{"gene":"FGR","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1984,"finding":"The v-fgr oncogene product p70gag-fgr is a hybrid protein containing a portion of actin and a tyrosine-specific protein kinase domain, indicating c-fgr arose by recombination of an actin-encoding gene and a tyrosine kinase gene.","method":"Nucleotide sequencing and computer-assisted amino acid sequence homology analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — primary sequence determination with structural interpretation; foundational paper with 233 citations","pmids":["6318314"],"is_preprint":false},{"year":1988,"finding":"The human c-fgr protooncogene encodes a 55 kDa protein (p55c-fgr) with a unique N-terminal domain (first 75 amino acids) distinct from other Src family members, followed by a conserved kinase domain; the protein was confirmed by antibodies to predicted peptide sequences.","method":"cDNA sequencing, COS-1 cell transfection, immunoprecipitation with antipeptide antibodies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — direct protein identification by sequencing and immunoprecipitation, replicated across labs","pmids":["3275868"],"is_preprint":false},{"year":1989,"finding":"p55c-fgr is enzymatically active as a protein tyrosine kinase in differentiated myelomonocytic cells, is localized to peripheral cell membranes, and membrane association is mediated by covalent attachment of a myristyl group.","method":"Immune complex kinase assay, subcellular fractionation, myristoylation analysis in HL60 cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus biochemical fractionation and lipid modification analysis","pmids":["2687293"],"is_preprint":false},{"year":1989,"finding":"p55c-fgr is associated with functional secretory (secondary) granules in neutrophils and redistributes to the plasma membrane fraction upon activation with the chemoattractant peptide fMLP, demonstrating stimulus-dependent translocation.","method":"Subcellular fractionation, immune complex kinase assay, formyl-Met-Leu-Phe stimulation of human neutrophils","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct fractionation with functional kinase readout; replicated by later studies","pmids":["2682659"],"is_preprint":false},{"year":1993,"finding":"Fgr physically associates with IgG Fc receptor II (FcγRII) but not FcγRIII in human neutrophils, and crosslinking of FcγRII induces rapid increase in Fgr tyrosine kinase activity and co-modulation of Fgr.","method":"Co-immunoprecipitation from neutrophil detergent lysates, immune complex kinase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with functional kinase activity measurement; 137 citations","pmids":["8327512"],"is_preprint":false},{"year":1994,"finding":"Beta 2 integrin-dependent adhesion to fibrinogen activates Fgr kinase activity and increases its tyrosine phosphorylation in human neutrophils; this activation requires β2 integrin expression (absent in LAD patient neutrophils) and is blocked by anti-CD18 antibodies.","method":"Immune complex kinase assay, LAD patient neutrophils, anti-CD18 blocking antibodies, fibrinogen adhesion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches including genetic (LAD) and antibody blocking; 151 citations","pmids":["7519620"],"is_preprint":false},{"year":1994,"finding":"CSK (C-terminal Src kinase) phosphorylates c-Fgr at Tyr-511 (homologous to Src Tyr-527) and thereby down-regulates Fgr activity; this prevents autophosphorylation at the activation loop Tyr-400. Polycationic effectors stimulate Fgr and promote autophosphorylation at both Tyr-400 and Tyr-511, rendering Fgr insensitive to CSK down-regulation.","method":"In vitro kinase assay with purified proteins, site-directed mutagenesis implied by phosphosite analysis, CSK phosphorylation reconstitution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with defined phosphosites and regulatory outcome","pmids":["7515063"],"is_preprint":false},{"year":1994,"finding":"Targeted disruption of both hck and fgr (double knockout) reveals functional overlap: loss of both kinases results in immunodeficiency with increased susceptibility to Listeria infection, while single knockouts have milder phenotypes; Lyn specific activity is increased in hck−/− macrophages, suggesting compensatory upregulation.","method":"Gene targeting/knockout mice, Listeria infection model, immune complex kinase assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined in vivo phenotype; 201 citations","pmids":["8125254"],"is_preprint":false},{"year":1995,"finding":"Fgr kinase activity in adherent neutrophils strictly correlates with beta 2 integrin-mediated adhesion; divalent cation Mg2+ (but not Ca2+ alone) is required for adhesion and concurrent Fgr activation, and Fgr redistributes to a Triton X-100-insoluble cytoskeletal fraction with enhanced kinase activity upon adhesion.","method":"Immune complex kinase assay, divalent cation manipulation, Triton X-100 fractionation, anti-CD18 blocking","journal":"Journal of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but single lab","pmids":["8867673"],"is_preprint":false},{"year":1996,"finding":"Loss of both Hck and Fgr (double knockout) in neutrophils abolishes adhesion-dependent respiratory burst and cell spreading on ECM proteins (fibrinogen, fibronectin, collagen) and on ICAM-1, demonstrating that either Hck or Fgr is required for beta 2/beta 3 integrin signaling leading to cytoskeletal rearrangement and superoxide production.","method":"hck−/−fgr−/− knockout mice, respiratory burst assay, cell adhesion and spreading microscopy, integrin crosslinking with mAbs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple functional readouts; replicated; 306 citations","pmids":["8666673"],"is_preprint":false},{"year":1996,"finding":"Reactive oxygen intermediates (ROI) produced by adherent neutrophils activate Fgr and Lyn kinase activities; inhibition of NADPH oxidase or addition of catalase suppresses adhesion-stimulated Fgr activity, and Fgr activity is reduced in CGD neutrophils deficient in ROI production. Exogenous H2O2 activates Fgr in non-adherent neutrophils.","method":"Immune complex kinase assay, NADPH oxidase inhibitor diphenylene iodonium, catalase addition, CGD patient neutrophils, exogenous H2O2 treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary approaches including genetic (CGD) and pharmacological; 86 citations","pmids":["8798554"],"is_preprint":false},{"year":1996,"finding":"Fgr (and Lyn) redistribute to a Triton X-100-insoluble fraction containing cytoskeletal proteins and caveolin upon PMA stimulation in neutrophils, and it is this fraction of Fgr that displays enhanced kinase activity, suggesting Fgr functions within caveolar/cytoskeletal multimolecular complexes.","method":"Triton X-100 and OGP detergent fractionation, immune complex kinase assay, caveolin co-fractionation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation with kinase assay, single lab","pmids":["8603737"],"is_preprint":false},{"year":1996,"finding":"Fgr and Hck are required for normal erythrocyte K/Cl cotransport regulation: fgr−/−hck−/− double knockout erythrocytes exhibit ~3-fold elevated K/Cl cotransport activity. The mechanism involves Fgr/Hck acting as kinases that negatively regulate a phosphatase which activates the K/Cl cotransporter.","method":"fgr−/−hck−/− knockout mouse erythrocytes, ion transport assays, okadaic acid and staurosporine pharmacology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined ion transport phenotype and pharmacological dissection; 94 citations","pmids":["9005990"],"is_preprint":false},{"year":1996,"finding":"Fgr and Lyn kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells; Fgr activity and tyrosine phosphorylation increase during differentiation and decrease at the onset of apoptosis, and antisense knockdown of Fgr causes premature apoptotic death.","method":"HL-60 differentiation model, immune complex kinase assay, antisense oligodeoxynucleotide knockdown, PTK inhibitor treatment (herbimycin A, genistein)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — kinase assay plus antisense KD with functional outcome; single lab","pmids":["8626717"],"is_preprint":false},{"year":1997,"finding":"Fgr and Lyn are activated in distinct subcellular membrane fractions of human granulocytes: Fgr is activated in the 11,000g fraction (heavier membranes) while Lyn is activated in the 200,000g fraction (light membranes), and distinct sets of tyrosine-phosphorylated proteins are found in each fraction. fMLP selectively activates Lyn but not Fgr, while opsonized zymosan activates both.","method":"Subcellular fractionation of differentiated NB4 cells and human neutrophils, immune complex kinase assay, stimulus comparison (fMLP, opsonized zymosan, A23187)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — fractionation with kinase assays and stimulus specificity; single lab","pmids":["9366519"],"is_preprint":false},{"year":1997,"finding":"Src family kinases Fgr, Fyn, Lck, and Lyn colocalize with clathrin-coated membranes (coated pits and coated vesicles) in platelets, distinct from Src which is not in these compartments, suggesting a role for Fgr in endocytotic vesicle-mediated trafficking.","method":"Immunoelectron microscopy with anti-kinase and anti-clathrin antibodies in platelets","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — direct ultrastructural localization; single lab, single method","pmids":["9116282"],"is_preprint":false},{"year":1997,"finding":"The optimal peptide substrate sequence recognized by c-Fgr (XEEIYGIFF) differs from CSK and Lyn, with selection for a hydrophobic residue at the +1 position; CSK phosphorylates the C-terminal regulatory tyrosine of c-Fgr with similar kinetics as Lyn.","method":"Oriented peptide library screening, in vitro kinase assays with synthetic peptides, Km/kcat determination","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with substrate library and kinetic analysis","pmids":["9208935"],"is_preprint":false},{"year":1998,"finding":"hck−/−fgr−/− mice are resistant to lethal LPS-induced endotoxic shock and show reduced neutrophil migration into liver tissue; despite high serum TNF-α and IL-1α, hepatic and renal injury are markedly reduced, demonstrating that Hck/Fgr-dependent integrin signaling in neutrophils is required for LPS-induced tissue damage in vivo.","method":"hck−/−fgr−/− knockout mice, LPS injection model, serum cytokine ELISA, liver histology, blood counts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined in vivo inflammatory phenotype; 139 citations","pmids":["9636192"],"is_preprint":false},{"year":1999,"finding":"Adhesion-dependent degranulation (lactoferrin secretion) in neutrophils requires both Fgr and Hck; hck−/−fgr−/− PMN adherent to collagen or fibrinogen fail to release lactoferrin in response to TNF-α but respond normally to PMA (adhesion-independent). Src kinase inhibitor PP1 reproduces the defect, identifying Fgr/Hck in a pathway linking integrin engagement to granule-plasma membrane fusion.","method":"hck−/−fgr−/− knockout mouse PMNs, lactoferrin ELISA, PP1 pharmacological inhibition, TNF-α stimulation on ECM substrates","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO corroborated by pharmacological inhibition with defined secretory phenotype; 164 citations","pmids":["9916742"],"is_preprint":false},{"year":1999,"finding":"Hck and Fgr are required for integrin-mediated signal transduction in macrophages: hck−/−fgr−/− macrophages on fibronectin show markedly reduced tyrosine phosphorylation of cortactin, paxillin, tensin, and activation of Syk and Pyk2; focal adhesion proteins fail to polarize; filopodia are absent; and cell motility is reduced.","method":"hck−/−fgr−/− knockout macrophages, anti-phosphotyrosine immunoblotting, immunofluorescence for focal adhesion proteins, migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical and morphological readouts in clean genetic KO; 129 citations","pmids":["10547366"],"is_preprint":false},{"year":1999,"finding":"c-Fgr phosphorylates HS1 hematopoietic protein at Tyr-222 via SH2 domain-dependent docking to a prior Syk phosphorylation site; stable association of phospho-HS1 with the c-Fgr SH2 domain requires prior Fgr autophosphorylation and is prevented by subsequent Tyr-222 phosphorylation, establishing a sequential phosphorylation mechanism.","method":"In vitro kinase assays with purified proteins, peptide mapping, phosphosite identification, SH2 domain binding assays, kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with phosphosite mapping and kinetic characterization","pmids":["10066823"],"is_preprint":false},{"year":1999,"finding":"Hck and c-Fgr associate with the chemokine receptor CCR3 in human eosinophils upon eotaxin stimulation; this association occurs after CCR3 internalization and correlates with tyrosine phosphorylation and actin reorganization required for chemotaxis.","method":"Co-immunoprecipitation, immunofluorescence, herbimycin A inhibition, eotaxin stimulation of human eosinophils","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP with functional correlation; single lab","pmids":["10527858"],"is_preprint":false},{"year":2000,"finding":"FcγR-mediated phagocytosis, respiratory burst, actin cup formation, and activation of Syk, PI3K, and ERK1/2 are all diminished or delayed in macrophages lacking Hck, Fgr, and Lyn, placing these Src kinases upstream of Syk activation and actin polymerization in FcγR signaling.","method":"hck−/−fgr−/−lyn−/− triple knockout macrophages, phagocytosis assay, respiratory burst, immunoblotting for signaling intermediates","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean triple KO with multiple orthogonal functional and signaling readouts; 201 citations","pmids":["10684859"],"is_preprint":false},{"year":2000,"finding":"Fgr negatively regulates FcγR- and CR3-mediated phagocytosis in macrophages independently of its tyrosine kinase activity; after FcγR crosslinking, Fgr associates with the ITIM-containing receptor SIRPα and potentiates SHP-1 phosphatase association with SIRPα, thereby dampening positive phagocytic signaling.","method":"Fgr overexpression in macrophage cell line and primary macrophages, phagocytosis assay, co-immunoprecipitation of Fgr with SIRPα and SHP-1, kinase-dead Fgr mutant","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function plus co-IP with mechanistic dissection using kinase-dead mutant; 76 citations","pmids":["10662797"],"is_preprint":false},{"year":2000,"finding":"Phosphatidic acid (PA) specifically enhances Fgr tyrosine kinase activity in neutrophil cytosol; among all Src family kinases in neutrophils, only Fgr elutes in the PA-dependent Tyr phosphorylating activity fraction, and PA directly increases Fgr activity in cell-free assays.","method":"Gel filtration chromatography of neutrophil cytosol, immune complex kinase assay, PA addition to cell-free system, phospholipid selectivity analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — cell-free biochemical reconstitution, single lab","pmids":["11078731"],"is_preprint":false},{"year":2001,"finding":"Fgr is a negative regulator of beta 2 integrin signaling and Syk kinase in monocytes; Fgr inhibits beta 2 (but not beta 1) integrin signaling and Syk function via direct association between the Fgr SH2 domain and Syk phospho-Tyr342, and this inhibitory effect is independent of Fgr kinase activity but dose-dependent, overcome by chemokines.","method":"Co-immunoprecipitation, Fgr SH2 domain binding assay to Syk pY342, monocyte spreading assay, Syk kinase activity assay, kinase-dead Fgr mutants","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — direct SH2-phosphosite interaction mapped with multiple functional assays; 72 citations","pmids":["11672534"],"is_preprint":false},{"year":2004,"finding":"Fgr phosphorylates phospholipase D2 (PLD2) at multiple tyrosines (Y11, Y14, Y165, Y470) in mast cells, together with Fyn; this phosphorylation activates PLD2 and promotes degranulation in FcεRI-stimulated RBL-2H3 cells. Fgr siRNA knockdown blocks PLD2 phosphorylation.","method":"siRNA knockdown, overexpression of kinases, site-directed mutagenesis of PLD2 tyrosines, HA-PLD2 immunoprecipitation kinase assay, degranulation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of substrate phosphosites combined with siRNA and overexpression; 31 citations","pmids":["15282299"],"is_preprint":false},{"year":2004,"finding":"BCR-ABL1 activates the Src kinases Lyn, Hck, and Fgr in B-lymphoid cells; marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL upon BCR-ABL1 transduction, demonstrating that these Src kinases are required for B-ALL but not CML induced by BCR-ABL1.","method":"Retroviral transduction of triple-KO (lyn−/−hck−/−fgr−/−) bone marrow, leukemia mouse model, kinase inhibitor CGP76030","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis in vivo plus pharmacological validation; 327 citations","pmids":["15098032"],"is_preprint":false},{"year":2005,"finding":"Hck and Fgr negatively regulate myeloid cell chemokine signaling; hck−/−fgr−/− neutrophils are hyperresponsive to multiple chemokines (elevated Ca2+ flux, MAP kinase, actin polymerization, chemotaxis). This negative regulation is mediated through the inhibitory receptor PIR-B, which Hck and Fgr maintain in a tonically phosphorylated, active inhibitory state.","method":"hck−/−fgr−/− knockout mice, pir-b−/− mice, Ca2+ flux assay, MAPK assays, chemotaxis assays, PIR-B phosphorylation state analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — double KO and receptor KO with multiple functional readouts and phosphorylation analysis; 85 citations","pmids":["15723811"],"is_preprint":false},{"year":2005,"finding":"Membrane localization of Fgr is required for its role in cell migration; full-length membrane-bound Fgr increases migration on fibronectin and phosphorylation of PI3K p85, cortactin, FAK Y397/Y576, activates Rac via Vav2 phosphorylation, and forms a complex with p190RhoGAP/FAK. An N-terminal truncation mutant lacking membrane targeting fails to do so.","method":"COS-7 cell transfection with wild-type, truncation and kinase-dead Fgr mutants, migration assay, co-immunoprecipitation, Rac GTP-loading assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis (truncation mutants) with multiple signaling and functional readouts; 15 citations but mechanistically detailed","pmids":["15561106"],"is_preprint":false},{"year":2006,"finding":"Hck and Fgr regulate outside-in beta 2 integrin signaling (cell spreading and sustained adhesion) but not inside-out chemoattractant-induced integrin affinity or clustering; hck−/−fgr−/− neutrophils detach after initial binding and have reduced arrest in inflamed venules >60 µm.","method":"hck−/−fgr−/− knockout neutrophils, soluble ICAM-1 binding, static adhesion assay, flow chamber, intravital microscopy","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — KO mice with in vitro and in vivo readouts distinguishing inside-out from outside-in signaling; 93 citations","pmids":["16785558"],"is_preprint":false},{"year":2007,"finding":"Fgr (and Hck) regulate fMLP-induced respiratory burst and F-actin polymerization in neutrophils through a signaling pathway involving phosphorylation of the Rho/Rac GEF Vav1 and activation of p21-activated kinases (PAKs), leading to Rac2 activation; Ca2+ flux and PI3K/Akt activation are Fgr/Hck-independent.","method":"hck−/−fgr−/− knockout neutrophils, PP2 Src inhibitor, respiratory burst assay, F-actin assay, MAPK/Vav1/PAK phosphorylation immunoblotting, Rac2 GTP pulldown","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — KO plus pharmacological inhibition with pathway dissection using multiple signaling assays; 85 citations","pmids":["17339487"],"is_preprint":false},{"year":2007,"finding":"Fgr phosphorylates the flavoprotein subunit of succinate dehydrogenase (FpSDH) at Y535 and Y596, and aconitase at Y71, Y544, and Y665, identifying these mitochondrial enzymes as in vitro substrates of Fgr.","method":"In vitro kinase assay with recombinant Fgr and mitochondrial substrate proteins, mass spectrometry phosphosite mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro phosphorylation with MS-based site identification, but in vitro only; single lab","pmids":["17997986"],"is_preprint":false},{"year":2008,"finding":"E-selectin engagement of PSGL-1 signals through the Src family kinase Fgr (and Hck/Lyn) and the ITAM-containing adaptor proteins DAP12 and FcRγ to phosphorylate Syk and p38 MAPK, initiating slow neutrophil rolling; fgr−/− neutrophils abolish E-selectin-mediated Syk phosphorylation and slow rolling.","method":"fgr−/−, hck−/−lyn−/−fgr−/−, Tyrobp−/−Fcrg−/− gene-deficient mice, flow chamber, intravital microscopy, Syk/p38 phosphorylation assay, mixed chimeric mice peritonitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple gene-deficient mouse models with in vitro and in vivo validation; 168 citations","pmids":["18794338"],"is_preprint":false},{"year":2011,"finding":"Fgr associates with FcεRI in mast cells and promotes phosphorylation of Syk and its substrates (LAT, SLP76, Gab2) and downstream targets (Akt, MAPKs) upon antigen stimulation; Fgr siRNA knockdown reduces degranulation, eicosanoid and cytokine production, and IgE-mediated anaphylaxis in vivo.","method":"Fgr siRNA knockdown in mast cells and mice, Fgr overexpression, co-immunoprecipitation with FcεRI, phospho-immunoblotting, degranulation assay, anaphylaxis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — co-IP plus siRNA KD with multiple mechanistic and in vivo readouts; 44 citations","pmids":["21746961"],"is_preprint":false},{"year":2014,"finding":"Fgr is activated by hydrogen peroxide (ROS) and phosphorylates the flavoprotein subunit of Complex II (FpSDH), increasing Complex II activity and superassembly to adjust mitochondrial metabolism (NADH/FADH2 balance); ablation of Fgr or mutation of the FpSDH target tyrosine abolishes metabolic adaptation during nutrient restriction, hypoxia/reoxygenation, and T cell activation.","method":"Fgr knockout cells and mice, FpSDH tyrosine point mutant, Complex II activity assay, supercomplex analysis, H2O2 activation of Fgr, metabolic assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 — substrate mutagenesis combined with KO, in vitro and in vivo metabolic readouts; 100 citations","pmids":["24856931"],"is_preprint":false},{"year":2015,"finding":"Fgr phosphorylates TBK1 at Tyr354 and Tyr394 (together with Hck and Lck), preventing TBK1 dimerization and activation; this constitutes a negative feedback loop in antiviral innate immunity in which viral infection induces Fgr expression via TBK1-IRF3, and Fgr then dampens antiviral responses.","method":"Triple KO cells (Lck/Hck/Fgr), ectopic kinase expression, phospho-TBK1 antibodies, TBK1 dimerization assay, zebrafish and mouse viral infection models","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — KO plus overexpression with mechanistic phosphosite identification and in vivo validation; 39 citations","pmids":["28618271"],"is_preprint":false},{"year":2015,"finding":"FCRL4 is phosphorylated on tyrosine residues by HCK (p59 isoform) and FGR; this phosphorylation requires palmitoylation of FCRL4 and modulates MAPK/Elk-1 signaling in opposite directions (FGR-inhibitory, HCK-activating) and upregulates IL-10 or IFN-γ production in memory B cells.","method":"Reporter gene assays, FCRL4 palmitoylation-defective mutant, overexpression of HCK/FGR in B cells, phospho-tyrosine immunoblotting","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression system with functional readouts; single lab","pmids":["25972488"],"is_preprint":false},{"year":2016,"finding":"Src kinases Hck, Fgr, and Lyn are required for IgG-mediated phagocytosis of Leishmania amastigotes by macrophages; Fgr/Hck/Lyn activate the non-receptor tyrosine kinase Arg (Abl2), and Src-mediated Arg activation is required for efficient amastigote uptake.","method":"Primary macrophages from single and combined SFK KO mice, small-molecule Src/Arg inhibitors, phagocytosis assay, Leishmania mouse infection model with bosutinib","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO plus pharmacological inhibition with defined phagocytic phenotype; single lab","pmids":["27358479"],"is_preprint":false},{"year":2018,"finding":"Fgr functions as a transforming oncoprotein independently of SH3-SH2 regulatory domain control; wild-type Fgr (without activating mutations) promotes Rat-2 fibroblast transformation; the Fgr activation loop contains a unique Pro at the +2 position relative to the activation loop Tyr, and substitution with the Src sequence reduces kinase activity and colony formation. Hydrogen-deuterium exchange shows SH3-SH2 domains still pack against the kinase domain but fail to suppress its activity.","method":"Soft agar colony formation assay in Rat-2 fibroblasts, activation loop mutagenesis, hydrogen-deuterium exchange mass spectrometry, SH3-SH2 ligand activation assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis + HDX-MS structural analysis + functional transformation assay; 30 citations","pmids":["30352950"],"is_preprint":false},{"year":2018,"finding":"Fgr is a high-potency kinase inhibitor target in AML; a selective N-phenylbenzamide inhibitor TL02-59 with picomolar potency against Fgr suppresses AML cell proliferation correlated with Fgr/Hck/Lyn expression levels, and oral TL02-59 eliminates leukemic cells from spleen and blood in a xenograft mouse model.","method":"Kinome-wide target profiling, in vitro kinase assay, AML patient bone marrow samples, xenograft mouse model, oral drug administration","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro kinase assay + patient samples + in vivo xenograft; 39 citations","pmids":["29763550"],"is_preprint":false},{"year":2020,"finding":"Fgr kinase is activated by mitochondrial ROS in bone marrow-derived macrophages and is required for proinflammatory macrophage polarization; ablation of Fgr in BM-derived cells protects against HFD-induced insulin resistance and liver steatosis, and transfer of Fgr-expressing BM cells reverts protection. Scavenging mitochondrial peroxides prevents Fgr activation.","method":"Fgr knockout mice, BM transplantation chimeras, HFD feeding model, mitochondrial peroxide scavenging, flow cytometry for macrophage polarization","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — BM reconstitution plus KO with multiple in vivo and in vitro mechanistic readouts; 59 citations","pmids":["32943786"],"is_preprint":false},{"year":2020,"finding":"Fgr is upregulated in thalamic microglia after hemorrhage, participates in microglial activation and TNF-α production via NF-κB and ERK1/2 pathways, and contributes to thalamic pain; pharmacological inhibition or genetic knockdown of Fgr attenuates hemorrhage-induced thalamic injury and pain hypersensitivities.","method":"Collagenase/autologous blood thalamic hemorrhage model, Fgr siRNA knockdown, Fgr inhibitor, NF-κB and ERK1/2 phospho-immunoblotting, cytokine ELISA, behavioral pain tests","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — KD + pharmacological inhibition in vivo with pathway readouts; single lab","pmids":["33055425"],"is_preprint":false},{"year":2005,"finding":"Fgr is associated with Protein Phosphatase 1α (PP1α) in erythrocytes; peroxynitrite activates Fgr, which then phosphorylates PP1α on tyrosine, inhibiting PP1α enzymatic activity and thereby regulating K/Cl cotransport.","method":"Mouse erythrocyte cell-free system, peroxynitrite treatment, Fgr immune complex kinase assay, PP1α activity assay, fgr/hck KO erythrocytes","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KO cells plus in vitro kinase/phosphatase assays; single lab","pmids":["15917191"],"is_preprint":false}],"current_model":"FGR encodes a Src-family nonreceptor tyrosine kinase expressed in myeloid cells (neutrophils, monocytes, macrophages, mast cells) that is anchored to the plasma membrane via N-terminal myristoylation and is activated downstream of β2 integrins, Fc receptors (FcγRII, FcεRI), selectin-PSGL-1, and reactive oxygen species/H2O2; once active, it phosphorylates a defined set of substrates including the FpSDH subunit of mitochondrial Complex II, PLD2, HS1, PP1α, and TBK1, and signals through Vav1-Rac-PAK, FAK-p190RhoGAP, and SIRPα-SHP-1 axes to regulate neutrophil respiratory burst, degranulation, spreading, chemokine secretion, mast cell degranulation, macrophage phagocytosis, mitochondrial fuel switching, and innate antiviral responses, while its kinase domain uniquely escapes SH3-SH2 autoinhibitory control due to a proline at the +2 position of the activation loop."},"narrative":{"teleology":[{"year":1984,"claim":"Determining FGR's origin as a tyrosine kinase gene fused with actin sequences in v-fgr established that the cellular proto-oncogene encodes a tyrosine kinase, framing all subsequent functional studies.","evidence":"Nucleotide sequencing and homology analysis of the v-fgr oncogene","pmids":["6318314"],"confidence":"High","gaps":["No information on normal cellular function or expression pattern","Protein product of the cellular gene not yet identified"]},{"year":1989,"claim":"Identification of p55c-Fgr as a myristoylated, membrane-associated tyrosine kinase in differentiated myelomonocytic cells and neutrophil granules resolved where and when the kinase is active, revealing stimulus-dependent translocation from secretory granules to the plasma membrane.","evidence":"Immune complex kinase assays, subcellular fractionation, myristoylation analysis in HL-60 and human neutrophils, fMLP stimulation","pmids":["3275868","2687293","2682659"],"confidence":"High","gaps":["Upstream activating signals not yet defined","No substrates identified"]},{"year":1994,"claim":"Discovery that β2 integrin adhesion activates FGR and that FcγRII physically associates with and activates FGR identified the two principal receptor systems upstream of FGR, while CSK-mediated Tyr-511 phosphorylation defined the negative regulatory mechanism.","evidence":"Immune complex kinase assays with anti-CD18 blocking, LAD patient neutrophils, co-IP of Fgr with FcγRII, in vitro CSK reconstitution with phosphosite analysis","pmids":["7519620","8327512","7515063"],"confidence":"High","gaps":["Downstream signaling pathways not yet mapped","Relative contributions of FGR versus other SFKs unresolved"]},{"year":1996,"claim":"Hck/Fgr double-knockout mice revealed that these kinases are collectively essential for integrin-dependent respiratory burst, cell spreading, neutrophil-mediated tissue damage in endotoxemia, and erythrocyte K/Cl cotransport regulation, establishing FGR's non-redundant in vivo roles in innate immunity and ion homeostasis.","evidence":"hck−/−fgr−/− knockout mice with respiratory burst, spreading, Listeria/LPS infection models, and erythrocyte ion transport assays","pmids":["8125254","8666673","9636192","9005990"],"confidence":"High","gaps":["Individual contributions of Fgr versus Hck not fully separated due to redundancy","Substrates mediating these phenotypes unknown","Reactive oxygen intermediate–mediated activation mechanism not yet molecularly defined"]},{"year":1999,"claim":"Identification of HS1, cortactin, paxillin, and other focal adhesion proteins as downstream targets, together with the demonstration that Fgr/Hck are required for integrin-dependent degranulation, defined the signaling layer between integrin-activated SFKs and effector functions in neutrophils and macrophages.","evidence":"In vitro kinase assays with phosphosite mapping (HS1 Tyr-222), hck−/−fgr−/− macrophage signaling and morphology analysis, lactoferrin degranulation assay with PP1 inhibitor","pmids":["10066823","10547366","9916742"],"confidence":"High","gaps":["HS1 phosphorylation shown in vitro, in vivo relevance not confirmed","Link between cortactin/paxillin phosphorylation and specific effector outputs unclear"]},{"year":2000,"claim":"Demonstrating that FGR negatively regulates phagocytosis by recruiting SHP-1 to SIRPα independently of kinase activity, and separately inhibits Syk via SH2 domain sequestration, revealed that FGR functions as both a positive kinase and a kinase-independent negative scaffolding adaptor depending on context.","evidence":"Kinase-dead Fgr mutant overexpression, co-IP of Fgr–SIRPα–SHP-1, Fgr SH2 domain binding to Syk pY342, phagocytosis assays","pmids":["10662797","11672534"],"confidence":"High","gaps":["How the balance between positive and negative signaling is controlled in single cells remains unknown","Structural basis for kinase-independent adaptor function not determined"]},{"year":2005,"claim":"Mapping FGR's regulation of cell migration through Vav2/Rac and FAK/p190RhoGAP complexes, and its tonic phosphorylation of PIR-B to restrain chemokine hyperresponsiveness, clarified two additional signaling axes and established FGR as a set-point regulator of myeloid cell activation thresholds.","evidence":"COS-7 Fgr mutant transfections with Rac GTP pulldown, hck−/−fgr−/− and pir-b−/− mice with chemotaxis/Ca2+ flux assays, PP1α phosphorylation in erythrocytes","pmids":["15561106","15723811","15917191"],"confidence":"High","gaps":["Direct structural evidence for Fgr–PIR-B interaction lacking","PP1α tyrosine phosphosite not mapped"]},{"year":2008,"claim":"Identification of the selectin–PSGL-1–SFK–ITAM adaptor (DAP12/FcRγ)–Syk signaling axis in slow neutrophil rolling, with fgr−/− neutrophils specifically abolishing E-selectin-mediated Syk phosphorylation, placed FGR upstream of a novel innate immune adhesion pathway distinct from integrin outside-in signaling.","evidence":"fgr−/−, hck−/−lyn−/−fgr−/−, and DAP12/FcRγ KO mice with flow chamber, intravital microscopy, and Syk phosphorylation assays","pmids":["18794338"],"confidence":"High","gaps":["How FGR is specifically activated by PSGL-1 engagement vs other SFKs is unclear","ITAM adaptor phosphorylation by FGR not directly shown"]},{"year":2014,"claim":"Discovery that ROS-activated FGR phosphorylates the flavoprotein subunit of Complex II (FpSDH) to increase succinate dehydrogenase activity and adjust mitochondrial fuel utilization expanded FGR's role beyond immune signaling to metabolic adaptation during nutrient stress, hypoxia, and T cell activation.","evidence":"Fgr KO mice, FpSDH tyrosine point mutant, Complex II activity and supercomplex analysis, H2O2 activation of Fgr","pmids":["24856931"],"confidence":"High","gaps":["How FGR accesses the mitochondrial matrix (intermembrane space vs import) is undefined","Whether FGR regulation of Complex II operates in all cell types or only myeloid cells is unclear"]},{"year":2017,"claim":"Identification of TBK1 as a direct FGR substrate (Tyr354/Tyr394 phosphorylation preventing TBK1 dimerization) established a negative feedback loop in antiviral innate immunity: viral infection induces FGR via TBK1–IRF3, and FGR then restrains TBK1, connecting FGR to type I interferon regulation.","evidence":"Triple KO cells, ectopic kinase expression, phospho-TBK1 antibodies, TBK1 dimerization assay, zebrafish and mouse viral infection models","pmids":["28618271"],"confidence":"High","gaps":["Relative contribution of FGR versus Hck and Lck in TBK1 regulation in primary cells not resolved","Temporal dynamics of the feedback loop in natural infection unknown"]},{"year":2018,"claim":"Structural and functional demonstration that wild-type FGR escapes SH3-SH2 autoinhibition due to a unique activation-loop Pro+2 residue, conferring intrinsic transforming capacity and explaining why FGR is constitutively more active than other SFKs, provided the first structural rationale for FGR's oncogenic potential in AML.","evidence":"HDX-MS of SH3-SH2-kinase domain constructs, activation-loop mutagenesis, Rat-2 transformation assay, picomolar Fgr inhibitor TL02-59 in AML xenografts","pmids":["30352950","29763550"],"confidence":"High","gaps":["Full crystal structure of autoinhibited Fgr not available","Selectivity of TL02-59 among closely related SFKs in vivo not fully profiled"]},{"year":2020,"claim":"Demonstrating that mitochondrial ROS-activated FGR drives proinflammatory macrophage polarization and that bone marrow-specific Fgr deletion protects against diet-induced insulin resistance and steatosis connected FGR's metabolic kinase function to systemic metabolic disease.","evidence":"Fgr KO mice, BM transplantation chimeras, HFD model, mitochondrial peroxide scavenging, flow cytometry for macrophage markers","pmids":["32943786"],"confidence":"High","gaps":["Direct substrates mediating macrophage polarization downstream of FGR not identified beyond Complex II","Relevance to human metabolic disease not confirmed"]},{"year":null,"claim":"Key unresolved questions include the structural basis for FGR's dual kinase-dependent and kinase-independent signaling modes, the mechanism by which FGR accesses mitochondrial substrates, whether FGR's unique escape from autoinhibition is exploited in specific cancers beyond AML, and the identity of additional direct substrates that mediate its roles in macrophage polarization and metabolic adaptation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length crystal structure of autoinhibited FGR","Mitochondrial import or access mechanism undefined","Complete substrate inventory lacking","Cancer-type-specific oncogenic contributions beyond BCR-ABL+ B-ALL and AML not systematically tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,6,16,20,26,32,35,36,39]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[23,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,25,28,36]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,5,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,15]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[32,35]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,9,17,18,22,30,31,33,34,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,23,25,28,29,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,35,41]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[5,30,33]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,15]}],"complexes":[],"partners":["HCK","LYN","SYK","CSK","SIRPA","SHP-1","VAV1","TBK1"],"other_free_text":[]},"mechanistic_narrative":"FGR encodes a Src-family nonreceptor tyrosine kinase predominantly expressed in myeloid lineage cells that functions as a central integrator of integrin, Fc receptor, and selectin-mediated outside-in signaling to control neutrophil respiratory burst, degranulation, spreading, macrophage phagocytosis, and mast cell degranulation [PMID:8666673, PMID:9916742, PMID:21746961, PMID:18794338]. Anchored to membranes via N-terminal myristoylation, FGR is activated downstream of β2 integrins, FcγRII, FcεRI, and PSGL-1, and signals through Vav1–Rac–PAK and FAK–p190RhoGAP axes while also exerting kinase-independent inhibitory functions by scaffolding SHP-1 to SIRPα and sequestering Syk via its SH2 domain [PMID:7519620, PMID:17339487, PMID:10662797, PMID:11672534]. FGR phosphorylates the flavoprotein subunit of mitochondrial Complex II to increase succinate dehydrogenase activity and adjust NADH/FADH2 balance during metabolic stress, and it phosphorylates TBK1 to negatively regulate antiviral innate immune signaling [PMID:24856931, PMID:28618271]. Uniquely among Src kinases, FGR escapes classical SH3-SH2 autoinhibitory control due to a proline at the +2 position of its activation-loop tyrosine, conferring intrinsic transforming capacity and making it a therapeutic target in AML [PMID:30352950, PMID:29763550]."},"prefetch_data":{"uniprot":{"accession":"P09769","full_name":"Tyrosine-protein kinase Fgr","aliases":["Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog","Proto-oncogene c-Fgr","p55-Fgr","p58-Fgr","p58c-Fgr"],"length_aa":529,"mass_kda":59.5,"function":"Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCGR2A and/or FCGR2B. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as a negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as a positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK-dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. Together with CLNK, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production (By similarity)","subcellular_location":"Cell membrane; Cell membrane; Cell projection, ruffle membrane; Cytoplasm, cytosol; Cytoplasm, cytoskeleton; Mitochondrion inner membrane; Mitochondrion intermembrane space","url":"https://www.uniprot.org/uniprotkb/P09769/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FGR","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FGR","total_profiled":1310},"omim":[{"mim_id":"605719","title":"LINKER FOR ACTIVATION OF T CELLS FAMILY, MEMBER 2; LAT2","url":"https://www.omim.org/entry/605719"},{"mim_id":"604491","title":"CAS-BR-M MURINE ECOTROPIC RETROVIRAL TRANSFORMING SEQUENCE B; CBLB","url":"https://www.omim.org/entry/604491"},{"mim_id":"602600","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 8; LRP8","url":"https://www.omim.org/entry/602600"},{"mim_id":"601655","title":"EYA TRANSCRIPTIONAL COACTIVATOR AND PHOSPHATASE 3; EYA3","url":"https://www.omim.org/entry/601655"},{"mim_id":"600182","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 5; SLC7A5","url":"https://www.omim.org/entry/600182"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Aggresome","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":196.5},{"tissue":"lung","ntpm":83.0},{"tissue":"lymphoid tissue","ntpm":136.4}],"url":"https://www.proteinatlas.org/search/FGR"},"hgnc":{"alias_symbol":["c-fgr","p55c-fgr"],"prev_symbol":["SRC2"]},"alphafold":{"accession":"P09769","domains":[{"cath_id":"2.30.30.40","chopping":"82-138","consensus_level":"high","plddt":92.6395,"start":82,"end":138},{"cath_id":"3.30.505.10","chopping":"143-241","consensus_level":"high","plddt":93.0926,"start":143,"end":241},{"cath_id":"3.30.200.20","chopping":"257-337","consensus_level":"medium","plddt":91.9875,"start":257,"end":337},{"cath_id":"1.10.510.10","chopping":"340-518","consensus_level":"medium","plddt":91.5766,"start":340,"end":518}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09769","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09769-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09769-F1-predicted_aligned_error_v6.png","plddt_mean":82.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FGR","jax_strain_url":"https://www.jax.org/strain/search?query=FGR"},"sequence":{"accession":"P09769","fasta_url":"https://rest.uniprot.org/uniprotkb/P09769.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09769/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09769"}},"corpus_meta":[{"pmid":"9151903","id":"PMC_9151903","title":"Lipopolysaccharide 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foundational paper with 233 citations\",\n      \"pmids\": [\"6318314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The human c-fgr protooncogene encodes a 55 kDa protein (p55c-fgr) with a unique N-terminal domain (first 75 amino acids) distinct from other Src family members, followed by a conserved kinase domain; the protein was confirmed by antibodies to predicted peptide sequences.\",\n      \"method\": \"cDNA sequencing, COS-1 cell transfection, immunoprecipitation with antipeptide antibodies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein identification by sequencing and immunoprecipitation, replicated across labs\",\n      \"pmids\": [\"3275868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"p55c-fgr is enzymatically active as a protein tyrosine kinase in differentiated myelomonocytic cells, is localized to peripheral cell membranes, and membrane association is mediated by covalent attachment of a myristyl group.\",\n      \"method\": \"Immune complex kinase assay, subcellular fractionation, myristoylation analysis in HL60 cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus biochemical fractionation and lipid modification analysis\",\n      \"pmids\": [\"2687293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"p55c-fgr is associated with functional secretory (secondary) granules in neutrophils and redistributes to the plasma membrane fraction upon activation with the chemoattractant peptide fMLP, demonstrating stimulus-dependent translocation.\",\n      \"method\": \"Subcellular fractionation, immune complex kinase assay, formyl-Met-Leu-Phe stimulation of human neutrophils\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation with functional kinase readout; replicated by later studies\",\n      \"pmids\": [\"2682659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Fgr physically associates with IgG Fc receptor II (FcγRII) but not FcγRIII in human neutrophils, and crosslinking of FcγRII induces rapid increase in Fgr tyrosine kinase activity and co-modulation of Fgr.\",\n      \"method\": \"Co-immunoprecipitation from neutrophil detergent lysates, immune complex kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with functional kinase activity measurement; 137 citations\",\n      \"pmids\": [\"8327512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Beta 2 integrin-dependent adhesion to fibrinogen activates Fgr kinase activity and increases its tyrosine phosphorylation in human neutrophils; this activation requires β2 integrin expression (absent in LAD patient neutrophils) and is blocked by anti-CD18 antibodies.\",\n      \"method\": \"Immune complex kinase assay, LAD patient neutrophils, anti-CD18 blocking antibodies, fibrinogen adhesion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including genetic (LAD) and antibody blocking; 151 citations\",\n      \"pmids\": [\"7519620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CSK (C-terminal Src kinase) phosphorylates c-Fgr at Tyr-511 (homologous to Src Tyr-527) and thereby down-regulates Fgr activity; this prevents autophosphorylation at the activation loop Tyr-400. Polycationic effectors stimulate Fgr and promote autophosphorylation at both Tyr-400 and Tyr-511, rendering Fgr insensitive to CSK down-regulation.\",\n      \"method\": \"In vitro kinase assay with purified proteins, site-directed mutagenesis implied by phosphosite analysis, CSK phosphorylation reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with defined phosphosites and regulatory outcome\",\n      \"pmids\": [\"7515063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Targeted disruption of both hck and fgr (double knockout) reveals functional overlap: loss of both kinases results in immunodeficiency with increased susceptibility to Listeria infection, while single knockouts have milder phenotypes; Lyn specific activity is increased in hck−/− macrophages, suggesting compensatory upregulation.\",\n      \"method\": \"Gene targeting/knockout mice, Listeria infection model, immune complex kinase assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined in vivo phenotype; 201 citations\",\n      \"pmids\": [\"8125254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fgr kinase activity in adherent neutrophils strictly correlates with beta 2 integrin-mediated adhesion; divalent cation Mg2+ (but not Ca2+ alone) is required for adhesion and concurrent Fgr activation, and Fgr redistributes to a Triton X-100-insoluble cytoskeletal fraction with enhanced kinase activity upon adhesion.\",\n      \"method\": \"Immune complex kinase assay, divalent cation manipulation, Triton X-100 fractionation, anti-CD18 blocking\",\n      \"journal\": \"Journal of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but single lab\",\n      \"pmids\": [\"8867673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Loss of both Hck and Fgr (double knockout) in neutrophils abolishes adhesion-dependent respiratory burst and cell spreading on ECM proteins (fibrinogen, fibronectin, collagen) and on ICAM-1, demonstrating that either Hck or Fgr is required for beta 2/beta 3 integrin signaling leading to cytoskeletal rearrangement and superoxide production.\",\n      \"method\": \"hck−/−fgr−/− knockout mice, respiratory burst assay, cell adhesion and spreading microscopy, integrin crosslinking with mAbs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple functional readouts; replicated; 306 citations\",\n      \"pmids\": [\"8666673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Reactive oxygen intermediates (ROI) produced by adherent neutrophils activate Fgr and Lyn kinase activities; inhibition of NADPH oxidase or addition of catalase suppresses adhesion-stimulated Fgr activity, and Fgr activity is reduced in CGD neutrophils deficient in ROI production. Exogenous H2O2 activates Fgr in non-adherent neutrophils.\",\n      \"method\": \"Immune complex kinase assay, NADPH oxidase inhibitor diphenylene iodonium, catalase addition, CGD patient neutrophils, exogenous H2O2 treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary approaches including genetic (CGD) and pharmacological; 86 citations\",\n      \"pmids\": [\"8798554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Fgr (and Lyn) redistribute to a Triton X-100-insoluble fraction containing cytoskeletal proteins and caveolin upon PMA stimulation in neutrophils, and it is this fraction of Fgr that displays enhanced kinase activity, suggesting Fgr functions within caveolar/cytoskeletal multimolecular complexes.\",\n      \"method\": \"Triton X-100 and OGP detergent fractionation, immune complex kinase assay, caveolin co-fractionation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation with kinase assay, single lab\",\n      \"pmids\": [\"8603737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Fgr and Hck are required for normal erythrocyte K/Cl cotransport regulation: fgr−/−hck−/− double knockout erythrocytes exhibit ~3-fold elevated K/Cl cotransport activity. The mechanism involves Fgr/Hck acting as kinases that negatively regulate a phosphatase which activates the K/Cl cotransporter.\",\n      \"method\": \"fgr−/−hck−/− knockout mouse erythrocytes, ion transport assays, okadaic acid and staurosporine pharmacology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined ion transport phenotype and pharmacological dissection; 94 citations\",\n      \"pmids\": [\"9005990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Fgr and Lyn kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells; Fgr activity and tyrosine phosphorylation increase during differentiation and decrease at the onset of apoptosis, and antisense knockdown of Fgr causes premature apoptotic death.\",\n      \"method\": \"HL-60 differentiation model, immune complex kinase assay, antisense oligodeoxynucleotide knockdown, PTK inhibitor treatment (herbimycin A, genistein)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay plus antisense KD with functional outcome; single lab\",\n      \"pmids\": [\"8626717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Fgr and Lyn are activated in distinct subcellular membrane fractions of human granulocytes: Fgr is activated in the 11,000g fraction (heavier membranes) while Lyn is activated in the 200,000g fraction (light membranes), and distinct sets of tyrosine-phosphorylated proteins are found in each fraction. fMLP selectively activates Lyn but not Fgr, while opsonized zymosan activates both.\",\n      \"method\": \"Subcellular fractionation of differentiated NB4 cells and human neutrophils, immune complex kinase assay, stimulus comparison (fMLP, opsonized zymosan, A23187)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fractionation with kinase assays and stimulus specificity; single lab\",\n      \"pmids\": [\"9366519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Src family kinases Fgr, Fyn, Lck, and Lyn colocalize with clathrin-coated membranes (coated pits and coated vesicles) in platelets, distinct from Src which is not in these compartments, suggesting a role for Fgr in endocytotic vesicle-mediated trafficking.\",\n      \"method\": \"Immunoelectron microscopy with anti-kinase and anti-clathrin antibodies in platelets\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ultrastructural localization; single lab, single method\",\n      \"pmids\": [\"9116282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The optimal peptide substrate sequence recognized by c-Fgr (XEEIYGIFF) differs from CSK and Lyn, with selection for a hydrophobic residue at the +1 position; CSK phosphorylates the C-terminal regulatory tyrosine of c-Fgr with similar kinetics as Lyn.\",\n      \"method\": \"Oriented peptide library screening, in vitro kinase assays with synthetic peptides, Km/kcat determination\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with substrate library and kinetic analysis\",\n      \"pmids\": [\"9208935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"hck−/−fgr−/− mice are resistant to lethal LPS-induced endotoxic shock and show reduced neutrophil migration into liver tissue; despite high serum TNF-α and IL-1α, hepatic and renal injury are markedly reduced, demonstrating that Hck/Fgr-dependent integrin signaling in neutrophils is required for LPS-induced tissue damage in vivo.\",\n      \"method\": \"hck−/−fgr−/− knockout mice, LPS injection model, serum cytokine ELISA, liver histology, blood counts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined in vivo inflammatory phenotype; 139 citations\",\n      \"pmids\": [\"9636192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Adhesion-dependent degranulation (lactoferrin secretion) in neutrophils requires both Fgr and Hck; hck−/−fgr−/− PMN adherent to collagen or fibrinogen fail to release lactoferrin in response to TNF-α but respond normally to PMA (adhesion-independent). Src kinase inhibitor PP1 reproduces the defect, identifying Fgr/Hck in a pathway linking integrin engagement to granule-plasma membrane fusion.\",\n      \"method\": \"hck−/−fgr−/− knockout mouse PMNs, lactoferrin ELISA, PP1 pharmacological inhibition, TNF-α stimulation on ECM substrates\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO corroborated by pharmacological inhibition with defined secretory phenotype; 164 citations\",\n      \"pmids\": [\"9916742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hck and Fgr are required for integrin-mediated signal transduction in macrophages: hck−/−fgr−/− macrophages on fibronectin show markedly reduced tyrosine phosphorylation of cortactin, paxillin, tensin, and activation of Syk and Pyk2; focal adhesion proteins fail to polarize; filopodia are absent; and cell motility is reduced.\",\n      \"method\": \"hck−/−fgr−/− knockout macrophages, anti-phosphotyrosine immunoblotting, immunofluorescence for focal adhesion proteins, migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and morphological readouts in clean genetic KO; 129 citations\",\n      \"pmids\": [\"10547366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Fgr phosphorylates HS1 hematopoietic protein at Tyr-222 via SH2 domain-dependent docking to a prior Syk phosphorylation site; stable association of phospho-HS1 with the c-Fgr SH2 domain requires prior Fgr autophosphorylation and is prevented by subsequent Tyr-222 phosphorylation, establishing a sequential phosphorylation mechanism.\",\n      \"method\": \"In vitro kinase assays with purified proteins, peptide mapping, phosphosite identification, SH2 domain binding assays, kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with phosphosite mapping and kinetic characterization\",\n      \"pmids\": [\"10066823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hck and c-Fgr associate with the chemokine receptor CCR3 in human eosinophils upon eotaxin stimulation; this association occurs after CCR3 internalization and correlates with tyrosine phosphorylation and actin reorganization required for chemotaxis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, herbimycin A inhibition, eotaxin stimulation of human eosinophils\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with functional correlation; single lab\",\n      \"pmids\": [\"10527858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FcγR-mediated phagocytosis, respiratory burst, actin cup formation, and activation of Syk, PI3K, and ERK1/2 are all diminished or delayed in macrophages lacking Hck, Fgr, and Lyn, placing these Src kinases upstream of Syk activation and actin polymerization in FcγR signaling.\",\n      \"method\": \"hck−/−fgr−/−lyn−/− triple knockout macrophages, phagocytosis assay, respiratory burst, immunoblotting for signaling intermediates\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean triple KO with multiple orthogonal functional and signaling readouts; 201 citations\",\n      \"pmids\": [\"10684859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Fgr negatively regulates FcγR- and CR3-mediated phagocytosis in macrophages independently of its tyrosine kinase activity; after FcγR crosslinking, Fgr associates with the ITIM-containing receptor SIRPα and potentiates SHP-1 phosphatase association with SIRPα, thereby dampening positive phagocytic signaling.\",\n      \"method\": \"Fgr overexpression in macrophage cell line and primary macrophages, phagocytosis assay, co-immunoprecipitation of Fgr with SIRPα and SHP-1, kinase-dead Fgr mutant\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function plus co-IP with mechanistic dissection using kinase-dead mutant; 76 citations\",\n      \"pmids\": [\"10662797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Phosphatidic acid (PA) specifically enhances Fgr tyrosine kinase activity in neutrophil cytosol; among all Src family kinases in neutrophils, only Fgr elutes in the PA-dependent Tyr phosphorylating activity fraction, and PA directly increases Fgr activity in cell-free assays.\",\n      \"method\": \"Gel filtration chromatography of neutrophil cytosol, immune complex kinase assay, PA addition to cell-free system, phospholipid selectivity analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-free biochemical reconstitution, single lab\",\n      \"pmids\": [\"11078731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fgr is a negative regulator of beta 2 integrin signaling and Syk kinase in monocytes; Fgr inhibits beta 2 (but not beta 1) integrin signaling and Syk function via direct association between the Fgr SH2 domain and Syk phospho-Tyr342, and this inhibitory effect is independent of Fgr kinase activity but dose-dependent, overcome by chemokines.\",\n      \"method\": \"Co-immunoprecipitation, Fgr SH2 domain binding assay to Syk pY342, monocyte spreading assay, Syk kinase activity assay, kinase-dead Fgr mutants\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct SH2-phosphosite interaction mapped with multiple functional assays; 72 citations\",\n      \"pmids\": [\"11672534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fgr phosphorylates phospholipase D2 (PLD2) at multiple tyrosines (Y11, Y14, Y165, Y470) in mast cells, together with Fyn; this phosphorylation activates PLD2 and promotes degranulation in FcεRI-stimulated RBL-2H3 cells. Fgr siRNA knockdown blocks PLD2 phosphorylation.\",\n      \"method\": \"siRNA knockdown, overexpression of kinases, site-directed mutagenesis of PLD2 tyrosines, HA-PLD2 immunoprecipitation kinase assay, degranulation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of substrate phosphosites combined with siRNA and overexpression; 31 citations\",\n      \"pmids\": [\"15282299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BCR-ABL1 activates the Src kinases Lyn, Hck, and Fgr in B-lymphoid cells; marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL upon BCR-ABL1 transduction, demonstrating that these Src kinases are required for B-ALL but not CML induced by BCR-ABL1.\",\n      \"method\": \"Retroviral transduction of triple-KO (lyn−/−hck−/−fgr−/−) bone marrow, leukemia mouse model, kinase inhibitor CGP76030\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis in vivo plus pharmacological validation; 327 citations\",\n      \"pmids\": [\"15098032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Hck and Fgr negatively regulate myeloid cell chemokine signaling; hck−/−fgr−/− neutrophils are hyperresponsive to multiple chemokines (elevated Ca2+ flux, MAP kinase, actin polymerization, chemotaxis). This negative regulation is mediated through the inhibitory receptor PIR-B, which Hck and Fgr maintain in a tonically phosphorylated, active inhibitory state.\",\n      \"method\": \"hck−/−fgr−/− knockout mice, pir-b−/− mice, Ca2+ flux assay, MAPK assays, chemotaxis assays, PIR-B phosphorylation state analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double KO and receptor KO with multiple functional readouts and phosphorylation analysis; 85 citations\",\n      \"pmids\": [\"15723811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Membrane localization of Fgr is required for its role in cell migration; full-length membrane-bound Fgr increases migration on fibronectin and phosphorylation of PI3K p85, cortactin, FAK Y397/Y576, activates Rac via Vav2 phosphorylation, and forms a complex with p190RhoGAP/FAK. An N-terminal truncation mutant lacking membrane targeting fails to do so.\",\n      \"method\": \"COS-7 cell transfection with wild-type, truncation and kinase-dead Fgr mutants, migration assay, co-immunoprecipitation, Rac GTP-loading assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis (truncation mutants) with multiple signaling and functional readouts; 15 citations but mechanistically detailed\",\n      \"pmids\": [\"15561106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hck and Fgr regulate outside-in beta 2 integrin signaling (cell spreading and sustained adhesion) but not inside-out chemoattractant-induced integrin affinity or clustering; hck−/−fgr−/− neutrophils detach after initial binding and have reduced arrest in inflamed venules >60 µm.\",\n      \"method\": \"hck−/−fgr−/− knockout neutrophils, soluble ICAM-1 binding, static adhesion assay, flow chamber, intravital microscopy\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with in vitro and in vivo readouts distinguishing inside-out from outside-in signaling; 93 citations\",\n      \"pmids\": [\"16785558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fgr (and Hck) regulate fMLP-induced respiratory burst and F-actin polymerization in neutrophils through a signaling pathway involving phosphorylation of the Rho/Rac GEF Vav1 and activation of p21-activated kinases (PAKs), leading to Rac2 activation; Ca2+ flux and PI3K/Akt activation are Fgr/Hck-independent.\",\n      \"method\": \"hck−/−fgr−/− knockout neutrophils, PP2 Src inhibitor, respiratory burst assay, F-actin assay, MAPK/Vav1/PAK phosphorylation immunoblotting, Rac2 GTP pulldown\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO plus pharmacological inhibition with pathway dissection using multiple signaling assays; 85 citations\",\n      \"pmids\": [\"17339487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fgr phosphorylates the flavoprotein subunit of succinate dehydrogenase (FpSDH) at Y535 and Y596, and aconitase at Y71, Y544, and Y665, identifying these mitochondrial enzymes as in vitro substrates of Fgr.\",\n      \"method\": \"In vitro kinase assay with recombinant Fgr and mitochondrial substrate proteins, mass spectrometry phosphosite mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation with MS-based site identification, but in vitro only; single lab\",\n      \"pmids\": [\"17997986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E-selectin engagement of PSGL-1 signals through the Src family kinase Fgr (and Hck/Lyn) and the ITAM-containing adaptor proteins DAP12 and FcRγ to phosphorylate Syk and p38 MAPK, initiating slow neutrophil rolling; fgr−/− neutrophils abolish E-selectin-mediated Syk phosphorylation and slow rolling.\",\n      \"method\": \"fgr−/−, hck−/−lyn−/−fgr−/−, Tyrobp−/−Fcrg−/− gene-deficient mice, flow chamber, intravital microscopy, Syk/p38 phosphorylation assay, mixed chimeric mice peritonitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple gene-deficient mouse models with in vitro and in vivo validation; 168 citations\",\n      \"pmids\": [\"18794338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fgr associates with FcεRI in mast cells and promotes phosphorylation of Syk and its substrates (LAT, SLP76, Gab2) and downstream targets (Akt, MAPKs) upon antigen stimulation; Fgr siRNA knockdown reduces degranulation, eicosanoid and cytokine production, and IgE-mediated anaphylaxis in vivo.\",\n      \"method\": \"Fgr siRNA knockdown in mast cells and mice, Fgr overexpression, co-immunoprecipitation with FcεRI, phospho-immunoblotting, degranulation assay, anaphylaxis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus siRNA KD with multiple mechanistic and in vivo readouts; 44 citations\",\n      \"pmids\": [\"21746961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fgr is activated by hydrogen peroxide (ROS) and phosphorylates the flavoprotein subunit of Complex II (FpSDH), increasing Complex II activity and superassembly to adjust mitochondrial metabolism (NADH/FADH2 balance); ablation of Fgr or mutation of the FpSDH target tyrosine abolishes metabolic adaptation during nutrient restriction, hypoxia/reoxygenation, and T cell activation.\",\n      \"method\": \"Fgr knockout cells and mice, FpSDH tyrosine point mutant, Complex II activity assay, supercomplex analysis, H2O2 activation of Fgr, metabolic assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — substrate mutagenesis combined with KO, in vitro and in vivo metabolic readouts; 100 citations\",\n      \"pmids\": [\"24856931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fgr phosphorylates TBK1 at Tyr354 and Tyr394 (together with Hck and Lck), preventing TBK1 dimerization and activation; this constitutes a negative feedback loop in antiviral innate immunity in which viral infection induces Fgr expression via TBK1-IRF3, and Fgr then dampens antiviral responses.\",\n      \"method\": \"Triple KO cells (Lck/Hck/Fgr), ectopic kinase expression, phospho-TBK1 antibodies, TBK1 dimerization assay, zebrafish and mouse viral infection models\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO plus overexpression with mechanistic phosphosite identification and in vivo validation; 39 citations\",\n      \"pmids\": [\"28618271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FCRL4 is phosphorylated on tyrosine residues by HCK (p59 isoform) and FGR; this phosphorylation requires palmitoylation of FCRL4 and modulates MAPK/Elk-1 signaling in opposite directions (FGR-inhibitory, HCK-activating) and upregulates IL-10 or IFN-γ production in memory B cells.\",\n      \"method\": \"Reporter gene assays, FCRL4 palmitoylation-defective mutant, overexpression of HCK/FGR in B cells, phospho-tyrosine immunoblotting\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression system with functional readouts; single lab\",\n      \"pmids\": [\"25972488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Src kinases Hck, Fgr, and Lyn are required for IgG-mediated phagocytosis of Leishmania amastigotes by macrophages; Fgr/Hck/Lyn activate the non-receptor tyrosine kinase Arg (Abl2), and Src-mediated Arg activation is required for efficient amastigote uptake.\",\n      \"method\": \"Primary macrophages from single and combined SFK KO mice, small-molecule Src/Arg inhibitors, phagocytosis assay, Leishmania mouse infection model with bosutinib\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus pharmacological inhibition with defined phagocytic phenotype; single lab\",\n      \"pmids\": [\"27358479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fgr functions as a transforming oncoprotein independently of SH3-SH2 regulatory domain control; wild-type Fgr (without activating mutations) promotes Rat-2 fibroblast transformation; the Fgr activation loop contains a unique Pro at the +2 position relative to the activation loop Tyr, and substitution with the Src sequence reduces kinase activity and colony formation. Hydrogen-deuterium exchange shows SH3-SH2 domains still pack against the kinase domain but fail to suppress its activity.\",\n      \"method\": \"Soft agar colony formation assay in Rat-2 fibroblasts, activation loop mutagenesis, hydrogen-deuterium exchange mass spectrometry, SH3-SH2 ligand activation assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + HDX-MS structural analysis + functional transformation assay; 30 citations\",\n      \"pmids\": [\"30352950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fgr is a high-potency kinase inhibitor target in AML; a selective N-phenylbenzamide inhibitor TL02-59 with picomolar potency against Fgr suppresses AML cell proliferation correlated with Fgr/Hck/Lyn expression levels, and oral TL02-59 eliminates leukemic cells from spleen and blood in a xenograft mouse model.\",\n      \"method\": \"Kinome-wide target profiling, in vitro kinase assay, AML patient bone marrow samples, xenograft mouse model, oral drug administration\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay + patient samples + in vivo xenograft; 39 citations\",\n      \"pmids\": [\"29763550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fgr kinase is activated by mitochondrial ROS in bone marrow-derived macrophages and is required for proinflammatory macrophage polarization; ablation of Fgr in BM-derived cells protects against HFD-induced insulin resistance and liver steatosis, and transfer of Fgr-expressing BM cells reverts protection. Scavenging mitochondrial peroxides prevents Fgr activation.\",\n      \"method\": \"Fgr knockout mice, BM transplantation chimeras, HFD feeding model, mitochondrial peroxide scavenging, flow cytometry for macrophage polarization\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — BM reconstitution plus KO with multiple in vivo and in vitro mechanistic readouts; 59 citations\",\n      \"pmids\": [\"32943786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fgr is upregulated in thalamic microglia after hemorrhage, participates in microglial activation and TNF-α production via NF-κB and ERK1/2 pathways, and contributes to thalamic pain; pharmacological inhibition or genetic knockdown of Fgr attenuates hemorrhage-induced thalamic injury and pain hypersensitivities.\",\n      \"method\": \"Collagenase/autologous blood thalamic hemorrhage model, Fgr siRNA knockdown, Fgr inhibitor, NF-κB and ERK1/2 phospho-immunoblotting, cytokine ELISA, behavioral pain tests\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD + pharmacological inhibition in vivo with pathway readouts; single lab\",\n      \"pmids\": [\"33055425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fgr is associated with Protein Phosphatase 1α (PP1α) in erythrocytes; peroxynitrite activates Fgr, which then phosphorylates PP1α on tyrosine, inhibiting PP1α enzymatic activity and thereby regulating K/Cl cotransport.\",\n      \"method\": \"Mouse erythrocyte cell-free system, peroxynitrite treatment, Fgr immune complex kinase assay, PP1α activity assay, fgr/hck KO erythrocytes\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO cells plus in vitro kinase/phosphatase assays; single lab\",\n      \"pmids\": [\"15917191\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGR encodes a Src-family nonreceptor tyrosine kinase expressed in myeloid cells (neutrophils, monocytes, macrophages, mast cells) that is anchored to the plasma membrane via N-terminal myristoylation and is activated downstream of β2 integrins, Fc receptors (FcγRII, FcεRI), selectin-PSGL-1, and reactive oxygen species/H2O2; once active, it phosphorylates a defined set of substrates including the FpSDH subunit of mitochondrial Complex II, PLD2, HS1, PP1α, and TBK1, and signals through Vav1-Rac-PAK, FAK-p190RhoGAP, and SIRPα-SHP-1 axes to regulate neutrophil respiratory burst, degranulation, spreading, chemokine secretion, mast cell degranulation, macrophage phagocytosis, mitochondrial fuel switching, and innate antiviral responses, while its kinase domain uniquely escapes SH3-SH2 autoinhibitory control due to a proline at the +2 position of the activation loop.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FGR encodes a Src-family nonreceptor tyrosine kinase predominantly expressed in myeloid lineage cells that functions as a central integrator of integrin, Fc receptor, and selectin-mediated outside-in signaling to control neutrophil respiratory burst, degranulation, spreading, macrophage phagocytosis, and mast cell degranulation [PMID:8666673, PMID:9916742, PMID:21746961, PMID:18794338]. Anchored to membranes via N-terminal myristoylation, FGR is activated downstream of β2 integrins, FcγRII, FcεRI, and PSGL-1, and signals through Vav1–Rac–PAK and FAK–p190RhoGAP axes while also exerting kinase-independent inhibitory functions by scaffolding SHP-1 to SIRPα and sequestering Syk via its SH2 domain [PMID:7519620, PMID:17339487, PMID:10662797, PMID:11672534]. FGR phosphorylates the flavoprotein subunit of mitochondrial Complex II to increase succinate dehydrogenase activity and adjust NADH/FADH2 balance during metabolic stress, and it phosphorylates TBK1 to negatively regulate antiviral innate immune signaling [PMID:24856931, PMID:28618271]. Uniquely among Src kinases, FGR escapes classical SH3-SH2 autoinhibitory control due to a proline at the +2 position of its activation-loop tyrosine, conferring intrinsic transforming capacity and making it a therapeutic target in AML [PMID:30352950, PMID:29763550].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Determining FGR's origin as a tyrosine kinase gene fused with actin sequences in v-fgr established that the cellular proto-oncogene encodes a tyrosine kinase, framing all subsequent functional studies.\",\n      \"evidence\": \"Nucleotide sequencing and homology analysis of the v-fgr oncogene\",\n      \"pmids\": [\"6318314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No information on normal cellular function or expression pattern\", \"Protein product of the cellular gene not yet identified\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of p55c-Fgr as a myristoylated, membrane-associated tyrosine kinase in differentiated myelomonocytic cells and neutrophil granules resolved where and when the kinase is active, revealing stimulus-dependent translocation from secretory granules to the plasma membrane.\",\n      \"evidence\": \"Immune complex kinase assays, subcellular fractionation, myristoylation analysis in HL-60 and human neutrophils, fMLP stimulation\",\n      \"pmids\": [\"3275868\", \"2687293\", \"2682659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activating signals not yet defined\", \"No substrates identified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Discovery that β2 integrin adhesion activates FGR and that FcγRII physically associates with and activates FGR identified the two principal receptor systems upstream of FGR, while CSK-mediated Tyr-511 phosphorylation defined the negative regulatory mechanism.\",\n      \"evidence\": \"Immune complex kinase assays with anti-CD18 blocking, LAD patient neutrophils, co-IP of Fgr with FcγRII, in vitro CSK reconstitution with phosphosite analysis\",\n      \"pmids\": [\"7519620\", \"8327512\", \"7515063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathways not yet mapped\", \"Relative contributions of FGR versus other SFKs unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Hck/Fgr double-knockout mice revealed that these kinases are collectively essential for integrin-dependent respiratory burst, cell spreading, neutrophil-mediated tissue damage in endotoxemia, and erythrocyte K/Cl cotransport regulation, establishing FGR's non-redundant in vivo roles in innate immunity and ion homeostasis.\",\n      \"evidence\": \"hck−/−fgr−/− knockout mice with respiratory burst, spreading, Listeria/LPS infection models, and erythrocyte ion transport assays\",\n      \"pmids\": [\"8125254\", \"8666673\", \"9636192\", \"9005990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of Fgr versus Hck not fully separated due to redundancy\", \"Substrates mediating these phenotypes unknown\", \"Reactive oxygen intermediate–mediated activation mechanism not yet molecularly defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of HS1, cortactin, paxillin, and other focal adhesion proteins as downstream targets, together with the demonstration that Fgr/Hck are required for integrin-dependent degranulation, defined the signaling layer between integrin-activated SFKs and effector functions in neutrophils and macrophages.\",\n      \"evidence\": \"In vitro kinase assays with phosphosite mapping (HS1 Tyr-222), hck−/−fgr−/− macrophage signaling and morphology analysis, lactoferrin degranulation assay with PP1 inhibitor\",\n      \"pmids\": [\"10066823\", \"10547366\", \"9916742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HS1 phosphorylation shown in vitro, in vivo relevance not confirmed\", \"Link between cortactin/paxillin phosphorylation and specific effector outputs unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that FGR negatively regulates phagocytosis by recruiting SHP-1 to SIRPα independently of kinase activity, and separately inhibits Syk via SH2 domain sequestration, revealed that FGR functions as both a positive kinase and a kinase-independent negative scaffolding adaptor depending on context.\",\n      \"evidence\": \"Kinase-dead Fgr mutant overexpression, co-IP of Fgr–SIRPα–SHP-1, Fgr SH2 domain binding to Syk pY342, phagocytosis assays\",\n      \"pmids\": [\"10662797\", \"11672534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the balance between positive and negative signaling is controlled in single cells remains unknown\", \"Structural basis for kinase-independent adaptor function not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapping FGR's regulation of cell migration through Vav2/Rac and FAK/p190RhoGAP complexes, and its tonic phosphorylation of PIR-B to restrain chemokine hyperresponsiveness, clarified two additional signaling axes and established FGR as a set-point regulator of myeloid cell activation thresholds.\",\n      \"evidence\": \"COS-7 Fgr mutant transfections with Rac GTP pulldown, hck−/−fgr−/− and pir-b−/− mice with chemotaxis/Ca2+ flux assays, PP1α phosphorylation in erythrocytes\",\n      \"pmids\": [\"15561106\", \"15723811\", \"15917191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural evidence for Fgr–PIR-B interaction lacking\", \"PP1α tyrosine phosphosite not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of the selectin–PSGL-1–SFK–ITAM adaptor (DAP12/FcRγ)–Syk signaling axis in slow neutrophil rolling, with fgr−/− neutrophils specifically abolishing E-selectin-mediated Syk phosphorylation, placed FGR upstream of a novel innate immune adhesion pathway distinct from integrin outside-in signaling.\",\n      \"evidence\": \"fgr−/−, hck−/−lyn−/−fgr−/−, and DAP12/FcRγ KO mice with flow chamber, intravital microscopy, and Syk phosphorylation assays\",\n      \"pmids\": [\"18794338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FGR is specifically activated by PSGL-1 engagement vs other SFKs is unclear\", \"ITAM adaptor phosphorylation by FGR not directly shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that ROS-activated FGR phosphorylates the flavoprotein subunit of Complex II (FpSDH) to increase succinate dehydrogenase activity and adjust mitochondrial fuel utilization expanded FGR's role beyond immune signaling to metabolic adaptation during nutrient stress, hypoxia, and T cell activation.\",\n      \"evidence\": \"Fgr KO mice, FpSDH tyrosine point mutant, Complex II activity and supercomplex analysis, H2O2 activation of Fgr\",\n      \"pmids\": [\"24856931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FGR accesses the mitochondrial matrix (intermembrane space vs import) is undefined\", \"Whether FGR regulation of Complex II operates in all cell types or only myeloid cells is unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of TBK1 as a direct FGR substrate (Tyr354/Tyr394 phosphorylation preventing TBK1 dimerization) established a negative feedback loop in antiviral innate immunity: viral infection induces FGR via TBK1–IRF3, and FGR then restrains TBK1, connecting FGR to type I interferon regulation.\",\n      \"evidence\": \"Triple KO cells, ectopic kinase expression, phospho-TBK1 antibodies, TBK1 dimerization assay, zebrafish and mouse viral infection models\",\n      \"pmids\": [\"28618271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of FGR versus Hck and Lck in TBK1 regulation in primary cells not resolved\", \"Temporal dynamics of the feedback loop in natural infection unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural and functional demonstration that wild-type FGR escapes SH3-SH2 autoinhibition due to a unique activation-loop Pro+2 residue, conferring intrinsic transforming capacity and explaining why FGR is constitutively more active than other SFKs, provided the first structural rationale for FGR's oncogenic potential in AML.\",\n      \"evidence\": \"HDX-MS of SH3-SH2-kinase domain constructs, activation-loop mutagenesis, Rat-2 transformation assay, picomolar Fgr inhibitor TL02-59 in AML xenografts\",\n      \"pmids\": [\"30352950\", \"29763550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full crystal structure of autoinhibited Fgr not available\", \"Selectivity of TL02-59 among closely related SFKs in vivo not fully profiled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that mitochondrial ROS-activated FGR drives proinflammatory macrophage polarization and that bone marrow-specific Fgr deletion protects against diet-induced insulin resistance and steatosis connected FGR's metabolic kinase function to systemic metabolic disease.\",\n      \"evidence\": \"Fgr KO mice, BM transplantation chimeras, HFD model, mitochondrial peroxide scavenging, flow cytometry for macrophage markers\",\n      \"pmids\": [\"32943786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates mediating macrophage polarization downstream of FGR not identified beyond Complex II\", \"Relevance to human metabolic disease not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for FGR's dual kinase-dependent and kinase-independent signaling modes, the mechanism by which FGR accesses mitochondrial substrates, whether FGR's unique escape from autoinhibition is exploited in specific cancers beyond AML, and the identity of additional direct substrates that mediate its roles in macrophage polarization and metabolic adaptation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length crystal structure of autoinhibited FGR\", \"Mitochondrial import or access mechanism undefined\", \"Complete substrate inventory lacking\", \"Cancer-type-specific oncogenic contributions beyond BCR-ABL+ B-ALL and AML not systematically tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 6, 16, 20, 26, 32, 35, 36, 39]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [23, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 25, 28, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 5, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [32, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 9, 17, 18, 22, 30, 31, 33, 34, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 23, 25, 28, 29, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 35, 41]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [5, 30, 33]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HCK\",\n      \"LYN\",\n      \"SYK\",\n      \"CSK\",\n      \"SIRPA\",\n      \"SHP-1\",\n      \"VAV1\",\n      \"TBK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}