in cardiomyocytes), p130Cas (rigidity sensing), Vav (cytoskeletal reorganization and immunologic synapse formation), caveolin (viral entry), APP Tyr757 (amyloid precursor processing), Pyk2, and cortactin; its activity is positively regulated by PTPα (which dephosphorylates the inhibitory Tyr531) and by PKC-eta, and negatively regulated by STEP (which dephosphorylates the activating Tyr420) and by Srcasm-mediated kinase downregulation, with the Lyn/Fyn balance on SHP-1 determining whether ITAM signaling is inhibitory (Lyn-driven) or activatory (Fyn-driven), and with the oncogenic FYN-TRAF3IP2 fusion driving NF-κB-dependent T cell lymphoma."},"narrative":{"mechanistic_narrative":"FYN is a dually acylated Src-family non-receptor tyrosine kinase that is targeted to plasma-membrane lipid-raft/caveolar microdomains by sequential N-myristoylation on cytosolic polysomes and subsequent palmitoylation, where these microdomains constitute a suppressive microenvironment that keeps the kinase inactive until receptor engagement [PMID:9839441, PMID:30588803]. Its catalytic output is set by phospho-regulation of its activating and inhibitory tyrosines: PTPα dephosphorylates raft-associated FYN to control its activity and couple it to the Cbp/PAG–Csk axis [PMID:16339530], and this PTPα→FYN module is itself gated by STEP, which is relieved upon ethanol-driven PKA signaling to allow FYN-dependent upregulation of GluN2B NMDA-receptor signaling [PMID:25951993]. Acting downstream of a broad range of receptors—the TCR, FcεRI, integrins, RTKs (Trk, TrkB, Tyro3, FLT3), GPCRs, TLR4 and P2X7—FYN transduces signals to cytoskeletal, adhesion, and transcriptional effectors [PMID:11005864, PMID:12089510, PMID:12917446, PMID:16860569, PMID:25106729]. In the nervous system FYN is the principal kinase (with Src) phosphorylating the Reelin adaptor Dab1 to direct neuronal migration [PMID:12526739, PMID:16162939], drives myelination through TrkB/Erk and DCC/N-WASP/RhoA pathways in oligodendrocytes [PMID:26449489, PMID:19141671], and is a central node in neurodegeneration, mediating Aβ-oligomer signaling through Pyk2 to NR2B and controlling tau hyperphosphorylation and aggregation in vivo [PMID:25707991, PMID:29782321, PMID:32814048]. In immune cells FYN phosphorylates Vav to build the immunologic synapse [PMID:11005864] and inactivates SHP-1 at Ser591 to switch ITAM signaling toward activation, opposing Lyn [PMID:28811476]. FYN phosphorylates a defined substrate set—Nephrin (slit-diaphragm integrity) [PMID:12668668, PMID:15579503], flotillin-1/2 Tyr160/163 (raft endocytosis) [PMID:19258392], p130Cas (rigidity sensing) [PMID:16597701], NOX4 Tyr566 (negative ROS regulation in cardiomyocytes) [PMID:27525436], β-catenin Tyr142 (osteoarthritic cartilage degradation) [PMID:29555825], and APP Tyr757 [PMID:18089558]—coupling membrane microdomain organization to cytoskeletal remodeling, cell adhesion, and transcriptional programs. FYN dysregulation is oncogenic: the recurrent FYN-TRAF3IP2 fusion drives NF-κB-dependent T-cell lymphoma [PMID:33928261].","teleology":[{"year":1995,"claim":"Establishing that FYN occupies a distinct node in adhesion and cytoskeletal signaling addressed whether Src-family kinases are functionally redundant; genetic dissection showed FYN and Src have overlapping but separable substrate preferences.","evidence":"Genetic epistasis in src/fyn/csk mutant mouse embryos with phospho-substrate biochemistry, plus fyn-null keratinocyte differentiation assays","pmids":["7617039","7557381"],"confidence":"High","gaps":["Did not resolve how membrane localization dictates the substrate split between FYN and Src","Cortactin phosphorylation attribution remained partly shared"]},{"year":1998,"claim":"Defining how FYN reaches its site of action answered where its activity is spatially constrained; dual acylation was shown to cluster FYN in caveolae-like microdomains.","evidence":"Biochemical acylation and membrane-fractionation analysis (review with primary data), plus fyn-/- requirement in CD73 GPI-anchored signaling","pmids":["9839441","9808167"],"confidence":"Medium","gaps":["Acylation evidence from a review rather than a primary structural study","How palmitoylation dynamically partitions FYN between active and suppressive pools not addressed"]},{"year":1999,"claim":"Demonstrating FYN-specific (not Src-redundant) signaling answered whether individual SFKs run dedicated pathways; FYN was shown to be uniquely required for H2O2-induced JAK2/Shc/Ras activation.","evidence":"Fyn-/- vs Src-/- fibroblasts with isogenic FYN-but-not-Src rescue of JAK2 activation","pmids":["10409649"],"confidence":"High","gaps":["Direct FYN substrate in the ROS→JAK2 step not identified","Mechanism of redox activation of FYN unresolved"]},{"year":2000,"claim":"Identifying upstream activators answered how FYN is switched on in epithelia and lymphocytes; PKC-eta was shown to directly bind and activate FYN, and antagonist-TCR signaling to selectively engage FYN→Vav.","evidence":"In vitro kinase reconstitution with recombinant PKC-eta and co-IP; Fyn-/- TCR-transgenic T cells with Vav phosphorylation and conjugate-formation readouts","pmids":["11106751","11005864"],"confidence":"High","gaps":["Structural basis of PKC-eta/FYN activation not defined","How antagonist peptides bias toward FYN over Lck mechanistically unresolved"]},{"year":2003,"claim":"Linking FYN to receptor-specific developmental and barrier substrates answered which physiological pathways depend on it; FYN was shown to be the dominant Dab1 kinase in Reelin signaling and a direct Nephrin SH3-binding kinase in podocytes.","evidence":"Pharmacological/genetic SFK dissection of Dab1 phosphorylation in fyn/src/yes embryos; SH3 pulldown, in vitro kinase assay, and Fyn-KO podocyte ultrastructure","pmids":["12526739","16162939","12668668","15579503"],"confidence":"High","gaps":["Direct Dab1 phosphosite stoichiometry in vivo only partially quantified","Whether Nephrin and Dab1 share FYN regulatory inputs unknown"]},{"year":2006,"claim":"Defining how membrane targeting confers function answered why FYN, not Src, supports rigidity sensing and caveolar entry; the palmitoylation site was shown to be necessary and sufficient to confer the FYN-specific rigidity response, and FYN was required for caveolar virus uptake.","evidence":"Palmitoylation-site Src chimeras with live imaging of p130Cas phosphorylation; inhibitor/siRNA/caveolar transport assays for coxsackievirus entry","pmids":["16597701","16413486"],"confidence":"Medium","gaps":["Single-lab imaging for the rigidity-response chimera","How leading-edge FYN couples mechanical force to kinase activation unresolved"]},{"year":2005,"claim":"Resolving how FYN catalytic output is set answered the phosphatase control logic; PTPα was shown to govern raft FYN activity via its activating/inhibitory tyrosines and the Cbp/PAG–Csk circuit.","evidence":"PTPα-knockout thymocytes with lipid-raft fractionation, phospho-specific FYN Tyr antibodies, and Cbp/PAG-Csk co-IP","pmids":["16339530"],"confidence":"High","gaps":["Net activity outcome of simultaneous Tyr417/Tyr528 changes not fully reconciled","Tissue-specificity of PTPα-FYN coupling not addressed"]},{"year":2009,"claim":"Defining FYN endocytic substrates answered how it remodels raft membrane traffic; FYN was shown to directly phosphorylate flotillin-1 Tyr160 and flotillin-2 Tyr163 to drive internalization.","evidence":"SYF null-cell reconstitution, inducible FYN activation, Y→F mutagenesis, and GPI-protein endocytosis readout","pmids":["19258392"],"confidence":"High","gaps":["Cargo selectivity of flotillin-mediated endocytosis downstream of FYN not delineated"]},{"year":2015,"claim":"Establishing FYN as a druggable hub in Alzheimer signaling answered whether targeting it reverses pathology; FYN inhibition blocked Aβ→Pyk2→NR2B signaling and rescued memory and synapses, and STEP was shown to gate the PTPα→FYN→GluN2B axis.","evidence":"AZD0530 in APP/PS1 and triple-transgenic mice with behavioral/biochemical readouts; STEP knockdown, in vitro phosphatase assay, and synaptosomal fractionation","pmids":["25707991","25951993","29782321"],"confidence":"High","gaps":["Direct vs indirect contribution of FYN-Pyk2 to NR2B phosphorylation partly inferential","Pyk2-as-tau-kinase placement downstream of FYN is Medium-confidence single-lab"]},{"year":2016,"claim":"Identifying organ-specific substrates answered how FYN drives disease in heart and joint; FYN directly phosphorylates NOX4 Tyr566 to restrain ROS and β-catenin Tyr142 to accelerate osteoarthritis.","evidence":"Co-IP, site-directed mutagenesis, in vitro kinase assays, and Fyn-KO (with Nox4-KO rescue / DMM OA) mouse models","pmids":["27525436","29555825","28811476"],"confidence":"High","gaps":["Whether NOX4 and β-catenin phosphorylation share an upstream receptor trigger unknown","FYN/Lyn SHP-1 phospho-switch generality across receptors not fully mapped"]},{"year":2020,"claim":"Separating FYN's tau role from amyloid answered whether FYN acts on tauopathy independently of Aβ; FYN knockout nearly abolished neurofibrillary tangles and reduced tau seeding, and α-synuclein/inflammasome work extended FYN to broader neurodegeneration.","evidence":"Fyn-KO crossed to tau-transgenic mice, tau seeding biosensor, phosphomimetic Y18E fibrillization; Fyn-KO α-synuclein PD models with NLRP3/NF-κB readouts","pmids":["32814048","31036561"],"confidence":"High","gaps":["Whether direct tau Y18 phosphorylation vs Pyk2-mediated phosphorylation dominates in vivo unresolved","Relative contribution of microglial vs neuronal FYN to tau spread not separated"]},{"year":2021,"claim":"Defining oncogenic FYN dysregulation answered how it transforms T cells; the FYN-TRAF3IP2 fusion was shown to drive NF-κB-dependent lymphoma sensitive to IKK inhibition.","evidence":"Fusion identification by sequencing, hematopoietic progenitor reconstitution mouse models, NF-κB assays, and IKK-inhibitor rescue","pmids":["33928261"],"confidence":"High","gaps":["Whether FYN kinase activity per se or TRAF3IP2-mediated scaffolding drives NF-κB not fully dissected","Cooperating lesions beyond Tet2 loss not enumerated"]},{"year":2023,"claim":"Distinguishing FYN from LCK in engineered T cells answered which SFK drives durable CAR-T responses; CD28-CARs were shown to signal through FYN to promote memory while LCK drives exhaustion.","evidence":"LCK-deficient CAR-T cells, CD28 intracellular-domain mutant CARs, and in vivo anti-tumor efficacy/phenotyping","pmids":["36696897"],"confidence":"Medium","gaps":["Direct FYN substrates underlying the memory program not identified","Single-lab in vivo efficacy data"]},{"year":null,"claim":"How the suppressive lipid-raft microenvironment, receptor-specific recruitment, and phosphatase gating are integrated to select among FYN's many substrates in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking membrane microdomain residency to substrate choice","Structural basis of FYN activation by diverse receptors lacking","Quantitative rules governing FYN vs Src/Lyn substrate partitioning unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,10,19,23,46]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,4,10,19,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,2,12,38]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,47,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,11,30,45]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,13,20,44]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,16,17,26,38]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,21,24]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10,5,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,24,23,40]}],"complexes":[],"partners":["NOX4","PIKE-A","NEPHRIN","TLR4","FLT3","TYRO3","DCC","P2X7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06241","full_name":"Tyrosine-protein kinase Fyn","aliases":["Proto-oncogene Syn","Proto-oncogene c-Fyn","Src-like kinase","SLK","p59-Fyn"],"length_aa":537,"mass_kda":60.8,"function":"Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance (PubMed:11536198, PubMed:15489916, PubMed:15557120, PubMed:16387660, PubMed:20100835, PubMed:7568038, PubMed:7822789). Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain (PubMed:15489916). Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions (PubMed:15489916). Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin) (PubMed:17194753). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT (PubMed:14707117, PubMed:15536091). Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage (PubMed:16841086). Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6 (PubMed:14761972, PubMed:18258597, PubMed:19179337). Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein (PubMed:11162638, PubMed:12788081, PubMed:19652227). Involved in reelin signaling by mediating phosphorylation of DAB1 following reelin (RELN)-binding to its receptor (By similarity). Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation (PubMed:22080863). Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation (PubMed:20028775). Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1 and PDCD1 (PubMed:18056706, PubMed:32184441). Phosphorylation of PAG1 promotes interaction between PAG1 and CSK and recruitment of CSK to lipid rafts (PubMed:18056706). Phosphorylation of PDCD1 leads to the recruitment of PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules (PubMed:32184441). CSK maintains LCK and FYN in an inactive form (By similarity). Promotes CD28-induced phosphorylation of VAV1 (PubMed:11005864). In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling (By similarity). Can also promote CD244-mediated NK cell activation (PubMed:15713798)","subcellular_location":"Cytoplasm; Nucleus; Cell membrane; Perikaryon","url":"https://www.uniprot.org/uniprotkb/P06241/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FYN","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000010810","cell_line_id":"CID001179","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"BYSL","stoichiometry":0.2},{"gene":"RUVBL1","stoichiometry":0.2},{"gene":"RUVBL2","stoichiometry":0.2},{"gene":"NSRP1;CCDC55","stoichiometry":0.2},{"gene":"PTPN23","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001179","total_profiled":1310},"omim":[{"mim_id":"621309","title":"SERINE/THREONINE KINASE 32B; STK32B","url":"https://www.omim.org/entry/621309"},{"mim_id":"620134","title":"PLECKSTRIN HOMOLOGY DOMAIN- AND RhoGEF DOMAIN-CONTAINING PROTEIN G1; PLEKHG1","url":"https://www.omim.org/entry/620134"},{"mim_id":"618888","title":"CAS SCAFFOLD PROTEIN FAMILY, MEMBER 4; CASS4","url":"https://www.omim.org/entry/618888"},{"mim_id":"618478","title":"FYN-BINDING PROTEIN 2; FYB2","url":"https://www.omim.org/entry/618478"},{"mim_id":"617407","title":"POLYCOMB GROUP RING FINGER PROTEIN 5; PCGF5","url":"https://www.omim.org/entry/617407"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FYN"},"hgnc":{"alias_symbol":["SYN","SLK","MGC45350"],"prev_symbol":[]},"alphafold":{"accession":"P06241","domains":[{"cath_id":"2.30.30.40","chopping":"85-144","consensus_level":"high","plddt":92.1845,"start":85,"end":144},{"cath_id":"3.30.505.10","chopping":"147-244","consensus_level":"high","plddt":92.13,"start":147,"end":244},{"cath_id":"3.30.200.20","chopping":"260-344","consensus_level":"medium","plddt":89.4501,"start":260,"end":344},{"cath_id":"1.10.510.10","chopping":"349-524","consensus_level":"medium","plddt":91.0439,"start":349,"end":524}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06241","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06241-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06241-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FYN","jax_strain_url":"https://www.jax.org/strain/search?query=FYN"},"sequence":{"accession":"P06241","fasta_url":"https://rest.uniprot.org/uniprotkb/P06241.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06241/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06241"}},"corpus_meta":[{"pmid":"24413734","id":"PMC_24413734","title":"Recurrent 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Fyn directly phosphorylates Dab1, and genetic reduction of Fyn copy number reduces Dab1 phosphorylation stoichiometry in vivo; Src partially compensates when Fyn is reduced, but Yes does not.\",\n      \"method\": \"Pharmacological Src-family kinase inhibition, analysis of Dab1 phosphorylation in fyn/src/yes mutant mouse embryos, cultured neuron assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockouts combined with biochemical phosphorylation assays, replicated across multiple kinase-deficient backgrounds\",\n      \"pmids\": [\"12526739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Combined absence of Src and Fyn nearly abolishes Dab1 tyrosine phosphorylation and phenocopies the reeler phenotype (inverted cortical layering, impaired Purkinje plate formation), demonstrating that Src and Fyn are the principal kinases mediating Reelin-dependent neuronal migration in vivo.\",\n      \"method\": \"Double Src/Fyn knockout mice, immunohistochemistry, Dab1 phosphorylation biochemistry\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockouts showing near-complete loss of signaling, replicated in multiple brain regions\",\n      \"pmids\": [\"16162939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FcεRI activation of mast cells engages a Fyn kinase-dependent signaling pathway that is distinct from the Lyn/LAT pathway and is specifically required for mast cell degranulation. Fyn deficiency impairs degranulation while leaving the calcium response intact; Lyn deficiency enhances Fyn-dependent signals.\",\n      \"method\": \"Fyn-knockout and Lyn-knockout mast cells, degranulation assays, calcium measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout of Fyn and Lyn with distinct functional readouts (degranulation vs. calcium), multiple orthogonal assays\",\n      \"pmids\": [\"12089510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Fyn directly binds Nephrin via its SH3 domain and phosphorylates Nephrin on tyrosine in podocyte lipid-raft membrane fractions. Genetic deletion of Fyn in mice causes coarsening of podocyte foot processes and markedly reduces Nephrin phosphorylation in glomerular detergent-resistant membrane fractions.\",\n      \"method\": \"Biochemical fractionation, direct binding assays (SH3-domain pulldown), in vitro kinase assay, Fyn/Yes knockout mice, glomerular morphology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro direct binding and kinase assay combined with Fyn-KO mouse genetics and ultrastructural morphology\",\n      \"pmids\": [\"12668668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fyn phosphorylates the cytoplasmic domain of Nephrin on multiple tyrosine residues more potently than Src. This phosphorylation augments the interaction between Nephrin and Podocin and activates AP-1 promoter signaling downstream of Nephrin/Podocin.\",\n      \"method\": \"Co-transfection of Cos-1 cells, tyrosine-to-phenylalanine mutagenesis, co-immunoprecipitation, AP-1 reporter assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis, co-IP, and functional reporter assay in a single study\",\n      \"pmids\": [\"15579503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Coxsackievirus attachment to DAF on the apical epithelial surface activates Fyn kinase, which is required for phosphorylation of caveolin and transport of the virus into the cell within caveolar vesicles.\",\n      \"method\": \"Inhibitor studies, siRNA, caveolar transport assays in polarized epithelial cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pharmacological inhibition, RNAi, caveolar fractionation) in a single rigorous study\",\n      \"pmids\": [\"16413486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fyn participates in regulation of focal adhesion kinase (FAK) and paxillin phosphorylation in the cytoskeleton downstream of Csk. Double-mutant genetic analysis shows Fyn and Src have overlapping but distinct roles: Src controls cortactin and tensin phosphorylation, while FAK/paxillin phosphorylation is partly dependent on both.\",\n      \"method\": \"Genetic epistasis in src/fyn/csk triple-mutant mouse embryos, tyrosine phosphorylation biochemistry, immunofluorescence of actin and cortactin\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double/triple mutant epistasis combined with biochemical substrate phosphorylation analysis\",\n      \"pmids\": [\"7617039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fyn kinase is activated in mouse keratinocytes during calcium- or TPA-induced differentiation, phosphorylates cortactin (p80-85), and is specifically required for keratinocyte differentiation; fyn-null keratinocytes show no p80-85 phosphorylation induction and are impaired in differentiation both in vitro and in vivo.\",\n      \"method\": \"Kinase activity immunoprecipitation assay, fyn/yes knockout keratinocytes, in vitro and in vivo differentiation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout compared with yes-null controls, biochemical kinase assay, dual in vitro/in vivo phenotype\",\n      \"pmids\": [\"7557381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Fyn mediates reactive oxygen species (H2O2)-induced activation of JAK2, leading to Shc tyrosine phosphorylation and Ras activation. This pathway is Fyn-specific: H2O2-stimulated JAK2, Shc, and Ras activation are abolished in Fyn-/- fibroblasts but unaltered in Src-/- fibroblasts; re-expression of Fyn (but not Src) rescues JAK2 activation.\",\n      \"method\": \"Fyn-/- and Src-/- fibroblasts, kinase activity assays, Ras-GTP pull-down, rescue by transfection of Fyn vs. Src\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with isogenic rescue experiment, multiple downstream readouts, Src vs. Fyn specificity established\",\n      \"pmids\": [\"10409649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PKC-eta directly associates with Fyn and directly activates Fyn kinase activity in vitro. PKC-eta-driven growth suppression of keratinocytes depends on Fyn, placing Fyn downstream of PKC-eta in the keratinocyte growth-arrest/differentiation pathway. Fyn activation alone suppresses keratinocyte (but not fibroblast) growth by downmodulating EGF receptor signaling.\",\n      \"method\": \"Co-immunoprecipitation of PKC-eta and Fyn, in vitro kinase assay with recombinant PKC-eta, fyn-KO keratinocytes, EGFR signaling analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of PKC-eta activation of Fyn, genetic KO cell phenotype, co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11106751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fyn kinase regulates endocytosis of flotillin-1 and flotillin-2: EGF induces flotillin internalization via Fyn (but not Src or Yes) by directly phosphorylating Tyr160 on flotillin-1 and Tyr163 on flotillin-2; mutation of these residues to phenylalanine blocks Fyn-induced flotillin internalization and reduces uptake of the GPI-linked protein CD59.\",\n      \"method\": \"SYF cells (Src/Yes/Fyn-null) with individual kinase re-expression, rapamycin-inducible Fyn activation system, site-directed mutagenesis (Y→F), GPI-protein endocytosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in null cells, site-directed mutagenesis of phosphorylation sites, inducible kinase activation, functional endocytosis readout\",\n      \"pmids\": [\"19258392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cell rigidity response on fibronectin requires Fyn (but not endogenous c-Src) at the leading edge. Fyn recruitment depends on its palmitoylation site; adding that palmitoylation site to c-Src enables it to support the rigidity response. Fyn phosphorylates p130Cas at the leading edge in a rigidity-dependent manner.\",\n      \"method\": \"Live-cell imaging of GFP-tagged Src-family kinases, palmitoylation-site chimeras, p130Cas phosphorylation assay at leading edges\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — imaging and chimera experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"16597701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Integrin αvβ6 ligation by fibronectin in oral squamous cell carcinoma forms a complex with Fyn, activates Fyn kinase, recruits and activates FAK, activates Shc, and couples to the Raf-ERK/MAPK pathway, leading to MMP-3 transcription and promoting cancer cell proliferation and experimental metastasis.\",\n      \"method\": \"Co-immunoprecipitation of β6/Fyn/FAK complex, kinase activity assays, MMP-3 reporter, in vivo metastasis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP signaling complex, multiple downstream pathway readouts, in vivo validation; single lab\",\n      \"pmids\": [\"12917446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TCR antagonist stimulation selectively activates Fyn kinase and induces Vav tyrosine phosphorylation in a Fyn-dependent manner, without activating Lck or ZAP-70. Fyn-deficient T cells fail to phosphorylate/activate Vav and cannot form APC-T cell conjugates (immunologic synapse) in response to either agonist or antagonist peptides.\",\n      \"method\": \"Fyn-/- TCR-transgenic mice, Jurkat cells with differential Lck/Fyn expression, kinase activity assays, Vav phosphorylation, conjugate formation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mice plus complementary cell-line experiments, multiple readouts, specificity established by Lck/Fyn differential expression\",\n      \"pmids\": [\"11005864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Fyn is N-myristoylated on cytosolic polysomes and then targeted to the plasma membrane where it is palmitoylated. Dual acylation clusters Fyn in caveolae-like membrane microdomains.\",\n      \"method\": \"Biochemical acylation analysis, membrane fractionation, lipid raft/caveolae isolation (review with primary biochemical data cited)\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of acylation and membrane targeting reviewed with cited experimental data; review article\",\n      \"pmids\": [\"9839441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD73 ligation-mediated signal transduction in murine T lymphocytes requires Fyn kinase: fyn-/- mice are unresponsive to CD73-mediated signaling, demonstrating a necessary role for Fyn in this GPI-anchored protein signaling pathway.\",\n      \"method\": \"fyn-/- mice, anti-CD73 mAb stimulation, T cell proliferation and IL-2 secretion assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with functional readout, single lab, single method\",\n      \"pmids\": [\"9808167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Receptor protein tyrosine phosphatase alpha (PTPα) suppresses Fyn activity in thymocyte lipid rafts. In PTPα-/- thymocytes, raft-associated Fyn is hyperactivated due to increased phosphorylation at its activating (Tyr417) and inhibitory (Tyr528) residues. Hyperactive Fyn then phosphorylates Cbp/PAG, promoting its association with C-terminal Src kinase (Csk).\",\n      \"method\": \"PTPα-knockout thymocytes, lipid raft fractionation, Fyn kinase activity assay, phospho-specific antibodies for Fyn Tyr417/528, Cbp/PAG co-IP with Csk\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with lipid raft fractionation, site-specific phosphorylation analysis, and co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"16339530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STEP (STriatal-Enriched protein tyrosine Phosphatase) dephosphorylates PTPα at Tyr789, preventing PTPα translocation to synaptic membranes and blocking its ability to activate Fyn. Upon ethanol exposure, PKA phosphorylates and inactivates STEP, allowing PTPα to translocate to lipid rafts and activate Fyn, which then upregulates GluN2B-containing NMDA receptor signaling.\",\n      \"method\": \"Primary neuronal cultures, STEP knockdown/pharmacological inhibition, phospho-specific antibodies, synaptosomal fractionation, in vitro phosphatase assay, in vivo ethanol treatment\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — identified STEP as PTPα phosphatase by in vitro assay, genetic and pharmacological manipulation, synaptic fractionation, in vivo validation\",\n      \"pmids\": [\"25951993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Netrin-1 binding to DCC on mature oligodendrocytes recruits Fyn to a complex with the DCC intracellular domain that includes FAK and N-WASP, resulting in RhoA inhibition and induction of process remodeling. Fyn-/- oligodendrocytes fail to increase process branching in response to netrin-1.\",\n      \"method\": \"Fyn-knockout oligodendrocyte cultures, co-immunoprecipitation of DCC/Fyn/FAK/N-WASP complex, RhoA activity assay, in vitro process branching assay, in vivo netrin-1/DCC expression studies\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, complex co-IP, RhoA activity assay, and functional morphology readout in one study\",\n      \"pmids\": [\"19141671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FYN interacts with the C-terminal domain of NOX4, colocalizes with NOX4 in perinuclear mitochondria/ER/nuclear fractions in cardiomyocytes, and directly phosphorylates NOX4 at Tyr566 to negatively regulate NOX4-induced superoxide production and apoptosis. FYN-deficient mice show exacerbated cardiac hypertrophy; Nox4 deletion rescues this phenotype.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, site-directed mutagenesis of Tyr566, in vitro kinase assay, Fyn-KO and Nox4-KO mice, transverse aortic constriction model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, co-IP, genetic rescue (Nox4 deletion in Fyn-KO), multiple in vivo models\",\n      \"pmids\": [\"27525436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fyn phosphorylates SHP-1 at Ser591 (inactivating the phosphatase), enabling activatory immunoreceptor (ITAM) signaling. By contrast, Lyn phosphorylates SHP-1 at Tyr536 (activating the phosphatase), promoting inhibitory signaling. Thus Fyn and Lyn have opposing roles in controlling immunoreceptor signaling status.\",\n      \"method\": \"Site-specific phosphorylation assays, SHP-1 mutagenesis, Fyn-/- and Lyn-/- mice, nephritis and arthritis in vivo models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — identification of specific phosphorylation sites with mutagenesis, opposing-kinase specificity established, validated in vivo in disease models\",\n      \"pmids\": [\"28811476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fyn inhibition (AZD0530) potently inhibits Fyn and prevents Aβ oligomer-induced signaling through Fyn to Pyk2 and NR2B NMDA receptors in brain slices. In APP/PS1 mice, AZD0530 fully rescues spatial memory, synaptic depletion, and reduces microglial activation without affecting Aβ metabolism; it also rescues Tau phosphorylation in APP/PS1/Tau mice.\",\n      \"method\": \"Brain slice signaling assays, pharmacokinetics, Morris water maze, novel object recognition, immunohistochemistry, immunoblotting in APP/PS1 and triple-transgenic mice\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological Fyn inhibition in ex vivo and in vivo models, multiple orthogonal behavioral and biochemical readouts, two transgenic models\",\n      \"pmids\": [\"25707991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fyn kinase, in conjunction with CD36, regulates microglial uptake of aggregated α-synuclein. Fyn mediates PKCδ-dependent NF-κB-p65 nuclear translocation leading to NLRP3 inflammasome priming, and facilitates αSyn import into microglia to generate mitochondrial ROS that activate the NLRP3 inflammasome.\",\n      \"method\": \"Fyn-KO mice, A53T and viral αSyn overexpression mouse models, siRNA knockdown, NF-κB reporter, NLRP3 inflammasome activation assays, human PD neuropathology\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, pharmacological inhibition, multiple mouse models, mechanistic pathway dissection with multiple readouts\",\n      \"pmids\": [\"31036561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fyn directly colocalizes with and phosphorylates β-catenin at Tyr142 in articular chondrocytes, stabilizing β-catenin and promoting its nuclear translocation, thereby upregulating catabolic enzymes and accelerating cartilage degradation and osteoarthritis development.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay with Tyr142 site-specific analysis, Fyn-KO mice with destabilization-of-medial-meniscus OA model, pharmacological Fyn inhibition (AZD0530, PP1)\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct phosphorylation assay of β-catenin Tyr142, co-IP, genetic KO mouse model, pharmacological validation\",\n      \"pmids\": [\"29555825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fyn kinase controls tau aggregation in vivo independently of Aβ. Fyn-knockout in a mutant-tau transgenic mouse (Tg/Fyn-/-) nearly abolishes neurofibrillary tangles, reduces tau hyperphosphorylation, alters tau solubility, diminishes synaptic tau accumulation, and reduces tau seeding capacity. Pseudophosphorylation of tau at the Fyn epitope Y18 boosts tau fibrillization in vitro.\",\n      \"method\": \"Fyn-KO crossed to tau-transgenic mice, tau seeding biosensor assay, in vitro fibrillization assay with phosphomimetic tau Y18E\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO in tauopathy model, in vitro reconstitution of fibrillization with phosphomimetic, tau seeding assay, multiple orthogonal readouts\",\n      \"pmids\": [\"32814048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pyk2 is a novel tau tyrosine kinase that colocalizes, interacts with, and phosphorylates tau in vivo and in vitro. Pyk2 activity is increased in Fyn-constitutively-active mice and decreased in Fyn-KO mice, placing Pyk2 as a direct tau kinase acting downstream of Fyn.\",\n      \"method\": \"Pyk2-transgenic and Pyk2/tau double-transgenic mice, in vitro kinase assay of Pyk2 phosphorylating tau, co-immunoprecipitation, FynCA and FynKO mice\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, co-IP, and in vivo genetic models in single lab\",\n      \"pmids\": [\"29782321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fyn mediates transactivation of Trk receptor tyrosine kinases by adenosine (a G-protein-coupled receptor ligand). Fyn and Trk colocalize in a juxtanuclear membrane compartment, adenosine activates Fyn, and Fyn directly phosphorylates Trk in vitro with kinetics matching Trk activation in cells.\",\n      \"method\": \"Co-localization imaging, in vitro Fyn phosphorylation of Trk assay, adenosine stimulation time-course, Fyn overexpression rescue\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, co-localization, and functional transactivation; single lab, single study\",\n      \"pmids\": [\"16860569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BDNF activation of oligodendroglial TrkB receptors stimulates Fyn phosphorylation, which is necessary for subsequent phosphorylation of Erk1/2 and promotion of CNS myelination. A kinase-dead Fyn mutant inhibits BDNF-induced Erk1/2 activation and abrogates BDNF's promyelinating effect.\",\n      \"method\": \"Myelinating cocultures, PP2 inhibitor, kinase-dead Fyn overexpression, Fyn overexpression in oligodendrocytes, in vivo Fyn phosphorylation co-localization with mature oligodendrocytes\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead dominant-negative, pharmacological inhibition, in vivo localization; single lab, multiple methods\",\n      \"pmids\": [\"26449489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tyro3 receptor tyrosine kinase binds Fyn via affinity chromatography of the Tyro3 intracellular domain, and Fyn kinase activity is downregulated in Tyro3-KO mice. Fyn-KO mice exhibit reduced myelin thickness and decreased myelination in Schwann cell-neuron cocultures, identifying Tyro3-Fyn as a receptor-linked signaling mechanism controlling Schwann cell myelination.\",\n      \"method\": \"Affinity chromatography to identify Fyn as Tyro3 binding partner, Tyro3-KO and Fyn-KO mice, dorsal root ganglion cocultures, myelin thickness measurement\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography pulldown, genetic knockouts, functional myelination assay; single lab\",\n      \"pmids\": [\"26224309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fyn regulates apoptosis in pancreatic cancer by controlling HnRNPA2B1 and Sam68: Fyn activity maintains HnRNPA2B1 expression (which promotes anti-apoptotic Bcl-xL splicing via blocking Bcl-xS formation) and phosphorylates Sam68 (reducing its pro-Bcl-xL splicing activity). Loss of Fyn kinase activity reduces HnRNPA2B1 and decreases Sam68 phosphorylation, shifting Bcl-x splicing toward the pro-apoptotic Bcl-xS.\",\n      \"method\": \"Kinase-dead Fyn transfection, HnRNPA2B1 siRNA, Sam68 siRNA, Bcl-x splicing assay, apoptosis assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead Fyn, siRNA knockdowns, splicing assays, multiple pathway readouts; single lab\",\n      \"pmids\": [\"21642356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fyn mediates hyperosmolarity-induced retrieval of the bile canalicular transporters Mrp2 and Bsep from the canalicular membrane in rat liver. This is driven by NADPH oxidase-generated ROS activating Fyn. Fyn associates with cortactin and increases cortactin phosphorylation beneath the canalicular membrane, contributing to transporter retrieval.\",\n      \"method\": \"Perfused rat liver model, Fyn-specific inhibitor PP-2, Fyn siRNA knockdown, p47phox-KO mice, co-immunoprecipitation of Fyn-cortactin, cortactin phosphorylation assay, biliary excretion measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition, siRNA, genetic KO mice (p47phox), co-IP with cortactin; single lab, multiple methods\",\n      \"pmids\": [\"22057277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FYN associates with FLT3 (both wild-type and oncogenic FLT3-ITD) via the FYN SH2 domain interacting with multiple FLT3 phosphotyrosine sites in a kinase-activity-dependent manner. FYN expression selectively potentiates FLT3-ITD-dependent STAT5 phosphorylation and colony formation.\",\n      \"method\": \"Co-immunoprecipitation, SH2-domain mutant FYN, FYN overexpression in FLT3-ITD cells, phospho-STAT5/AKT/ERK immunoblotting, colony formation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutant, overexpression with multiple pathway readouts; single lab\",\n      \"pmids\": [\"26848862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFNγ induces Fyn-dependent phosphorylation of E-cadherin and p120-catenin, leading to E-cadherin internalization, ubiquitinylation (via Hakai E3 ligase), and proteasomal degradation. Fyn siRNA or the Src-kinase inhibitor PP1 prevents IFNγ-induced E-cadherin internalization and subsequent epithelial barrier disruption.\",\n      \"method\": \"siRNA knockdown of Fyn, immunoprecipitation, immunofluorescence confocal microscopy, E-cadherin ubiquitinylation assay, barrier integrity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown, co-IP, imaging, and functional barrier assay; single lab, multiple methods\",\n      \"pmids\": [\"22715382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fyn deficiency attenuates renal fibrosis through a STAT3-dependent mechanism that is independent of the Smad pathway. STAT3 small interfering RNA in Fyn-deficient cells further suppresses α-SMA expression, and a STAT3 activator partially restores fibrotic markers, placing STAT3 downstream of Fyn in renal fibrogenesis.\",\n      \"method\": \"Fyn-KO mice with unilateral ureteral obstruction, pharmacological Fyn inhibition in kidney cell lines, STAT3 siRNA in Fyn-deficient cells, STAT3 activator rescue\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model, pharmacological inhibition, epistasis via siRNA rescue; single lab\",\n      \"pmids\": [\"27616741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MOBP (myelin-associated oligodendrocytic basic protein) synthesis is stimulated by Fyn kinase activity in cultured primary oligodendrocytes, and MOBP promotes morphological differentiation of oligodendrocytes.\",\n      \"method\": \"Fyn kinase inhibition and activation in primary oligodendrocyte cultures, MOBP expression and morphology analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological manipulation, morphological readout; limited mechanistic detail from abstract\",\n      \"pmids\": [\"26801084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fyn-phosphorylated PIKE-A binds to and inhibits AMPK's catalytic alpha subunit, impairing T172 phosphorylation and reducing AMPK kinase activity. Fyn depletion or pharmacological Fyn inhibition prevents PIKE-A/AMPK association, restoring AMPK tumor-suppressive activity.\",\n      \"method\": \"Co-immunoprecipitation of PIKE-A and AMPK, Fyn phosphorylation-site mutagenesis of PIKE-A, Fyn siRNA/inhibitor, AMPK substrate phosphorylation assay, cell proliferation assay, glioblastoma samples\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, site-directed mutagenesis, Fyn KD, kinase activity assay; single lab, multiple methods\",\n      \"pmids\": [\"26001218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fyn regulates adipogenesis by phosphorylating PIKE-A, which then enhances PIKE-A interaction with STAT5a, reducing STAT5a transcriptional activity. Fyn-null or pharmacologically inhibited adipocytes fail to fully differentiate, and PIKE-/- adipose tissue also shows reduced STAT5a activity.\",\n      \"method\": \"3T3-L1 adipogenesis model, Fyn-KO cells, Fyn pharmacological inhibition, co-IP of PIKE-A/STAT5a, STAT5a transcriptional reporter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, co-IP, functional differentiation assay; single lab\",\n      \"pmids\": [\"23438599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lysophosphatidic acid (LPA) induces rapid Fyn activation and increased association of Fyn with p120-catenin at cell-cell junctions in ovarian cancer cells, driving junction dispersal and single-cell migration. This is the principal Src-family kinase recruited to p120-catenin in this context.\",\n      \"method\": \"Co-immunoprecipitation of Fyn and p120-catenin after LPA stimulation, PP2 inhibitor, immunofluorescence of junction dynamics\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment, pharmacological inhibitor, single lab\",\n      \"pmids\": [\"18506685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLR4 physically interacts with Fyn upon LPS stimulation in astrocytes (shown by co-immunoprecipitation and co-localization), and this TLR4-Fyn interaction drives PI3K/Akt/NF-κB-dependent upregulation of PAI-1. Fyn siRNA or PP2 blocks TLR4 tyrosine phosphorylation and LPS-induced PAI-1 expression.\",\n      \"method\": \"Co-immunoprecipitation of TLR4-Fyn, immunofluorescence co-localization, Fyn siRNA, PP2 inhibitor, PAI-1 expression assay, neurite outgrowth assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA plus functional neurite assay; single lab, multiple methods\",\n      \"pmids\": [\"25106729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fyn kinase is required for dengue virus RNA replication. RNAi depletion of Fyn reduces DV2 RNA replication, and serial passaging of virus under dasatinib or AZD0530 selects a resistance mutation in the NS4B transmembrane domain 3, genetically linking Fyn to the viral RNA replication step.\",\n      \"method\": \"RNAi depletion of Src-family kinases, Northern blot and reporter replicon assays, resistance mutation mapping by serial passaging\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown combined with viral resistance mutation that bypasses Fyn RNAi, two orthogonal methods; single lab\",\n      \"pmids\": [\"23616652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FYN-TRAF3IP2 is a recurrent oncogenic gene fusion in AITL and PTCL, NOS that drives aberrant NF-κB signaling downstream of T cell receptor activation. Expression of FYN-TRAF3IP2 in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with Tet2 loss in PTCL development; IκB kinase inhibitors suppress FYN-TRAF3IP2-induced lymphoma.\",\n      \"method\": \"Identification of fusion by sequencing, hematopoietic progenitor reconstitution mouse model, NF-κB reporter and signaling assays, IKK inhibitor treatment in vitro and in vivo\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transformation assay, NF-κB pathway mechanistic dissection, pharmacological IKK inhibition rescue, multiple mouse models\",\n      \"pmids\": [\"33928261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fyn is a modulator of erythropoietin signaling: Fyn-/- mice exhibit reduced tyrosine phosphorylation of EPO-R and decreased STAT5 activity. Fyn also acts as a physiologic repressor of Nrf2; absence of Fyn leads to persistent Nrf2 activation, ROS-induced Jak2-Akt-mTOR pathway overactivation, and impaired autophagy, which can be rescued by rapamycin.\",\n      \"method\": \"Fyn-/- mice, EPO-R tyrosine phosphorylation assay, STAT5 activity, Nrf2 target gene expression, mTOR pathway immunoblotting, rapamycin treatment\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple pathway readouts and pharmacological rescue; single lab\",\n      \"pmids\": [\"30252956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aβ oligomers promote oligodendrocyte differentiation and MBP translation via integrin β1 receptor and Fyn kinase, with Ca2+/CaMKII as downstream effectors. Pharmacological Fyn inhibition attenuates Aβ-induced oligodendrocyte differentiation and MBP upregulation in organotypic cerebellar slices.\",\n      \"method\": \"Integrin β1 blockade, Fyn pharmacological inhibition, MBP local translation assay, organotypic cerebellar slice model with lysolecithin demyelination\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of Fyn, integrin β1 blockade, ex vivo remyelination model; single lab\",\n      \"pmids\": [\"31171765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"P2X7 receptor physically interacts with Fyn kinase (co-immunoprecipitation), and P2X7 receptor agonist BzATP enhances Fyn kinase activity. Blocking Fyn activity or downregulating Fyn expression inhibits BzATP-induced oligodendrocyte progenitor cell migration.\",\n      \"method\": \"Co-immunoprecipitation of P2X7 and Fyn, Fyn kinase activity assay, Fyn inhibitor and siRNA knockdown, OPC migration assay\",\n      \"journal\": \"Purinergic signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and kinase assay, pharmacological and siRNA validation; single lab, limited mechanistic detail\",\n      \"pmids\": [\"26099359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD28-containing CAR-T cells signal through FYN kinase rather than LCK for their primary activation. FYN-dependent CAR signaling (requiring both FYN and CD28 intracellular domain) promotes T cell proliferation and memory formation, whereas LCK-dependent signaling leads to exhaustion. LCK-deficient CAR-T cells with intact FYN show superior in vivo anti-tumor efficacy.\",\n      \"method\": \"LCK-deficient CAR-T cells, in vivo CAR-T efficacy models, phenotypic analysis of exhaustion/memory markers, CD28 domain mutant CARs\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic LCK deficiency, CD28 domain requirement established, in vivo efficacy readout; single lab, multiple methods\",\n      \"pmids\": [\"36696897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fyn kinase localizes to the egg cortex, polar body, fertilizing cone, and meiotic/mitotic spindles of rat eggs. In mammalian oocytes, Fyn concentrates asymmetrically at the site of cleavage furrow ingression co-localizing with F-actin during meiosis and mitosis; dominant-negative Fyn prolongs furrow ingression duration and leads to larger polar bodies and longer spindles.\",\n      \"method\": \"Live-cell confocal imaging, microinjection of Fyn cRNA (wild-type and dominant-negative), SFK inhibitor SU6656, polar body extrusion timing and spindle length measurement\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging, dominant-negative microinjection, pharmacological inhibition, quantitative phenotypic readout; single lab\",\n      \"pmids\": [\"20841362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fyn phosphorylates APP at Tyr757 of the YENPTY motif and increases APP cell-surface expression. In the presence of Dab1, Fyn significantly increases sAPPα production and C-terminal fragment levels, and potentiates Dab1-dependent APP phosphorylation and surface trafficking. Fyn-KO mice show reduced sAPPα in vivo.\",\n      \"method\": \"Co-immunoprecipitation, co-immunostaining, FLIM (fluorescence lifetime imaging), Fyn overexpression with/without Dab1, Fyn-KO mouse brain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, FLIM, overexpression, and in vivo KO; multiple methods; single lab\",\n      \"pmids\": [\"18089558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fyn kinase activity is regulated by submembrane localization: a FRET biosensor shows that Fyn outside its membrane microdomains is hyperactive, while microdomains provide a suppressive microenvironment. A relatively high Fyn activity is also observed at perinuclear regions.\",\n      \"method\": \"FRET biosensor for Fyn kinase activity in live cells, membrane microdomain-targeted biosensor variants (Fyn-tag vs. Lyn-tag), pharmacological perturbations of membrane domains\",\n      \"journal\": \"ACS sensors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET live-cell biosensor with targeted variants, pharmacological perturbation; single lab, novel tool paper\",\n      \"pmids\": [\"30588803\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FYN is a dually acylated (N-myristoylated and palmitoylated) Src-family non-receptor tyrosine kinase that localizes to plasma membrane lipid-raft/caveolar microdomains where its activity is suppressed, and is activated downstream of diverse receptors (TCR, FcεRI, integrins, GPCRs, RTKs, TLR4, P2X7) to phosphorylate substrates including Dab1 (regulating Reelin-dependent neuronal migration), Nephrin (modulating podocyte slit-diaphragm integrity), GluN2B/NR2B NMDA receptor subunits (controlling synaptic plasticity and ethanol responses), tau (promoting tau hyperphosphorylation and aggregation in tauopathy), flotillin-1/2 Tyr160/163 (driving endocytosis), β-catenin Tyr142 (promoting osteoarthritis), NOX4 Tyr566 (negatively regulating ROS production in cardiomyocytes), p130Cas (rigidity sensing), Vav (cytoskeletal reorganization and immunologic synapse formation), caveolin (viral entry), APP Tyr757 (amyloid precursor processing), Pyk2, and cortactin; its activity is positively regulated by PTPα (which dephosphorylates the inhibitory Tyr531) and by PKC-eta, and negatively regulated by STEP (which dephosphorylates the activating Tyr420) and by Srcasm-mediated kinase downregulation, with the Lyn/Fyn balance on SHP-1 determining whether ITAM signaling is inhibitory (Lyn-driven) or activatory (Fyn-driven), and with the oncogenic FYN-TRAF3IP2 fusion driving NF-κB-dependent T cell lymphoma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FYN is a dually acylated Src-family non-receptor tyrosine kinase that is targeted to plasma-membrane lipid-raft/caveolar microdomains by sequential N-myristoylation on cytosolic polysomes and subsequent palmitoylation, where these microdomains constitute a suppressive microenvironment that keeps the kinase inactive until receptor engagement [#14, #47]. Its catalytic output is set by phospho-regulation of its activating and inhibitory tyrosines: PTPα dephosphorylates raft-associated FYN to control its activity and couple it to the Cbp/PAG–Csk axis [#16], and this PTPα→FYN module is itself gated by STEP, which is relieved upon ethanol-driven PKA signaling to allow FYN-dependent upregulation of GluN2B NMDA-receptor signaling [#17]. Acting downstream of a broad range of receptors—the TCR, FcεRI, integrins, RTKs (Trk, TrkB, Tyro3, FLT3), GPCRs, TLR4 and P2X7—FYN transduces signals to cytoskeletal, adhesion, and transcriptional effectors [#13, #2, #12, #26, #38]. In the nervous system FYN is the principal kinase (with Src) phosphorylating the Reelin adaptor Dab1 to direct neuronal migration [#0, #1], drives myelination through TrkB/Erk and DCC/N-WASP/RhoA pathways in oligodendrocytes [#27, #18], and is a central node in neurodegeneration, mediating Aβ-oligomer signaling through Pyk2 to NR2B and controlling tau hyperphosphorylation and aggregation in vivo [#21, #25, #24]. In immune cells FYN phosphorylates Vav to build the immunologic synapse [#13] and inactivates SHP-1 at Ser591 to switch ITAM signaling toward activation, opposing Lyn [#20]. FYN phosphorylates a defined substrate set—Nephrin (slit-diaphragm integrity) [#3, #4], flotillin-1/2 Tyr160/163 (raft endocytosis) [#10], p130Cas (rigidity sensing) [#11], NOX4 Tyr566 (negative ROS regulation in cardiomyocytes) [#19], β-catenin Tyr142 (osteoarthritic cartilage degradation) [#23], and APP Tyr757 [#46]—coupling membrane microdomain organization to cytoskeletal remodeling, cell adhesion, and transcriptional programs. FYN dysregulation is oncogenic: the recurrent FYN-TRAF3IP2 fusion drives NF-κB-dependent T-cell lymphoma [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that FYN occupies a distinct node in adhesion and cytoskeletal signaling addressed whether Src-family kinases are functionally redundant; genetic dissection showed FYN and Src have overlapping but separable substrate preferences.\",\n      \"evidence\": \"Genetic epistasis in src/fyn/csk mutant mouse embryos with phospho-substrate biochemistry, plus fyn-null keratinocyte differentiation assays\",\n      \"pmids\": [\"7617039\", \"7557381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how membrane localization dictates the substrate split between FYN and Src\", \"Cortactin phosphorylation attribution remained partly shared\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining how FYN reaches its site of action answered where its activity is spatially constrained; dual acylation was shown to cluster FYN in caveolae-like microdomains.\",\n      \"evidence\": \"Biochemical acylation and membrane-fractionation analysis (review with primary data), plus fyn-/- requirement in CD73 GPI-anchored signaling\",\n      \"pmids\": [\"9839441\", \"9808167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acylation evidence from a review rather than a primary structural study\", \"How palmitoylation dynamically partitions FYN between active and suppressive pools not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating FYN-specific (not Src-redundant) signaling answered whether individual SFKs run dedicated pathways; FYN was shown to be uniquely required for H2O2-induced JAK2/Shc/Ras activation.\",\n      \"evidence\": \"Fyn-/- vs Src-/- fibroblasts with isogenic FYN-but-not-Src rescue of JAK2 activation\",\n      \"pmids\": [\"10409649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FYN substrate in the ROS→JAK2 step not identified\", \"Mechanism of redox activation of FYN unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying upstream activators answered how FYN is switched on in epithelia and lymphocytes; PKC-eta was shown to directly bind and activate FYN, and antagonist-TCR signaling to selectively engage FYN→Vav.\",\n      \"evidence\": \"In vitro kinase reconstitution with recombinant PKC-eta and co-IP; Fyn-/- TCR-transgenic T cells with Vav phosphorylation and conjugate-formation readouts\",\n      \"pmids\": [\"11106751\", \"11005864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PKC-eta/FYN activation not defined\", \"How antagonist peptides bias toward FYN over Lck mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linking FYN to receptor-specific developmental and barrier substrates answered which physiological pathways depend on it; FYN was shown to be the dominant Dab1 kinase in Reelin signaling and a direct Nephrin SH3-binding kinase in podocytes.\",\n      \"evidence\": \"Pharmacological/genetic SFK dissection of Dab1 phosphorylation in fyn/src/yes embryos; SH3 pulldown, in vitro kinase assay, and Fyn-KO podocyte ultrastructure\",\n      \"pmids\": [\"12526739\", \"16162939\", \"12668668\", \"15579503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Dab1 phosphosite stoichiometry in vivo only partially quantified\", \"Whether Nephrin and Dab1 share FYN regulatory inputs unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining how membrane targeting confers function answered why FYN, not Src, supports rigidity sensing and caveolar entry; the palmitoylation site was shown to be necessary and sufficient to confer the FYN-specific rigidity response, and FYN was required for caveolar virus uptake.\",\n      \"evidence\": \"Palmitoylation-site Src chimeras with live imaging of p130Cas phosphorylation; inhibitor/siRNA/caveolar transport assays for coxsackievirus entry\",\n      \"pmids\": [\"16597701\", \"16413486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab imaging for the rigidity-response chimera\", \"How leading-edge FYN couples mechanical force to kinase activation unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolving how FYN catalytic output is set answered the phosphatase control logic; PTPα was shown to govern raft FYN activity via its activating/inhibitory tyrosines and the Cbp/PAG–Csk circuit.\",\n      \"evidence\": \"PTPα-knockout thymocytes with lipid-raft fractionation, phospho-specific FYN Tyr antibodies, and Cbp/PAG-Csk co-IP\",\n      \"pmids\": [\"16339530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Net activity outcome of simultaneous Tyr417/Tyr528 changes not fully reconciled\", \"Tissue-specificity of PTPα-FYN coupling not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining FYN endocytic substrates answered how it remodels raft membrane traffic; FYN was shown to directly phosphorylate flotillin-1 Tyr160 and flotillin-2 Tyr163 to drive internalization.\",\n      \"evidence\": \"SYF null-cell reconstitution, inducible FYN activation, Y→F mutagenesis, and GPI-protein endocytosis readout\",\n      \"pmids\": [\"19258392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity of flotillin-mediated endocytosis downstream of FYN not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing FYN as a druggable hub in Alzheimer signaling answered whether targeting it reverses pathology; FYN inhibition blocked Aβ→Pyk2→NR2B signaling and rescued memory and synapses, and STEP was shown to gate the PTPα→FYN→GluN2B axis.\",\n      \"evidence\": \"AZD0530 in APP/PS1 and triple-transgenic mice with behavioral/biochemical readouts; STEP knockdown, in vitro phosphatase assay, and synaptosomal fractionation\",\n      \"pmids\": [\"25707991\", \"25951993\", \"29782321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect contribution of FYN-Pyk2 to NR2B phosphorylation partly inferential\", \"Pyk2-as-tau-kinase placement downstream of FYN is Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying organ-specific substrates answered how FYN drives disease in heart and joint; FYN directly phosphorylates NOX4 Tyr566 to restrain ROS and β-catenin Tyr142 to accelerate osteoarthritis.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, in vitro kinase assays, and Fyn-KO (with Nox4-KO rescue / DMM OA) mouse models\",\n      \"pmids\": [\"27525436\", \"29555825\", \"28811476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NOX4 and β-catenin phosphorylation share an upstream receptor trigger unknown\", \"FYN/Lyn SHP-1 phospho-switch generality across receptors not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Separating FYN's tau role from amyloid answered whether FYN acts on tauopathy independently of Aβ; FYN knockout nearly abolished neurofibrillary tangles and reduced tau seeding, and α-synuclein/inflammasome work extended FYN to broader neurodegeneration.\",\n      \"evidence\": \"Fyn-KO crossed to tau-transgenic mice, tau seeding biosensor, phosphomimetic Y18E fibrillization; Fyn-KO α-synuclein PD models with NLRP3/NF-κB readouts\",\n      \"pmids\": [\"32814048\", \"31036561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether direct tau Y18 phosphorylation vs Pyk2-mediated phosphorylation dominates in vivo unresolved\", \"Relative contribution of microglial vs neuronal FYN to tau spread not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining oncogenic FYN dysregulation answered how it transforms T cells; the FYN-TRAF3IP2 fusion was shown to drive NF-κB-dependent lymphoma sensitive to IKK inhibition.\",\n      \"evidence\": \"Fusion identification by sequencing, hematopoietic progenitor reconstitution mouse models, NF-κB assays, and IKK-inhibitor rescue\",\n      \"pmids\": [\"33928261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FYN kinase activity per se or TRAF3IP2-mediated scaffolding drives NF-κB not fully dissected\", \"Cooperating lesions beyond Tet2 loss not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguishing FYN from LCK in engineered T cells answered which SFK drives durable CAR-T responses; CD28-CARs were shown to signal through FYN to promote memory while LCK drives exhaustion.\",\n      \"evidence\": \"LCK-deficient CAR-T cells, CD28 intracellular-domain mutant CARs, and in vivo anti-tumor efficacy/phenotyping\",\n      \"pmids\": [\"36696897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FYN substrates underlying the memory program not identified\", \"Single-lab in vivo efficacy data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the suppressive lipid-raft microenvironment, receptor-specific recruitment, and phosphatase gating are integrated to select among FYN's many substrates in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking membrane microdomain residency to substrate choice\", \"Structural basis of FYN activation by diverse receptors lacking\", \"Quantitative rules governing FYN vs Src/Lyn substrate partitioning unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 10, 19, 23, 46]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 4, 10, 19, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 2, 12, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 47, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 11, 30, 45]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 13, 20, 44]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 16, 17, 26, 38]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 21, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10, 5, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 24, 23, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NOX4\", \"PIKE-A\", \"Nephrin\", \"TLR4\", \"FLT3\", \"Tyro3\", \"DCC\", \"P2X7\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}