{"gene":"LYN","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1991,"finding":"Lyn protein and its kinase activity co-immunoprecipitate with membrane-bound IgM from B cell detergent lysates, establishing that Lyn is physically associated with the B cell antigen receptor (BCR/IgM).","method":"Co-immunoprecipitation from B cell lysates","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrated in the founding paper and independently confirmed in multiple subsequent studies across labs","pmids":["1702903"],"is_preprint":false},{"year":1993,"finding":"Lyn (p56lyn and p53lyn) co-immunoprecipitates with both IgM and IgD from B cell detergent lysates; BCR cross-linking rapidly increases Lyn kinase activity and induces association of Lyn with the p85 subunit of PI3-kinase; HS1 was identified as a downstream substrate of Lyn.","method":"Co-immunoprecipitation, in vitro kinase assay","journal":"Immunological reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and kinase assay in single lab, multiple binding partners identified","pmids":["8349296"],"is_preprint":false},{"year":1994,"finding":"In Lyn-deficient B cells, BCR crosslinking produces delayed and slow Ca2+ mobilization despite normal IP3 generation kinetics, whereas Syk mediates IP3 generation; this epistasis places Lyn as regulating Ca2+ mobilization through an IP3-independent pathway downstream of BCR.","method":"Lyn-negative and Syk-negative B cell lines, calcium flux assay, IP3 measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function cell lines with multiple orthogonal readouts (Ca2+, IP3), widely replicated","pmids":["8137818"],"is_preprint":false},{"year":1995,"finding":"Activation of the N-formyl peptide chemoattractant receptor (G protein-coupled) in human neutrophils stimulates Lyn kinase, which then associates with and phosphorylates the Shc adapter protein via Shc's SH2 domain; phosphorylated Lyn-Shc complexes associate with PI3-kinase, correlating with PIP3 formation.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphotyrosine blotting in human neutrophils","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and kinase assay, single lab, multiple interactors identified","pmids":["7650013"],"is_preprint":false},{"year":1995,"finding":"LPS and Taxol rapidly induce autophosphorylation of Lyn (p53 and p56 isoforms) in LPS-responsive macrophages but not in LPS-hyporesponsive C3H/HeJ macrophages; tyrosine phosphatase inhibitors block LPS-induced Lyn autophosphorylation, indicating phosphatases participate in regulating Lyn kinase activity.","method":"Immunoprecipitation, in vitro kinase assay, 32P incorporation, LPS-responsive vs. hyporesponsive macrophage comparison","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with genetic model comparison, single lab","pmids":["8521300"],"is_preprint":false},{"year":1996,"finding":"Lyn phosphorylates the cytoplasmic domain of band-3 protein in human erythrocytes; the Syk-catalyzed phosphorylation of band-3 is a prerequisite for Lyn membrane association and subsequent Lyn-catalyzed phosphorylation of distinct band-3 tyrosine residues.","method":"In vitro kinase assay with isolated erythrocyte membranes and purified kinases","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified components, single lab","pmids":["8841404"],"is_preprint":false},{"year":1998,"finding":"Lyn is required for G-CSF-induced DNA synthesis; lyn-deficient chicken B cells transfected with human G-CSFR fail to proliferate in response to G-CSF despite normal JAK1/JAK2 phosphorylation; ectopic Lyn (but not c-Src) restores mitogenic response; kinase-dead Lyn acts as dominant negative.","method":"Genetic loss-of-function (lyn-deficient cell lines), rescue with ectopic Lyn or kinase-dead mutant, thymidine incorporation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function plus gain-of-function rescue with mutagenesis, multiple orthogonal controls","pmids":["9452436"],"is_preprint":false},{"year":1998,"finding":"Lyn negatively regulates BCR signaling by phosphorylating the inhibitory co-receptors FcγRIIB and CD22; in lyn-/- B cells, tyrosine phosphorylation of these co-receptors is severely impaired upon BCR co-ligation, preventing recruitment of SHP-1 and SHIP, and resulting in failure to suppress Ca2+ influx and proliferation.","method":"Lyn-/- mouse B cells, co-immunoprecipitation, phosphotyrosine blotting, Ca2+ mobilization assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with multiple mechanistic readouts, replicated across labs","pmids":["9547345"],"is_preprint":false},{"year":1998,"finding":"Lyn directly phosphorylates STAT3 in vitro; BCR engagement activates STAT3 in a Lyn-dependent, JAK-independent manner, as shown by failure of JAK1/JAK2 antisense or the JAK inhibitor AG490 to block STAT phosphorylation.","method":"In vitro phosphorylation assay, lyn-null cell lines, antisense JAK knockdown, kinase inhibitor, EMSA","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus multiple genetic/pharmacological controls, single lab","pmids":["17146444"],"is_preprint":false},{"year":1998,"finding":"Lyn's SH3 domain interacts directly with DNA-PKcs near a leucine zipper homology domain; Lyn phosphorylates DNA-PKcs but not Ku in vitro; this interaction inhibits DNA-PKcs activity and its ability to form a complex with Ku/DNA.","method":"Co-immunoprecipitation, GST pulldown with SH3 domain, in vitro kinase assay, DNA-PK activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and domain mapping, single lab","pmids":["9748231"],"is_preprint":false},{"year":1999,"finding":"AMPA receptors physically associate with Lyn in the cerebellum; AMPA receptor stimulation rapidly activates Lyn independently of Ca2+ or Na2+ influx; activated Lyn then activates the MAPK pathway, leading to increased BDNF mRNA expression in a Lyn kinase-dependent manner.","method":"Co-immunoprecipitation, in vitro kinase assay, dominant-negative Lyn, BDNF mRNA measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional validation, dominant-negative rescue, multiple orthogonal readouts","pmids":["9892356"],"is_preprint":false},{"year":2000,"finding":"Lyn functions downstream of the G-CSF receptor; in lyn-deficient cells, G-CSF fails to induce tyrosine phosphorylation of Shc or activation of Erk1/2 or PI3-kinase/Cbl; these pathways are required for DNA synthesis; Ras activation by G-CSF is Lyn-independent.","method":"Lyn-deficient DT40 cell lines, phosphotyrosine blotting, kinase assays, dominant-negative constructs","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple downstream readouts, single lab","pmids":["10644984"],"is_preprint":false},{"year":2001,"finding":"Lyn's SH3 domain interacts with GADD34 (and murine MyD116) identified by yeast two-hybrid and confirmed by GST-SH3 pulldown and co-immunoprecipitation; Lyn phosphorylates GADD34 in vitro and in vivo; wild-type but not kinase-inactive Lyn suppresses GADD34-promoted apoptosis following DNA damage.","method":"Yeast two-hybrid, GST-SH3 pulldown, co-immunoprecipitation, in vitro kinase assay, apoptosis assay with kinase-dead mutant","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (Y2H, pulldown, Co-IP, in vitro kinase, mutagenesis) in one study","pmids":["11517336"],"is_preprint":false},{"year":2001,"finding":"In J2E erythroleukemic cells, Lyn co-immunoprecipitates with SHP-1, SHP-2, Ras-GAP, STAT5a, STAT5b, and MAPK; dominant-negative Lyn (Y397F) disrupts most of these interactions except with SHP-1; Y397F Lyn blocks erythropoietin-induced differentiation, proliferation, and reduces GATA-1 and EKLF transcription factor levels; Lyn activation requires JAK2.","method":"Co-immunoprecipitation, dominant-negative mutant expression, cell differentiation assay, western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus dominant-negative mutagenesis, single lab","pmids":["11289114"],"is_preprint":false},{"year":2002,"finding":"Lyn kinase associates with the IL-5 receptor alpha (IL-5Rα) under basal conditions in eosinophils and phosphorylates both IL-5Rα and the common beta chain (βcR) in vitro; Lyn is required for IL-5-stimulated eosinophil differentiation.","method":"Co-immunoprecipitation, in vitro kinase assay, antisense oligodeoxynucleotide knockdown, Lyn-/- mouse bone marrow differentiation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with receptor substrate plus genetic KO confirmation, single lab","pmids":["11823534"],"is_preprint":false},{"year":2002,"finding":"DNA-damaging agents Ara-C and daunorubicin activate Lyn and trigger its translocation into sphingomyelin-enriched membrane rafts; raft-compartmentalized Lyn activates neutral sphingomyelinase, generating ceramide; both Lyn translocation and sphingomyelinase activation are blocked by tyrosine kinase inhibitors or raft disruption.","method":"Membrane fractionation, immunoblotting, kinase assay, lipid raft disruption, inhibitor studies","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation with functional consequence, pharmacological inhibition, single lab","pmids":["12206990"],"is_preprint":false},{"year":2004,"finding":"Constitutively active Lyn (Y508F mutant), but not kinase-dead Lyn (K275D), upregulates Bcl-2 mRNA and protein expression in CML cells and protects cells from imatinib-induced apoptosis; Src kinase inhibitor PP2 reduces Lyn activation and Bcl-2 levels in resistant cells.","method":"Stable transfection of constitutively active and kinase-dead Lyn mutants, western blot, siRNA, antisense, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function with mutagenesis (active vs. kinase-dead), multiple orthogonal loss-of-function approaches, functional readout","pmids":["15175350"],"is_preprint":false},{"year":2004,"finding":"SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism are regulated through Lyn kinase in platelets; Lyn-deficient platelets show enhanced Ca2+ flux and spreading; Lyn and SHIP1 negatively regulate integrin αIIbβ3 outside-in signaling.","method":"Lyn-/- and SHIP1-/- mouse platelets, lipid measurement, Ca2+ flux, platelet spreading assay under flow","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with multiple functional readouts, single lab","pmids":["15166241"],"is_preprint":false},{"year":2004,"finding":"In lyn-/- mast cells, SHIP tyrosine phosphorylation and activity are markedly reduced, while Fyn kinase shows increased basal and stimulated phosphorylation; these changes result in prolonged FcεRI signaling with elevated PIP3 and excessive degranulation.","method":"Lyn-/- bone marrow-derived mast cells, phosphotyrosine blotting, SHIP activity assay, kinase assay, Ca2+ measurement, PIP3 measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts, single lab","pmids":["15210764"],"is_preprint":false},{"year":2005,"finding":"Lyn positively regulates FcεRI signaling and mast cell degranulation at low stimulation intensity via enhanced association with FcεRI beta subunit and activation of Akt and p38, whereas at high stimulation intensity Lyn negatively regulates signaling through the FcεRI beta-ITAM and promotes SHIP and SHP-1 association with FcεRI beta.","method":"Wild-type and Lyn-/- mast cells, FcεRI beta ITAM mutants, kinase/phosphatase association assays, degranulation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus receptor domain mutagenesis, single lab","pmids":["16272347"],"is_preprint":false},{"year":2005,"finding":"In glioblastoma cells, Lyn (but not Fyn) kinase activity promotes cell migration in response to PDGFR-beta and integrin αvβ3 cooperative signaling; Lyn accounts for >90% of pan-Src kinase activity in glioblastoma tumor samples.","method":"Migration assay, selective kinase activity measurements, immunoprecipitation kinase assay from tumor biopsies","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase activity measurement from tumor samples plus cell-based migration, single lab","pmids":["15994925"],"is_preprint":false},{"year":2005,"finding":"G-CSF stimulation activates Lyn and Akt in a Lyn-PI3-kinase dependent manner; inhibition of Lyn, PI3-kinase, or Akt abrogates G-CSF-induced reactive oxygen species (ROS) production; G-CSF induces serine phosphorylation and membrane translocation of p47phox (NADPH oxidase subunit) in a Lyn-dependent manner; Lyn-/- neutrophils produce less ROS than wild-type.","method":"Lyn-/- mouse neutrophils, pharmacological inhibitors, ROS measurement, p47phox phosphorylation and fractionation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse plus pharmacological validation, multiple readouts, single lab","pmids":["16282349"],"is_preprint":false},{"year":2006,"finding":"Lyn is required for P. aeruginosa internalization into lung cells; Lyn activation and its interaction with lipid rafts and TLR2 are required for initial bacterial-host cell interaction; blockade of Lyn prevents bacterial internalization and downstream cytokine induction and apoptosis.","method":"Pharmacological inhibition (PP2), dominant-negative mutant, Lyn-/- bone marrow-derived mast cells, internalization assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus dominant-negative and pharmacological inhibition with functional readout, single lab","pmids":["16791881"],"is_preprint":false},{"year":2006,"finding":"Lyn phosphorylates Cbp (CSK-binding protein) on tyrosine residues including Tyr314; phospho-Tyr314 recruits Csk/Ctk to suppress Lyn kinase activity (rapid phase) and also recruits SOCS1, leading to ubiquitination and degradation of Lyn (delayed phase) in erythropoietin-stimulated cells.","method":"Co-immunoprecipitation, phosphorylation site mapping, Csk/SOCS1 recruitment assay, ubiquitination assay in primary erythroid cells and cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphosite mapping plus reconstitution of two-phase regulatory mechanism with multiple binding partners, functionally validated","pmids":["16920712"],"is_preprint":false},{"year":2006,"finding":"The C-lobe of the Lyn kinase domain associates with ACSL3 on the Golgi in a conformation-dependent (open conformation required) but kinase activity-independent manner; this interaction is required for Golgi export of Lyn to the plasma membrane; CSK-induced closed conformation prevents ACSL3 association and Golgi export.","method":"Co-immunoprecipitation, ACSL3 overexpression/knockdown, live cell imaging, fractionation, domain mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD/OE, live imaging, conformational mutants) establishing trafficking mechanism","pmids":["20605918"],"is_preprint":false},{"year":2008,"finding":"Lyn is required for P2X4 receptor upregulation in spinal microglia after nerve injury; Lyn-/- mice show impaired fibronectin-induced P2X4R expression in microglia and reduced tactile allodynia; Lyn is the predominant Src family kinase in spinal microglia.","method":"Lyn-/- mice, immunofluorescence, western blot, behavioral assays, primary microglial culture","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with cellular mechanism (P2X4R upregulation) and behavioral readout, single lab","pmids":["17918263"],"is_preprint":false},{"year":2008,"finding":"Lyn nuclear localization is regulated by Crm1-mediated nuclear export and is enhanced by inhibition of Lyn kinase activity (via SU6656, Csk overexpression, or ATP-binding site mutation); lipid modification (myristoylation/palmitoylation) also limits nuclear accumulation.","method":"Leptomycin B treatment, Csk overexpression, kinase-dead mutants, immunofluorescence, nuclear fractionation in HeLa and THP-1 cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic perturbations with localization readout, single lab","pmids":["18817770"],"is_preprint":false},{"year":2008,"finding":"Lyn associates with αvβ3 integrin (but not αvβ5) in oligodendrocytes and brain tissue; Lyn suppresses acid sphingomyelinase (ASMase) activity; Lyn knockdown induces apoptosis with ceramide accumulation via ASMase activation; brain ischemia/reperfusion disrupts the αvβ3-Lyn complex and activates ASMase.","method":"Co-immunoprecipitation, siRNA knockdown, ASMase activity assay, ceramide measurement, brain fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional KD and enzymatic readout, single lab","pmids":["18682390"],"is_preprint":false},{"year":2009,"finding":"Lyn forms a complex with RANK, SHP-1, and Gab2 in osteoclast precursors; upon RANKL stimulation in Lyn-/- cells, Gab2 phosphorylation and JNK and NF-κB activation are enhanced; Lyn negatively regulates osteoclast differentiation (not activity) downstream of RANK.","method":"Co-immunoprecipitation, Lyn-/- mouse osteoclast cultures, kinase/phosphorylation assays, in vivo bone resorption assay","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP complex identification plus KO mouse with mechanistic pathway readouts, single lab","pmids":["19171907"],"is_preprint":false},{"year":2010,"finding":"Lyn phosphorylates SHP-1 at Tyr564 (required for maximal phosphatase activity) and Tyr536 (required for efficient STAT5 interaction); in lyn-/-;PLC-β3-/- hematopoietic stem cells, both phosphorylation events are abrogated, resulting in reduced SHP-1 activity and constitutive STAT5 activation causing CMML-like disease.","method":"In vitro kinase assay with phosphosite mutants, phospho-specific antibodies, mouse genetics (double KO), STAT5 activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with phosphosite mutagenesis plus genetic mouse model validation, multiple mechanistic readouts","pmids":["20858858"],"is_preprint":false},{"year":2010,"finding":"RNAi-mediated knockdown of LYN in mesenchymal breast cancer lines inhibits cell migration and invasion but not proliferation; dasatinib at nanomolar concentrations blocks invasion consistent with LYN kinase inhibition.","method":"RNAi knockdown, cell migration and invasion assay, pharmacological inhibition","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with functional cellular readout, pharmacological corroboration, single lab","pmids":["20215510"],"is_preprint":false},{"year":2011,"finding":"Lyn is required for PECAM-1 tyrosine phosphorylation and subsequent recruitment of SHP-2 to PECAM-1 in platelets; PECAM-1-deficient and Lyn-deficient platelets show equal hyperresponsiveness to GPVI stimulation, establishing that they function in the same inhibitory pathway.","method":"PECAM-1-/- and Lyn-/- mouse platelets, PECAM-1/Lyn double-deficient mice, co-immunoprecipitation, platelet activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double KO), Co-IP, multiple functional readouts establishing pathway order","pmids":["21297004"],"is_preprint":false},{"year":2012,"finding":"Yes and Lyn interact with EGFR in cetuximab-resistant cells (but not sensitive cells); knockdown of either Yes or Lyn abolishes EGFR nuclear translocation; Lyn/Yes phosphorylate EGFR at Y1101, which is required for nuclear entry; nuclear EGFR complexes bind B-Myb and iNOS promoters.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression, ChIP assay, site-directed mutagenesis (Y1101)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNAi and OE with phosphosite mutant, single lab","pmids":["22430206"],"is_preprint":false},{"year":2013,"finding":"Lyn associates with FAK and phosphorylates FAK at tyrosines 576/577 and 925; this Lyn-FAK interaction is required for Lyn-dependent stabilization of endothelial adherens junctions; Lyn-/- mice show increased vascular permeability in response to LPS or VEGF.","method":"Co-immunoprecipitation, constitutively active Lyn, siRNA knockdown, Lyn-/- mice, permeability assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with phosphosite identification, genetic KO mouse, gain-of-function mutant, in vivo permeability readout","pmids":["24108461"],"is_preprint":false},{"year":2013,"finding":"Lyn phosphorylates the atypical kinase SgK269/PEAK1 at Y635, which is a Grb2-binding site promoting Stat3 and Erk activation; SgK269 Y635F mutant fails to enhance acinar size or cellular invasion, placing Lyn upstream of SgK269 in a basal breast cancer signaling pathway.","method":"In vitro kinase substrate identification, phosphosite mutant (Y635F), 3D culture, invasion assays, Stat3/Erk activation measurement","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with phosphosite mutagenesis and functional validation, single lab","pmids":["23378338"],"is_preprint":false},{"year":2016,"finding":"Lyn physically interacts with IRF5 and inhibits IRF5 ubiquitination and phosphorylation in the TLR-MyD88 pathway, thereby suppressing IRF5 transcriptional activity in a kinase activity-independent manner; monoallelic Irf5 deletion alleviates cytokine hyperproduction in Lyn-/- dendritic cells and SLE-like disease in Lyn-/- mice.","method":"Co-immunoprecipitation, ubiquitination assay, Lyn kinase-inactive mutant, Lyn-/-Irf5+/- double mutant mice, cytokine measurement","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, kinase-dead mutant distinguishing kinase-independent function, genetic epistasis in vivo, multiple readouts","pmids":["27521268"],"is_preprint":false},{"year":2017,"finding":"Lyn phosphorylates SHP-1 at tyrosine 536, activating the phosphatase and promoting inhibitory immunoreceptor signaling; by contrast, Fyn phosphorylates SHP-1 at serine 591, inactivating it and enabling activatory signaling; these opposing modifications on SHP-1 determine whether immunoreceptor signaling results in homeostasis or inflammation.","method":"In vitro kinase assays, phospho-specific antibodies, Lyn-/- and Fyn-/- mice, SHP-1 phosphomutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with site-specific mutants, genetic mouse models, replicated in vivo","pmids":["28811476"],"is_preprint":false},{"year":2017,"finding":"Lyn kinase controls SNAI family protein localization and stability through the Vav-Rac1-PAK1 signaling pathway; targeting Lyn in vitro reduces EMT markers and in vivo reduces metastasis of primary tumors.","method":"Lyn knockdown/inhibition, pathway inhibitors, in vivo tumor metastasis assay, EMT marker analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway placement and in vivo readout, single lab","pmids":["28288135"],"is_preprint":false},{"year":2017,"finding":"LPS-induced Lyn palmitoylation, SH2- and SH3-mediated interactions, and catalytic activity are all required for Lyn accumulation in membrane rafts; raft-associated Lyn negatively regulates TLR4-induced TNF-α, CCL5/RANTES production, and NF-κB/IRF3 activity in macrophages.","method":"Lyn-GFP domain mutants overexpressed in RAW264 macrophages and peritoneal macrophages, membrane fractionation, cytokine measurement, NF-κB/IRF3 reporter assays, Lyn siRNA silencing","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis panel with fractionation and functional readouts, single lab","pmids":["28228554"],"is_preprint":false},{"year":2018,"finding":"LYN activity is modulated by the prolyl isomerase PIN1 in BRCA1-mutant triple-negative breast cancer; the full-length LYN splice isoform (but not the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells; LYN is a downstream effector of c-KIT in normal mammary cells.","method":"Isoform-specific expression, RNAi knockdown, migration and invasion assays, PIN1 manipulation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific loss/gain of function with functional readouts, single lab","pmids":["30590041"],"is_preprint":false},{"year":2019,"finding":"CARD9 is a vital component of Lyn-mediated regulation of TLR2 and TLR4 signaling in dendritic cells; in the absence of Lyn, a CD11b-Syk-PKCδ-CARD9 pathway is amplified, leading to increased TLR-induced inflammatory cytokines; dendritic cell-specific CARD9 deletion reverses autoimmunity in Lyn-deficient mice.","method":"Lyn-/-CARD9-/- double KO mice, dendritic cell-specific CARD9 deletion, cytokine assays, pathway inhibitor studies","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with cell-type-specific KO, pathway placement, single lab","pmids":["31594855"],"is_preprint":false},{"year":2020,"finding":"High ECM stiffness induces ligand-independent phosphorylation of EPHA2, which recruits and activates LYN kinase; LYN phosphorylates TWIST1, releasing it from its cytoplasmic anchor G3BP2 to enter the nucleus and trigger EMT and invasion; genetic and pharmacological inhibition prevents breast tumor metastasis in vivo.","method":"Co-immunoprecipitation, phosphorylation assays, siRNA/genetic KO, in vivo tumor metastasis models, mechanically tunable substrates","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus pathway dissection with genetic/pharmacological inhibition and in vivo validation, multiple orthogonal methods","pmids":["32574556"],"is_preprint":false},{"year":2020,"finding":"Lyn kinase is critical for flavivirus (Dengue, Zika) secretion within autophagosome-derived vesicles; kinase-deficient and palmitoylation-deficient Lyn mutants fail to rescue virus release in Lyn-/- cells; Lyn-dependent viral egress requires Ulk1, Rab GTPases, and SNARE complexes implicated in secretory autophagy.","method":"Lyn-/- cells, reconstitution with WT or mutant Lyn, pharmacological inhibition, viral titer, autophagosome imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue by WT but not kinase-dead/palmitoylation mutants, multiple pathway components validated","pmids":["33060596"],"is_preprint":false},{"year":2021,"finding":"CBL mutations increase LYN activation and interaction with mutant CBL, driving enhanced CBL phosphorylation, PIK3R1 (p85α) recruitment, and downstream PI3K/AKT signaling; genetic ablation or dasatinib-mediated inhibition of LYN reduces CBL phosphorylation and CBL-PIK3R1 interaction.","method":"Mass spectrometry phosphoproteomics, co-immunoprecipitation, genetic LYN ablation, dasatinib treatment, functional assays in CBL-mutant cell lines and primary CMML","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome plus Co-IP and genetic KO with functional readout, validated in primary patient samples","pmids":["33512474"],"is_preprint":false},{"year":2022,"finding":"Fumarate directly succinates LYN at cysteine C381, covalently inhibiting LYN kinase activity; this blocks BCR signaling and B-cell activation, proliferation, and antibody production in vitro and in vivo; FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation through this LYN-dependent mechanism.","method":"In vitro kinase assay, mass spectrometry for succination site (C381), fumarate hydratase inhibition, dimethyl-fumarate treatment, B-cell functional assays in vitro and in vivo","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — covalent modification site identified by MS, in vitro kinase assay, in vivo validation, multiple orthogonal approaches","pmids":["35710616"],"is_preprint":false},{"year":2023,"finding":"Constitutively activating LYN mutations (p.Y508*, p.Q507*, p.Y508F) in humans increase ICAM-1 expression on endothelial cells and β2-integrin expression on neutrophils, enhancing neutrophil adhesion and transendothelial migration, causing cutaneous vasculitis and liver fibrosis; dasatinib (Lyn inhibitor) resolved liver fibrosis in a patient.","method":"Next-generation sequencing, patient-derived endothelial cells (iECs), neutrophil adhesion/TEM assays, dasatinib treatment in patients","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variants with functional iEC and neutrophil assays and clinical treatment response, small patient numbers","pmids":["36932076"],"is_preprint":false}],"current_model":"LYN is a Src-family non-receptor tyrosine kinase that physically associates with immunoreceptors (BCR, FcεRI, IL-5Rα, EPHA2, and others) and acts as both a positive initiator and negative terminator of signaling by phosphorylating activating substrates (Syk, PLCγ, STAT3, TWIST1, GADD34, SgK269/PEAK1, band-3, FAK, DNA-PKcs) and inhibitory molecules (FcγRIIB, CD22, SHIP, SHP-1 at Y536/Y564, Cbp/PAG leading to Csk/SOCS1 recruitment and Lyn self-degradation); its subcellular trafficking from the Golgi to the plasma membrane is controlled by ACSL3 binding to the Lyn C-lobe in open conformation, its nuclear accumulation is gated by Crm1-dependent export and kinase-activity-dependent retention, and its activity is abolished by direct covalent succination at C381 by fumarate; gain-of-function mutations or context-specific overactivation of LYN drive EMT, imatinib resistance (via Bcl-2 upregulation), flavivirus egress, and inflammatory vasculitis, while loss of LYN results in BCR hyperactivation, impaired inhibitory co-receptor phosphorylation, myeloproliferation, and lupus-like autoimmunity."},"narrative":{"mechanistic_narrative":"LYN is a Src-family non-receptor tyrosine kinase that physically couples to immunoreceptors and other surface receptors to set the threshold and outcome of their signaling, functioning as both a positive initiator and a negative terminator [PMID:1702903, PMID:9547345, PMID:16272347]. In B cells, LYN associates with the antigen receptor (IgM/IgD) and is activated upon receptor cross-linking, where it engages PI3-kinase and drives Ca2+ mobilization through an IP3-independent route downstream of the BCR [PMID:1702903, PMID:8349296, PMID:8137818]. Its defining regulatory role is to phosphorylate inhibitory co-receptors and phosphatases that brake immunoreceptor signaling: LYN phosphorylates FcγRIIB and CD22 to recruit SHP-1 and SHIP [PMID:9547345], phosphorylates SHIP1 in platelets and mast cells [PMID:15166241, PMID:15210764], and activates SHP-1 via phosphorylation of Tyr536 and Tyr564 to enforce homeostatic signaling [PMID:20858858, PMID:28811476]. Accordingly, loss of LYN produces BCR/FcεRI hyperactivation, defective inhibitory co-receptor phosphorylation, myeloproliferation, and lupus-like autoimmunity, the latter mediated through unrestrained IRF5 activity and an amplified CD11b-Syk-CARD9 axis in dendritic cells [PMID:9547345, PMID:15210764, PMID:27521268, PMID:31594855]. Beyond immune cells, LYN propagates signaling from G-CSF, IL-5, erythropoietin, AMPA, and integrin/growth-factor receptors, phosphorylating substrates including Shc, STAT3, band-3, Cbp/PAG, GADD34, FAK, and SgK269/PEAK1 [PMID:7650013, PMID:17146444, PMID:8841404, PMID:11517336, PMID:11823534, PMID:16920712, PMID:24108461, PMID:23378338]. LYN activity is tightly controlled: its open-conformation C-lobe binds ACSL3 to license Golgi-to-plasma-membrane export [PMID:20605918], its nuclear accumulation is gated by Crm1-dependent export and kinase-activity-dependent retention [PMID:18817770], it is recruited to membrane rafts in a palmitoylation- and catalysis-dependent manner [PMID:28228554], and its kinase activity is covalently abolished by fumarate-mediated succination at Cys381 [PMID:35710616]. Context-specific overactivation drives EMT and metastasis via EPHA2-LYN-TWIST1 and SNAI/Vav-Rac1-PAK1 signaling [PMID:32574556, PMID:28288135], imatinib resistance through Bcl-2 upregulation [PMID:15175350], CBL-mutant PI3K/AKT signaling [PMID:33512474], and flavivirus egress through secretory autophagy [PMID:33060596]. Germline constitutively activating LYN mutations cause a human disorder of cutaneous vasculitis and liver fibrosis driven by enhanced neutrophil-endothelial adhesion [PMID:36932076].","teleology":[{"year":1991,"claim":"Established the founding physical link between LYN and an immunoreceptor, defining it as a BCR-associated kinase rather than a freely diffusing enzyme.","evidence":"Co-immunoprecipitation of Lyn and its kinase activity with membrane IgM from B cell lysates","pmids":["1702903"],"confidence":"High","gaps":["Did not define the structural basis of receptor association","No catalytic substrate identified at this stage"]},{"year":1994,"claim":"Resolved the division of labor in BCR signaling by placing LYN as a regulator of Ca2+ mobilization through an IP3-independent pathway, distinct from Syk-driven IP3 generation.","evidence":"Lyn-negative and Syk-negative B cell lines with calcium flux and IP3 measurement","pmids":["8137818"],"confidence":"High","gaps":["Molecular identity of the IP3-independent Ca2+ pathway not defined","Did not separate positive from negative LYN functions"]},{"year":1998,"claim":"Defined LYN's central negative-regulatory function by showing it phosphorylates inhibitory co-receptors FcγRIIB and CD22 to recruit phosphatases and suppress BCR signaling.","evidence":"Lyn-/- mouse B cells with Co-IP, phosphotyrosine blotting, and Ca2+ assays","pmids":["9547345"],"confidence":"High","gaps":["Did not reconcile simultaneous positive and negative roles","Phosphosites on co-receptors not exhaustively mapped"]},{"year":1998,"claim":"Extended LYN signaling beyond immunoreceptors by demonstrating a non-redundant, kinase-dependent requirement for cytokine (G-CSF) and neurotransmitter (AMPA) receptor signaling.","evidence":"lyn-deficient cell rescue with WT vs kinase-dead Lyn; AMPA receptor Co-IP with dominant-negative Lyn","pmids":["9452436","9892356"],"confidence":"High","gaps":["Direct substrate in G-CSF mitogenic pathway not fully defined","Mechanism of receptor coupling in neurons unresolved"]},{"year":2001,"claim":"Identified SH3-domain-mediated substrate selection by showing LYN binds and phosphorylates GADD34 to suppress DNA-damage-induced apoptosis in a kinase-dependent manner.","evidence":"Yeast two-hybrid, GST-SH3 pulldown, Co-IP, in vitro kinase, kinase-dead apoptosis assay","pmids":["11517336"],"confidence":"High","gaps":["In vivo relevance of GADD34 phosphorylation not established","Phosphosite on GADD34 not mapped"]},{"year":2005,"claim":"Reconciled LYN's dual nature by showing stimulation intensity determines whether LYN amplifies or dampens FcεRI signaling, switching between activating association and phosphatase recruitment.","evidence":"WT and Lyn-/- mast cells with FcεRI beta-ITAM mutants and degranulation assays","pmids":["16272347"],"confidence":"Medium","gaps":["Molecular switch governing the intensity threshold not defined","Single-lab cell-based model"]},{"year":2006,"claim":"Uncovered a self-limiting feedback circuit in which LYN phosphorylates Cbp/PAG to recruit Csk (rapid inhibition) and SOCS1 (delayed LYN degradation), defining how its own activity is terminated.","evidence":"Co-IP, phosphosite mapping (Tyr314), Csk/SOCS1 recruitment and ubiquitination assays in erythroid cells","pmids":["16920712"],"confidence":"High","gaps":["Quantitative kinetics of the two-phase shutdown not modeled","Generality across cell types not tested"]},{"year":2010,"claim":"Mapped LYN-driven phosphatase activation to specific SHP-1 tyrosines (Y536, Y564) and showed loss causes constitutive STAT5 activation and CMML-like disease, linking the negative-regulatory role to malignancy.","evidence":"In vitro kinase with phosphosite mutants and lyn-/-;PLC-β3-/- mice","pmids":["20858858"],"confidence":"High","gaps":["Did not address site-specific regulation in non-hematopoietic cells","Contribution of PLC-β3 vs LYN loss partially confounded"]},{"year":2010,"claim":"Defined the conformational gating of LYN trafficking by showing the open-conformation C-lobe binds ACSL3 to enable Golgi-to-plasma-membrane export, with Csk-induced closure blocking it.","evidence":"Co-IP, ACSL3 KD/OE, live imaging, fractionation, conformational mutants","pmids":["20605918"],"confidence":"High","gaps":["Structural detail of the C-lobe-ACSL3 interface not resolved","Signals triggering conformational switching at the Golgi unknown"]},{"year":2013,"claim":"Established a LYN function in endothelial barrier integrity by showing LYN phosphorylates FAK to stabilize adherens junctions, with loss increasing vascular permeability in vivo.","evidence":"Co-IP, phosphosite identification, Lyn-/- mice, permeability assays","pmids":["24108461"],"confidence":"High","gaps":["Upstream activator of endothelial LYN not defined","Link to the later vasculitis phenotype not made at this stage"]},{"year":2016,"claim":"Demonstrated a kinase-independent scaffolding function by showing LYN binds IRF5 to block its ubiquitination/phosphorylation, with Irf5 deletion rescuing autoimmunity in Lyn-/- mice.","evidence":"Co-IP, ubiquitination assay, kinase-inactive mutant, Lyn-/-Irf5+/- mice","pmids":["27521268"],"confidence":"High","gaps":["Structural basis of LYN-IRF5 interaction not defined","How kinase-dependent and -independent functions are partitioned unclear"]},{"year":2017,"claim":"Resolved how opposing kinases tune the same phosphatase by showing LYN activates SHP-1 (Tyr536) while Fyn inactivates it (Ser591), determining immune homeostasis versus inflammation.","evidence":"In vitro kinase assays, phospho-specific antibodies, Lyn-/- and Fyn-/- mice, SHP-1 phosphomutants","pmids":["28811476"],"confidence":"High","gaps":["Spatial/temporal coordination of LYN vs Fyn on SHP-1 in vivo not resolved"]},{"year":2020,"claim":"Defined a mechanotransduction pathway in which matrix stiffness activates EPHA2-LYN, and LYN phosphorylates TWIST1 to release it from G3BP2 and drive EMT and metastasis.","evidence":"Co-IP, phosphorylation assays, genetic KO, mechanically tunable substrates, in vivo metastasis models","pmids":["32574556"],"confidence":"High","gaps":["TWIST1 phosphosite stoichiometry in tumors not quantified","Crosstalk with other LYN EMT routes (SNAI) not integrated"]},{"year":2022,"claim":"Identified a metabolic control point by showing fumarate covalently succinates LYN at Cys381 to inhibit its kinase activity and suppress B-cell activation.","evidence":"MS succination-site mapping, in vitro kinase assay, FH inhibition and DMF treatment in vitro and in vivo","pmids":["35710616"],"confidence":"High","gaps":["Extent of succination regulation in non-B-cell contexts unknown","Reversibility of the modification in vivo not defined"]},{"year":2023,"claim":"Connected LYN gain-of-function directly to human disease, showing constitutively activating mutations enhance neutrophil-endothelial adhesion causing vasculitis and liver fibrosis, treatable with dasatinib.","evidence":"NGS of patients, patient-derived endothelial cells and neutrophil adhesion/TEM assays, dasatinib treatment","pmids":["36932076"],"confidence":"Medium","gaps":["Small patient numbers","Mechanistic link between LYN activity and ICAM-1/β2-integrin transcription not fully defined"]},{"year":null,"claim":"How LYN's intrinsic conformational state, lipid modification, subcellular trafficking, and metabolic (succination) regulation are integrated to select between its positive and negative signaling outputs in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking conformation, localization, and substrate choice","Structural basis of receptor- and substrate-specific recruitment largely undefined","In vivo dynamics of the activating/inhibitory switch not directly measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7,12,29,33,34,36]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8,23,41,44]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,29,35,36]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15,24,38]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,18,35,40]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,10,23,41]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,29,43,45]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[17,31]}],"complexes":[],"partners":["CD22","FCGR2B","SHP-1","SHIP1","CBP/PAG","FAK","IRF5","EPHA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07948","full_name":"Tyrosine-protein kinase Lyn","aliases":["Lck/Yes-related novel protein tyrosine kinase","V-yes-1 Yamaguchi sarcoma viral related oncogene homolog","p53Lyn","p56Lyn"],"length_aa":512,"mass_kda":58.6,"function":"Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Involved in the regulation of endothelial activation, neutrophil adhesion and transendothelial migration (PubMed:36932076). Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138)","subcellular_location":"Cell membrane; Nucleus; Cytoplasm; Cytoplasm, perinuclear region; Golgi apparatus; Membrane","url":"https://www.uniprot.org/uniprotkb/P07948/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LYN","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BPNT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LYN","total_profiled":1310},"omim":[{"mim_id":"620376","title":"AUTOINFLAMMATORY DISEASE, SYSTEMIC, WITH VASCULITIS; SAIDV","url":"https://www.omim.org/entry/620376"},{"mim_id":"619798","title":"E74-LIKE ETS TRANSCRIPTION FACTOR 2; ELF2","url":"https://www.omim.org/entry/619798"},{"mim_id":"617315","title":"ANTERIOR SEGMENT DYSGENESIS 6; ASGD6","url":"https://www.omim.org/entry/617315"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"616082","title":"FERRY ENDOSOMAL RAB5 EFFECTOR COMPLEX SUBUNIT 3; FERRY3","url":"https://www.omim.org/entry/616082"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":69.6},{"tissue":"lymphoid tissue","ntpm":80.3}],"url":"https://www.proteinatlas.org/search/LYN"},"hgnc":{"alias_symbol":["JTK8"],"prev_symbol":[]},"alphafold":{"accession":"P07948","domains":[{"cath_id":"2.30.30.40","chopping":"66-123","consensus_level":"high","plddt":92.5291,"start":66,"end":123},{"cath_id":"3.30.505.10","chopping":"127-212","consensus_level":"high","plddt":91.7285,"start":127,"end":212},{"cath_id":"3.30.200.20","chopping":"238-321","consensus_level":"medium","plddt":90.6446,"start":238,"end":321},{"cath_id":"1.10.510.10","chopping":"326-502","consensus_level":"medium","plddt":90.7535,"start":326,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07948","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07948-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07948-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LYN","jax_strain_url":"https://www.jax.org/strain/search?query=LYN"},"sequence":{"accession":"P07948","fasta_url":"https://rest.uniprot.org/uniprotkb/P07948.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07948/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07948"}},"corpus_meta":[{"pmid":"8137818","id":"PMC_8137818","title":"Tyrosine 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BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells.","date":"2011","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21928281","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49227,"output_tokens":10757,"usd":0.154518,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21581,"output_tokens":5089,"usd":0.117565,"stage2_stop_reason":"end_turn"},"total_usd":0.272083,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"Lyn protein and its kinase activity co-immunoprecipitate with membrane-bound IgM from B cell detergent lysates, establishing that Lyn is physically associated with the B cell antigen receptor (BCR/IgM).\",\n      \"method\": \"Co-immunoprecipitation from B cell lysates\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrated in the founding paper and independently confirmed in multiple subsequent studies across labs\",\n      \"pmids\": [\"1702903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Lyn (p56lyn and p53lyn) co-immunoprecipitates with both IgM and IgD from B cell detergent lysates; BCR cross-linking rapidly increases Lyn kinase activity and induces association of Lyn with the p85 subunit of PI3-kinase; HS1 was identified as a downstream substrate of Lyn.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and kinase assay in single lab, multiple binding partners identified\",\n      \"pmids\": [\"8349296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In Lyn-deficient B cells, BCR crosslinking produces delayed and slow Ca2+ mobilization despite normal IP3 generation kinetics, whereas Syk mediates IP3 generation; this epistasis places Lyn as regulating Ca2+ mobilization through an IP3-independent pathway downstream of BCR.\",\n      \"method\": \"Lyn-negative and Syk-negative B cell lines, calcium flux assay, IP3 measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function cell lines with multiple orthogonal readouts (Ca2+, IP3), widely replicated\",\n      \"pmids\": [\"8137818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Activation of the N-formyl peptide chemoattractant receptor (G protein-coupled) in human neutrophils stimulates Lyn kinase, which then associates with and phosphorylates the Shc adapter protein via Shc's SH2 domain; phosphorylated Lyn-Shc complexes associate with PI3-kinase, correlating with PIP3 formation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphotyrosine blotting in human neutrophils\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and kinase assay, single lab, multiple interactors identified\",\n      \"pmids\": [\"7650013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"LPS and Taxol rapidly induce autophosphorylation of Lyn (p53 and p56 isoforms) in LPS-responsive macrophages but not in LPS-hyporesponsive C3H/HeJ macrophages; tyrosine phosphatase inhibitors block LPS-induced Lyn autophosphorylation, indicating phosphatases participate in regulating Lyn kinase activity.\",\n      \"method\": \"Immunoprecipitation, in vitro kinase assay, 32P incorporation, LPS-responsive vs. hyporesponsive macrophage comparison\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with genetic model comparison, single lab\",\n      \"pmids\": [\"8521300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Lyn phosphorylates the cytoplasmic domain of band-3 protein in human erythrocytes; the Syk-catalyzed phosphorylation of band-3 is a prerequisite for Lyn membrane association and subsequent Lyn-catalyzed phosphorylation of distinct band-3 tyrosine residues.\",\n      \"method\": \"In vitro kinase assay with isolated erythrocyte membranes and purified kinases\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified components, single lab\",\n      \"pmids\": [\"8841404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lyn is required for G-CSF-induced DNA synthesis; lyn-deficient chicken B cells transfected with human G-CSFR fail to proliferate in response to G-CSF despite normal JAK1/JAK2 phosphorylation; ectopic Lyn (but not c-Src) restores mitogenic response; kinase-dead Lyn acts as dominant negative.\",\n      \"method\": \"Genetic loss-of-function (lyn-deficient cell lines), rescue with ectopic Lyn or kinase-dead mutant, thymidine incorporation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function plus gain-of-function rescue with mutagenesis, multiple orthogonal controls\",\n      \"pmids\": [\"9452436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lyn negatively regulates BCR signaling by phosphorylating the inhibitory co-receptors FcγRIIB and CD22; in lyn-/- B cells, tyrosine phosphorylation of these co-receptors is severely impaired upon BCR co-ligation, preventing recruitment of SHP-1 and SHIP, and resulting in failure to suppress Ca2+ influx and proliferation.\",\n      \"method\": \"Lyn-/- mouse B cells, co-immunoprecipitation, phosphotyrosine blotting, Ca2+ mobilization assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with multiple mechanistic readouts, replicated across labs\",\n      \"pmids\": [\"9547345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lyn directly phosphorylates STAT3 in vitro; BCR engagement activates STAT3 in a Lyn-dependent, JAK-independent manner, as shown by failure of JAK1/JAK2 antisense or the JAK inhibitor AG490 to block STAT phosphorylation.\",\n      \"method\": \"In vitro phosphorylation assay, lyn-null cell lines, antisense JAK knockdown, kinase inhibitor, EMSA\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus multiple genetic/pharmacological controls, single lab\",\n      \"pmids\": [\"17146444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lyn's SH3 domain interacts directly with DNA-PKcs near a leucine zipper homology domain; Lyn phosphorylates DNA-PKcs but not Ku in vitro; this interaction inhibits DNA-PKcs activity and its ability to form a complex with Ku/DNA.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown with SH3 domain, in vitro kinase assay, DNA-PK activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and domain mapping, single lab\",\n      \"pmids\": [\"9748231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"AMPA receptors physically associate with Lyn in the cerebellum; AMPA receptor stimulation rapidly activates Lyn independently of Ca2+ or Na2+ influx; activated Lyn then activates the MAPK pathway, leading to increased BDNF mRNA expression in a Lyn kinase-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, dominant-negative Lyn, BDNF mRNA measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional validation, dominant-negative rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"9892356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Lyn functions downstream of the G-CSF receptor; in lyn-deficient cells, G-CSF fails to induce tyrosine phosphorylation of Shc or activation of Erk1/2 or PI3-kinase/Cbl; these pathways are required for DNA synthesis; Ras activation by G-CSF is Lyn-independent.\",\n      \"method\": \"Lyn-deficient DT40 cell lines, phosphotyrosine blotting, kinase assays, dominant-negative constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple downstream readouts, single lab\",\n      \"pmids\": [\"10644984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Lyn's SH3 domain interacts with GADD34 (and murine MyD116) identified by yeast two-hybrid and confirmed by GST-SH3 pulldown and co-immunoprecipitation; Lyn phosphorylates GADD34 in vitro and in vivo; wild-type but not kinase-inactive Lyn suppresses GADD34-promoted apoptosis following DNA damage.\",\n      \"method\": \"Yeast two-hybrid, GST-SH3 pulldown, co-immunoprecipitation, in vitro kinase assay, apoptosis assay with kinase-dead mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (Y2H, pulldown, Co-IP, in vitro kinase, mutagenesis) in one study\",\n      \"pmids\": [\"11517336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In J2E erythroleukemic cells, Lyn co-immunoprecipitates with SHP-1, SHP-2, Ras-GAP, STAT5a, STAT5b, and MAPK; dominant-negative Lyn (Y397F) disrupts most of these interactions except with SHP-1; Y397F Lyn blocks erythropoietin-induced differentiation, proliferation, and reduces GATA-1 and EKLF transcription factor levels; Lyn activation requires JAK2.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant expression, cell differentiation assay, western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus dominant-negative mutagenesis, single lab\",\n      \"pmids\": [\"11289114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Lyn kinase associates with the IL-5 receptor alpha (IL-5Rα) under basal conditions in eosinophils and phosphorylates both IL-5Rα and the common beta chain (βcR) in vitro; Lyn is required for IL-5-stimulated eosinophil differentiation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, antisense oligodeoxynucleotide knockdown, Lyn-/- mouse bone marrow differentiation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with receptor substrate plus genetic KO confirmation, single lab\",\n      \"pmids\": [\"11823534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DNA-damaging agents Ara-C and daunorubicin activate Lyn and trigger its translocation into sphingomyelin-enriched membrane rafts; raft-compartmentalized Lyn activates neutral sphingomyelinase, generating ceramide; both Lyn translocation and sphingomyelinase activation are blocked by tyrosine kinase inhibitors or raft disruption.\",\n      \"method\": \"Membrane fractionation, immunoblotting, kinase assay, lipid raft disruption, inhibitor studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with functional consequence, pharmacological inhibition, single lab\",\n      \"pmids\": [\"12206990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Constitutively active Lyn (Y508F mutant), but not kinase-dead Lyn (K275D), upregulates Bcl-2 mRNA and protein expression in CML cells and protects cells from imatinib-induced apoptosis; Src kinase inhibitor PP2 reduces Lyn activation and Bcl-2 levels in resistant cells.\",\n      \"method\": \"Stable transfection of constitutively active and kinase-dead Lyn mutants, western blot, siRNA, antisense, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function with mutagenesis (active vs. kinase-dead), multiple orthogonal loss-of-function approaches, functional readout\",\n      \"pmids\": [\"15175350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism are regulated through Lyn kinase in platelets; Lyn-deficient platelets show enhanced Ca2+ flux and spreading; Lyn and SHIP1 negatively regulate integrin αIIbβ3 outside-in signaling.\",\n      \"method\": \"Lyn-/- and SHIP1-/- mouse platelets, lipid measurement, Ca2+ flux, platelet spreading assay under flow\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with multiple functional readouts, single lab\",\n      \"pmids\": [\"15166241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In lyn-/- mast cells, SHIP tyrosine phosphorylation and activity are markedly reduced, while Fyn kinase shows increased basal and stimulated phosphorylation; these changes result in prolonged FcεRI signaling with elevated PIP3 and excessive degranulation.\",\n      \"method\": \"Lyn-/- bone marrow-derived mast cells, phosphotyrosine blotting, SHIP activity assay, kinase assay, Ca2+ measurement, PIP3 measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"15210764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Lyn positively regulates FcεRI signaling and mast cell degranulation at low stimulation intensity via enhanced association with FcεRI beta subunit and activation of Akt and p38, whereas at high stimulation intensity Lyn negatively regulates signaling through the FcεRI beta-ITAM and promotes SHIP and SHP-1 association with FcεRI beta.\",\n      \"method\": \"Wild-type and Lyn-/- mast cells, FcεRI beta ITAM mutants, kinase/phosphatase association assays, degranulation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus receptor domain mutagenesis, single lab\",\n      \"pmids\": [\"16272347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In glioblastoma cells, Lyn (but not Fyn) kinase activity promotes cell migration in response to PDGFR-beta and integrin αvβ3 cooperative signaling; Lyn accounts for >90% of pan-Src kinase activity in glioblastoma tumor samples.\",\n      \"method\": \"Migration assay, selective kinase activity measurements, immunoprecipitation kinase assay from tumor biopsies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase activity measurement from tumor samples plus cell-based migration, single lab\",\n      \"pmids\": [\"15994925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"G-CSF stimulation activates Lyn and Akt in a Lyn-PI3-kinase dependent manner; inhibition of Lyn, PI3-kinase, or Akt abrogates G-CSF-induced reactive oxygen species (ROS) production; G-CSF induces serine phosphorylation and membrane translocation of p47phox (NADPH oxidase subunit) in a Lyn-dependent manner; Lyn-/- neutrophils produce less ROS than wild-type.\",\n      \"method\": \"Lyn-/- mouse neutrophils, pharmacological inhibitors, ROS measurement, p47phox phosphorylation and fractionation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse plus pharmacological validation, multiple readouts, single lab\",\n      \"pmids\": [\"16282349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Lyn is required for P. aeruginosa internalization into lung cells; Lyn activation and its interaction with lipid rafts and TLR2 are required for initial bacterial-host cell interaction; blockade of Lyn prevents bacterial internalization and downstream cytokine induction and apoptosis.\",\n      \"method\": \"Pharmacological inhibition (PP2), dominant-negative mutant, Lyn-/- bone marrow-derived mast cells, internalization assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus dominant-negative and pharmacological inhibition with functional readout, single lab\",\n      \"pmids\": [\"16791881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Lyn phosphorylates Cbp (CSK-binding protein) on tyrosine residues including Tyr314; phospho-Tyr314 recruits Csk/Ctk to suppress Lyn kinase activity (rapid phase) and also recruits SOCS1, leading to ubiquitination and degradation of Lyn (delayed phase) in erythropoietin-stimulated cells.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site mapping, Csk/SOCS1 recruitment assay, ubiquitination assay in primary erythroid cells and cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphosite mapping plus reconstitution of two-phase regulatory mechanism with multiple binding partners, functionally validated\",\n      \"pmids\": [\"16920712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-lobe of the Lyn kinase domain associates with ACSL3 on the Golgi in a conformation-dependent (open conformation required) but kinase activity-independent manner; this interaction is required for Golgi export of Lyn to the plasma membrane; CSK-induced closed conformation prevents ACSL3 association and Golgi export.\",\n      \"method\": \"Co-immunoprecipitation, ACSL3 overexpression/knockdown, live cell imaging, fractionation, domain mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD/OE, live imaging, conformational mutants) establishing trafficking mechanism\",\n      \"pmids\": [\"20605918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lyn is required for P2X4 receptor upregulation in spinal microglia after nerve injury; Lyn-/- mice show impaired fibronectin-induced P2X4R expression in microglia and reduced tactile allodynia; Lyn is the predominant Src family kinase in spinal microglia.\",\n      \"method\": \"Lyn-/- mice, immunofluorescence, western blot, behavioral assays, primary microglial culture\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with cellular mechanism (P2X4R upregulation) and behavioral readout, single lab\",\n      \"pmids\": [\"17918263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lyn nuclear localization is regulated by Crm1-mediated nuclear export and is enhanced by inhibition of Lyn kinase activity (via SU6656, Csk overexpression, or ATP-binding site mutation); lipid modification (myristoylation/palmitoylation) also limits nuclear accumulation.\",\n      \"method\": \"Leptomycin B treatment, Csk overexpression, kinase-dead mutants, immunofluorescence, nuclear fractionation in HeLa and THP-1 cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic perturbations with localization readout, single lab\",\n      \"pmids\": [\"18817770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lyn associates with αvβ3 integrin (but not αvβ5) in oligodendrocytes and brain tissue; Lyn suppresses acid sphingomyelinase (ASMase) activity; Lyn knockdown induces apoptosis with ceramide accumulation via ASMase activation; brain ischemia/reperfusion disrupts the αvβ3-Lyn complex and activates ASMase.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ASMase activity assay, ceramide measurement, brain fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional KD and enzymatic readout, single lab\",\n      \"pmids\": [\"18682390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lyn forms a complex with RANK, SHP-1, and Gab2 in osteoclast precursors; upon RANKL stimulation in Lyn-/- cells, Gab2 phosphorylation and JNK and NF-κB activation are enhanced; Lyn negatively regulates osteoclast differentiation (not activity) downstream of RANK.\",\n      \"method\": \"Co-immunoprecipitation, Lyn-/- mouse osteoclast cultures, kinase/phosphorylation assays, in vivo bone resorption assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP complex identification plus KO mouse with mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"19171907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lyn phosphorylates SHP-1 at Tyr564 (required for maximal phosphatase activity) and Tyr536 (required for efficient STAT5 interaction); in lyn-/-;PLC-β3-/- hematopoietic stem cells, both phosphorylation events are abrogated, resulting in reduced SHP-1 activity and constitutive STAT5 activation causing CMML-like disease.\",\n      \"method\": \"In vitro kinase assay with phosphosite mutants, phospho-specific antibodies, mouse genetics (double KO), STAT5 activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with phosphosite mutagenesis plus genetic mouse model validation, multiple mechanistic readouts\",\n      \"pmids\": [\"20858858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNAi-mediated knockdown of LYN in mesenchymal breast cancer lines inhibits cell migration and invasion but not proliferation; dasatinib at nanomolar concentrations blocks invasion consistent with LYN kinase inhibition.\",\n      \"method\": \"RNAi knockdown, cell migration and invasion assay, pharmacological inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with functional cellular readout, pharmacological corroboration, single lab\",\n      \"pmids\": [\"20215510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lyn is required for PECAM-1 tyrosine phosphorylation and subsequent recruitment of SHP-2 to PECAM-1 in platelets; PECAM-1-deficient and Lyn-deficient platelets show equal hyperresponsiveness to GPVI stimulation, establishing that they function in the same inhibitory pathway.\",\n      \"method\": \"PECAM-1-/- and Lyn-/- mouse platelets, PECAM-1/Lyn double-deficient mice, co-immunoprecipitation, platelet activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double KO), Co-IP, multiple functional readouts establishing pathway order\",\n      \"pmids\": [\"21297004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Yes and Lyn interact with EGFR in cetuximab-resistant cells (but not sensitive cells); knockdown of either Yes or Lyn abolishes EGFR nuclear translocation; Lyn/Yes phosphorylate EGFR at Y1101, which is required for nuclear entry; nuclear EGFR complexes bind B-Myb and iNOS promoters.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression, ChIP assay, site-directed mutagenesis (Y1101)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNAi and OE with phosphosite mutant, single lab\",\n      \"pmids\": [\"22430206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lyn associates with FAK and phosphorylates FAK at tyrosines 576/577 and 925; this Lyn-FAK interaction is required for Lyn-dependent stabilization of endothelial adherens junctions; Lyn-/- mice show increased vascular permeability in response to LPS or VEGF.\",\n      \"method\": \"Co-immunoprecipitation, constitutively active Lyn, siRNA knockdown, Lyn-/- mice, permeability assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with phosphosite identification, genetic KO mouse, gain-of-function mutant, in vivo permeability readout\",\n      \"pmids\": [\"24108461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lyn phosphorylates the atypical kinase SgK269/PEAK1 at Y635, which is a Grb2-binding site promoting Stat3 and Erk activation; SgK269 Y635F mutant fails to enhance acinar size or cellular invasion, placing Lyn upstream of SgK269 in a basal breast cancer signaling pathway.\",\n      \"method\": \"In vitro kinase substrate identification, phosphosite mutant (Y635F), 3D culture, invasion assays, Stat3/Erk activation measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with phosphosite mutagenesis and functional validation, single lab\",\n      \"pmids\": [\"23378338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lyn physically interacts with IRF5 and inhibits IRF5 ubiquitination and phosphorylation in the TLR-MyD88 pathway, thereby suppressing IRF5 transcriptional activity in a kinase activity-independent manner; monoallelic Irf5 deletion alleviates cytokine hyperproduction in Lyn-/- dendritic cells and SLE-like disease in Lyn-/- mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Lyn kinase-inactive mutant, Lyn-/-Irf5+/- double mutant mice, cytokine measurement\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, kinase-dead mutant distinguishing kinase-independent function, genetic epistasis in vivo, multiple readouts\",\n      \"pmids\": [\"27521268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lyn phosphorylates SHP-1 at tyrosine 536, activating the phosphatase and promoting inhibitory immunoreceptor signaling; by contrast, Fyn phosphorylates SHP-1 at serine 591, inactivating it and enabling activatory signaling; these opposing modifications on SHP-1 determine whether immunoreceptor signaling results in homeostasis or inflammation.\",\n      \"method\": \"In vitro kinase assays, phospho-specific antibodies, Lyn-/- and Fyn-/- mice, SHP-1 phosphomutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with site-specific mutants, genetic mouse models, replicated in vivo\",\n      \"pmids\": [\"28811476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lyn kinase controls SNAI family protein localization and stability through the Vav-Rac1-PAK1 signaling pathway; targeting Lyn in vitro reduces EMT markers and in vivo reduces metastasis of primary tumors.\",\n      \"method\": \"Lyn knockdown/inhibition, pathway inhibitors, in vivo tumor metastasis assay, EMT marker analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway placement and in vivo readout, single lab\",\n      \"pmids\": [\"28288135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPS-induced Lyn palmitoylation, SH2- and SH3-mediated interactions, and catalytic activity are all required for Lyn accumulation in membrane rafts; raft-associated Lyn negatively regulates TLR4-induced TNF-α, CCL5/RANTES production, and NF-κB/IRF3 activity in macrophages.\",\n      \"method\": \"Lyn-GFP domain mutants overexpressed in RAW264 macrophages and peritoneal macrophages, membrane fractionation, cytokine measurement, NF-κB/IRF3 reporter assays, Lyn siRNA silencing\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis panel with fractionation and functional readouts, single lab\",\n      \"pmids\": [\"28228554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LYN activity is modulated by the prolyl isomerase PIN1 in BRCA1-mutant triple-negative breast cancer; the full-length LYN splice isoform (but not the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells; LYN is a downstream effector of c-KIT in normal mammary cells.\",\n      \"method\": \"Isoform-specific expression, RNAi knockdown, migration and invasion assays, PIN1 manipulation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific loss/gain of function with functional readouts, single lab\",\n      \"pmids\": [\"30590041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CARD9 is a vital component of Lyn-mediated regulation of TLR2 and TLR4 signaling in dendritic cells; in the absence of Lyn, a CD11b-Syk-PKCδ-CARD9 pathway is amplified, leading to increased TLR-induced inflammatory cytokines; dendritic cell-specific CARD9 deletion reverses autoimmunity in Lyn-deficient mice.\",\n      \"method\": \"Lyn-/-CARD9-/- double KO mice, dendritic cell-specific CARD9 deletion, cytokine assays, pathway inhibitor studies\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with cell-type-specific KO, pathway placement, single lab\",\n      \"pmids\": [\"31594855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"High ECM stiffness induces ligand-independent phosphorylation of EPHA2, which recruits and activates LYN kinase; LYN phosphorylates TWIST1, releasing it from its cytoplasmic anchor G3BP2 to enter the nucleus and trigger EMT and invasion; genetic and pharmacological inhibition prevents breast tumor metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, siRNA/genetic KO, in vivo tumor metastasis models, mechanically tunable substrates\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus pathway dissection with genetic/pharmacological inhibition and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"32574556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lyn kinase is critical for flavivirus (Dengue, Zika) secretion within autophagosome-derived vesicles; kinase-deficient and palmitoylation-deficient Lyn mutants fail to rescue virus release in Lyn-/- cells; Lyn-dependent viral egress requires Ulk1, Rab GTPases, and SNARE complexes implicated in secretory autophagy.\",\n      \"method\": \"Lyn-/- cells, reconstitution with WT or mutant Lyn, pharmacological inhibition, viral titer, autophagosome imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue by WT but not kinase-dead/palmitoylation mutants, multiple pathway components validated\",\n      \"pmids\": [\"33060596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CBL mutations increase LYN activation and interaction with mutant CBL, driving enhanced CBL phosphorylation, PIK3R1 (p85α) recruitment, and downstream PI3K/AKT signaling; genetic ablation or dasatinib-mediated inhibition of LYN reduces CBL phosphorylation and CBL-PIK3R1 interaction.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, co-immunoprecipitation, genetic LYN ablation, dasatinib treatment, functional assays in CBL-mutant cell lines and primary CMML\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome plus Co-IP and genetic KO with functional readout, validated in primary patient samples\",\n      \"pmids\": [\"33512474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fumarate directly succinates LYN at cysteine C381, covalently inhibiting LYN kinase activity; this blocks BCR signaling and B-cell activation, proliferation, and antibody production in vitro and in vivo; FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation through this LYN-dependent mechanism.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry for succination site (C381), fumarate hydratase inhibition, dimethyl-fumarate treatment, B-cell functional assays in vitro and in vivo\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — covalent modification site identified by MS, in vitro kinase assay, in vivo validation, multiple orthogonal approaches\",\n      \"pmids\": [\"35710616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Constitutively activating LYN mutations (p.Y508*, p.Q507*, p.Y508F) in humans increase ICAM-1 expression on endothelial cells and β2-integrin expression on neutrophils, enhancing neutrophil adhesion and transendothelial migration, causing cutaneous vasculitis and liver fibrosis; dasatinib (Lyn inhibitor) resolved liver fibrosis in a patient.\",\n      \"method\": \"Next-generation sequencing, patient-derived endothelial cells (iECs), neutrophil adhesion/TEM assays, dasatinib treatment in patients\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variants with functional iEC and neutrophil assays and clinical treatment response, small patient numbers\",\n      \"pmids\": [\"36932076\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LYN is a Src-family non-receptor tyrosine kinase that physically associates with immunoreceptors (BCR, FcεRI, IL-5Rα, EPHA2, and others) and acts as both a positive initiator and negative terminator of signaling by phosphorylating activating substrates (Syk, PLCγ, STAT3, TWIST1, GADD34, SgK269/PEAK1, band-3, FAK, DNA-PKcs) and inhibitory molecules (FcγRIIB, CD22, SHIP, SHP-1 at Y536/Y564, Cbp/PAG leading to Csk/SOCS1 recruitment and Lyn self-degradation); its subcellular trafficking from the Golgi to the plasma membrane is controlled by ACSL3 binding to the Lyn C-lobe in open conformation, its nuclear accumulation is gated by Crm1-dependent export and kinase-activity-dependent retention, and its activity is abolished by direct covalent succination at C381 by fumarate; gain-of-function mutations or context-specific overactivation of LYN drive EMT, imatinib resistance (via Bcl-2 upregulation), flavivirus egress, and inflammatory vasculitis, while loss of LYN results in BCR hyperactivation, impaired inhibitory co-receptor phosphorylation, myeloproliferation, and lupus-like autoimmunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LYN is a Src-family non-receptor tyrosine kinase that physically couples to immunoreceptors and other surface receptors to set the threshold and outcome of their signaling, functioning as both a positive initiator and a negative terminator [#0, #7, #19]. In B cells, LYN associates with the antigen receptor (IgM/IgD) and is activated upon receptor cross-linking, where it engages PI3-kinase and drives Ca2+ mobilization through an IP3-independent route downstream of the BCR [#0, #1, #2]. Its defining regulatory role is to phosphorylate inhibitory co-receptors and phosphatases that brake immunoreceptor signaling: LYN phosphorylates FcγRIIB and CD22 to recruit SHP-1 and SHIP [#7], phosphorylates SHIP1 in platelets and mast cells [#17, #18], and activates SHP-1 via phosphorylation of Tyr536 and Tyr564 to enforce homeostatic signaling [#29, #36]. Accordingly, loss of LYN produces BCR/FcεRI hyperactivation, defective inhibitory co-receptor phosphorylation, myeloproliferation, and lupus-like autoimmunity, the latter mediated through unrestrained IRF5 activity and an amplified CD11b-Syk-CARD9 axis in dendritic cells [#7, #18, #35, #40]. Beyond immune cells, LYN propagates signaling from G-CSF, IL-5, erythropoietin, AMPA, and integrin/growth-factor receptors, phosphorylating substrates including Shc, STAT3, band-3, Cbp/PAG, GADD34, FAK, and SgK269/PEAK1 [#3, #8, #5, #12, #14, #23, #33, #34]. LYN activity is tightly controlled: its open-conformation C-lobe binds ACSL3 to license Golgi-to-plasma-membrane export [#24], its nuclear accumulation is gated by Crm1-dependent export and kinase-activity-dependent retention [#26], it is recruited to membrane rafts in a palmitoylation- and catalysis-dependent manner [#38], and its kinase activity is covalently abolished by fumarate-mediated succination at Cys381 [#44]. Context-specific overactivation drives EMT and metastasis via EPHA2-LYN-TWIST1 and SNAI/Vav-Rac1-PAK1 signaling [#41, #37], imatinib resistance through Bcl-2 upregulation [#16], CBL-mutant PI3K/AKT signaling [#43], and flavivirus egress through secretory autophagy [#42]. Germline constitutively activating LYN mutations cause a human disorder of cutaneous vasculitis and liver fibrosis driven by enhanced neutrophil-endothelial adhesion [#45].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the founding physical link between LYN and an immunoreceptor, defining it as a BCR-associated kinase rather than a freely diffusing enzyme.\",\n      \"evidence\": \"Co-immunoprecipitation of Lyn and its kinase activity with membrane IgM from B cell lysates\",\n      \"pmids\": [\"1702903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of receptor association\", \"No catalytic substrate identified at this stage\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved the division of labor in BCR signaling by placing LYN as a regulator of Ca2+ mobilization through an IP3-independent pathway, distinct from Syk-driven IP3 generation.\",\n      \"evidence\": \"Lyn-negative and Syk-negative B cell lines with calcium flux and IP3 measurement\",\n      \"pmids\": [\"8137818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the IP3-independent Ca2+ pathway not defined\", \"Did not separate positive from negative LYN functions\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined LYN's central negative-regulatory function by showing it phosphorylates inhibitory co-receptors FcγRIIB and CD22 to recruit phosphatases and suppress BCR signaling.\",\n      \"evidence\": \"Lyn-/- mouse B cells with Co-IP, phosphotyrosine blotting, and Ca2+ assays\",\n      \"pmids\": [\"9547345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile simultaneous positive and negative roles\", \"Phosphosites on co-receptors not exhaustively mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended LYN signaling beyond immunoreceptors by demonstrating a non-redundant, kinase-dependent requirement for cytokine (G-CSF) and neurotransmitter (AMPA) receptor signaling.\",\n      \"evidence\": \"lyn-deficient cell rescue with WT vs kinase-dead Lyn; AMPA receptor Co-IP with dominant-negative Lyn\",\n      \"pmids\": [\"9452436\", \"9892356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate in G-CSF mitogenic pathway not fully defined\", \"Mechanism of receptor coupling in neurons unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified SH3-domain-mediated substrate selection by showing LYN binds and phosphorylates GADD34 to suppress DNA-damage-induced apoptosis in a kinase-dependent manner.\",\n      \"evidence\": \"Yeast two-hybrid, GST-SH3 pulldown, Co-IP, in vitro kinase, kinase-dead apoptosis assay\",\n      \"pmids\": [\"11517336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of GADD34 phosphorylation not established\", \"Phosphosite on GADD34 not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reconciled LYN's dual nature by showing stimulation intensity determines whether LYN amplifies or dampens FcεRI signaling, switching between activating association and phosphatase recruitment.\",\n      \"evidence\": \"WT and Lyn-/- mast cells with FcεRI beta-ITAM mutants and degranulation assays\",\n      \"pmids\": [\"16272347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular switch governing the intensity threshold not defined\", \"Single-lab cell-based model\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Uncovered a self-limiting feedback circuit in which LYN phosphorylates Cbp/PAG to recruit Csk (rapid inhibition) and SOCS1 (delayed LYN degradation), defining how its own activity is terminated.\",\n      \"evidence\": \"Co-IP, phosphosite mapping (Tyr314), Csk/SOCS1 recruitment and ubiquitination assays in erythroid cells\",\n      \"pmids\": [\"16920712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative kinetics of the two-phase shutdown not modeled\", \"Generality across cell types not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped LYN-driven phosphatase activation to specific SHP-1 tyrosines (Y536, Y564) and showed loss causes constitutive STAT5 activation and CMML-like disease, linking the negative-regulatory role to malignancy.\",\n      \"evidence\": \"In vitro kinase with phosphosite mutants and lyn-/-;PLC-β3-/- mice\",\n      \"pmids\": [\"20858858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address site-specific regulation in non-hematopoietic cells\", \"Contribution of PLC-β3 vs LYN loss partially confounded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the conformational gating of LYN trafficking by showing the open-conformation C-lobe binds ACSL3 to enable Golgi-to-plasma-membrane export, with Csk-induced closure blocking it.\",\n      \"evidence\": \"Co-IP, ACSL3 KD/OE, live imaging, fractionation, conformational mutants\",\n      \"pmids\": [\"20605918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the C-lobe-ACSL3 interface not resolved\", \"Signals triggering conformational switching at the Golgi unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a LYN function in endothelial barrier integrity by showing LYN phosphorylates FAK to stabilize adherens junctions, with loss increasing vascular permeability in vivo.\",\n      \"evidence\": \"Co-IP, phosphosite identification, Lyn-/- mice, permeability assays\",\n      \"pmids\": [\"24108461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activator of endothelial LYN not defined\", \"Link to the later vasculitis phenotype not made at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a kinase-independent scaffolding function by showing LYN binds IRF5 to block its ubiquitination/phosphorylation, with Irf5 deletion rescuing autoimmunity in Lyn-/- mice.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, kinase-inactive mutant, Lyn-/-Irf5+/- mice\",\n      \"pmids\": [\"27521268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LYN-IRF5 interaction not defined\", \"How kinase-dependent and -independent functions are partitioned unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how opposing kinases tune the same phosphatase by showing LYN activates SHP-1 (Tyr536) while Fyn inactivates it (Ser591), determining immune homeostasis versus inflammation.\",\n      \"evidence\": \"In vitro kinase assays, phospho-specific antibodies, Lyn-/- and Fyn-/- mice, SHP-1 phosphomutants\",\n      \"pmids\": [\"28811476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal coordination of LYN vs Fyn on SHP-1 in vivo not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a mechanotransduction pathway in which matrix stiffness activates EPHA2-LYN, and LYN phosphorylates TWIST1 to release it from G3BP2 and drive EMT and metastasis.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, genetic KO, mechanically tunable substrates, in vivo metastasis models\",\n      \"pmids\": [\"32574556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TWIST1 phosphosite stoichiometry in tumors not quantified\", \"Crosstalk with other LYN EMT routes (SNAI) not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a metabolic control point by showing fumarate covalently succinates LYN at Cys381 to inhibit its kinase activity and suppress B-cell activation.\",\n      \"evidence\": \"MS succination-site mapping, in vitro kinase assay, FH inhibition and DMF treatment in vitro and in vivo\",\n      \"pmids\": [\"35710616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent of succination regulation in non-B-cell contexts unknown\", \"Reversibility of the modification in vivo not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected LYN gain-of-function directly to human disease, showing constitutively activating mutations enhance neutrophil-endothelial adhesion causing vasculitis and liver fibrosis, treatable with dasatinib.\",\n      \"evidence\": \"NGS of patients, patient-derived endothelial cells and neutrophil adhesion/TEM assays, dasatinib treatment\",\n      \"pmids\": [\"36932076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small patient numbers\", \"Mechanistic link between LYN activity and ICAM-1/β2-integrin transcription not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LYN's intrinsic conformational state, lipid modification, subcellular trafficking, and metabolic (succination) regulation are integrated to select between its positive and negative signaling outputs in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking conformation, localization, and substrate choice\", \"Structural basis of receptor- and substrate-specific recruitment largely undefined\", \"In vivo dynamics of the activating/inhibitory switch not directly measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7, 12, 29, 33, 34, 36]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8, 23, 41, 44]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 29, 35, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15, 24, 38]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 18, 35, 40]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 10, 23, 41]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 29, 43, 45]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [17, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD22\", \"FCGR2B\", \"SHP-1\", \"SHIP1\", \"Cbp/PAG\", \"FAK\", \"IRF5\", \"EPHA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}