Affinage

FGR

Tyrosine-protein kinase Fgr · UniProt P09769

Length
529 aa
Mass
59.5 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1984 High

    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

    PMID:6318314

    Open questions at the time
    • No information on normal cellular function or expression pattern
    • Protein product of the cellular gene not yet identified
  2. 1989 High

    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

    PMID:2682659 PMID:2687293 PMID:3275868

    Open questions at the time
    • Upstream activating signals not yet defined
    • No substrates identified
  3. 1994 High

    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

    PMID:7515063 PMID:7519620 PMID:8327512

    Open questions at the time
    • Downstream signaling pathways not yet mapped
    • Relative contributions of FGR versus other SFKs unresolved
  4. 1996 High

    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

    PMID:8125254 PMID:8666673 PMID:9005990 PMID:9636192

    Open questions at the time
    • 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
  5. 1999 High

    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

    PMID:10066823 PMID:10547366 PMID:9916742

    Open questions at the time
    • HS1 phosphorylation shown in vitro, in vivo relevance not confirmed
    • Link between cortactin/paxillin phosphorylation and specific effector outputs unclear
  6. 2000 High

    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

    PMID:10662797 PMID:11672534

    Open questions at the time
    • How the balance between positive and negative signaling is controlled in single cells remains unknown
    • Structural basis for kinase-independent adaptor function not determined
  7. 2005 High

    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

    PMID:15561106 PMID:15723811 PMID:15917191

    Open questions at the time
    • Direct structural evidence for Fgr–PIR-B interaction lacking
    • PP1α tyrosine phosphosite not mapped
  8. 2008 High

    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

    PMID:18794338

    Open questions at the time
    • How FGR is specifically activated by PSGL-1 engagement vs other SFKs is unclear
    • ITAM adaptor phosphorylation by FGR not directly shown
  9. 2014 High

    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

    PMID:24856931

    Open questions at the time
    • 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
  10. 2017 High

    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

    PMID:28618271

    Open questions at the time
    • 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
  11. 2018 High

    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

    PMID:29763550 PMID:30352950

    Open questions at the time
    • Full crystal structure of autoinhibited Fgr not available
    • Selectivity of TL02-59 among closely related SFKs in vivo not fully profiled
  12. 2020 High

    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

    PMID:32943786

    Open questions at the time
    • Direct substrates mediating macrophage polarization downstream of FGR not identified beyond Complex II
    • Relevance to human metabolic disease not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 2 GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 3 R-HSA-1500931 Cell-Cell communication 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CSKHCKLYNSHP-1SIRPASYKTBK1VAV1

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 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. Nucleotide sequencing and computer-assisted amino acid sequence homology analysis Science High 6318314
1988 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. cDNA sequencing, COS-1 cell transfection, immunoprecipitation with antipeptide antibodies Molecular and cellular biology High 3275868
1989 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. Immune complex kinase assay, subcellular fractionation, myristoylation analysis in HL60 cells The Journal of cell biology High 2687293
1989 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. Subcellular fractionation, immune complex kinase assay, formyl-Met-Leu-Phe stimulation of human neutrophils Proceedings of the National Academy of Sciences of the United States of America High 2682659
1993 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. Co-immunoprecipitation from neutrophil detergent lysates, immune complex kinase assay Proceedings of the National Academy of Sciences of the United States of America High 8327512
1994 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. Immune complex kinase assay, LAD patient neutrophils, anti-CD18 blocking antibodies, fibrinogen adhesion assay The Journal of cell biology High 7519620
1994 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. In vitro kinase assay with purified proteins, site-directed mutagenesis implied by phosphosite analysis, CSK phosphorylation reconstitution The Journal of biological chemistry High 7515063
1994 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. Gene targeting/knockout mice, Listeria infection model, immune complex kinase assay Genes & development High 8125254
1995 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. Immune complex kinase assay, divalent cation manipulation, Triton X-100 fractionation, anti-CD18 blocking Journal of inflammation Medium 8867673
1996 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. hck−/−fgr−/− knockout mice, respiratory burst assay, cell adhesion and spreading microscopy, integrin crosslinking with mAbs The Journal of cell biology High 8666673
1996 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. Immune complex kinase assay, NADPH oxidase inhibitor diphenylene iodonium, catalase addition, CGD patient neutrophils, exogenous H2O2 treatment The Journal of biological chemistry High 8798554
1996 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. Triton X-100 and OGP detergent fractionation, immune complex kinase assay, caveolin co-fractionation FEBS letters Medium 8603737
1996 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. fgr−/−hck−/− knockout mouse erythrocytes, ion transport assays, okadaic acid and staurosporine pharmacology The Journal of clinical investigation High 9005990
1996 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. HL-60 differentiation model, immune complex kinase assay, antisense oligodeoxynucleotide knockdown, PTK inhibitor treatment (herbimycin A, genistein) The Journal of biological chemistry Medium 8626717
1997 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. Subcellular fractionation of differentiated NB4 cells and human neutrophils, immune complex kinase assay, stimulus comparison (fMLP, opsonized zymosan, A23187) Oncogene Medium 9366519
1997 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. Immunoelectron microscopy with anti-kinase and anti-clathrin antibodies in platelets Blood Medium 9116282
1997 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. Oriented peptide library screening, in vitro kinase assays with synthetic peptides, Km/kcat determination European journal of biochemistry High 9208935
1998 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. hck−/−fgr−/− knockout mice, LPS injection model, serum cytokine ELISA, liver histology, blood counts Proceedings of the National Academy of Sciences of the United States of America High 9636192
1999 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. hck−/−fgr−/− knockout mouse PMNs, lactoferrin ELISA, PP1 pharmacological inhibition, TNF-α stimulation on ECM substrates Journal of immunology High 9916742
1999 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. hck−/−fgr−/− knockout macrophages, anti-phosphotyrosine immunoblotting, immunofluorescence for focal adhesion proteins, migration assays Journal of cell science High 10547366
1999 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. In vitro kinase assays with purified proteins, peptide mapping, phosphosite identification, SH2 domain binding assays, kinetic analysis The Journal of biological chemistry High 10066823
1999 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. Co-immunoprecipitation, immunofluorescence, herbimycin A inhibition, eotaxin stimulation of human eosinophils Biochemical and biophysical research communications Medium 10527858
2000 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. hck−/−fgr−/−lyn−/− triple knockout macrophages, phagocytosis assay, respiratory burst, immunoblotting for signaling intermediates The Journal of experimental medicine High 10684859
2000 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. Fgr overexpression in macrophage cell line and primary macrophages, phagocytosis assay, co-immunoprecipitation of Fgr with SIRPα and SHP-1, kinase-dead Fgr mutant The Journal of experimental medicine High 10662797
2000 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. Gel filtration chromatography of neutrophil cytosol, immune complex kinase assay, PA addition to cell-free system, phospholipid selectivity analysis The Journal of biological chemistry Medium 11078731
2001 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. Co-immunoprecipitation, Fgr SH2 domain binding assay to Syk pY342, monocyte spreading assay, Syk kinase activity assay, kinase-dead Fgr mutants Immunity High 11672534
2004 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. siRNA knockdown, overexpression of kinases, site-directed mutagenesis of PLD2 tyrosines, HA-PLD2 immunoprecipitation kinase assay, degranulation assay Molecular and cellular biology High 15282299
2004 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. Retroviral transduction of triple-KO (lyn−/−hck−/−fgr−/−) bone marrow, leukemia mouse model, kinase inhibitor CGP76030 Nature genetics High 15098032
2005 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. hck−/−fgr−/− knockout mice, pir-b−/− mice, Ca2+ flux assay, MAPK assays, chemotaxis assays, PIR-B phosphorylation state analysis Immunity High 15723811
2005 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. COS-7 cell transfection with wild-type, truncation and kinase-dead Fgr mutants, migration assay, co-immunoprecipitation, Rac GTP-loading assay Experimental cell research High 15561106
2006 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. hck−/−fgr−/− knockout neutrophils, soluble ICAM-1 binding, static adhesion assay, flow chamber, intravital microscopy Journal of immunology High 16785558
2007 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. hck−/−fgr−/− knockout neutrophils, PP2 Src inhibitor, respiratory burst assay, F-actin assay, MAPK/Vav1/PAK phosphorylation immunoblotting, Rac2 GTP pulldown Journal of immunology High 17339487
2007 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. In vitro kinase assay with recombinant Fgr and mitochondrial substrate proteins, mass spectrometry phosphosite mapping FEBS letters Medium 17997986
2008 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. fgr−/−, hck−/−lyn−/−fgr−/−, Tyrobp−/−Fcrg−/− gene-deficient mice, flow chamber, intravital microscopy, Syk/p38 phosphorylation assay, mixed chimeric mice peritonitis model The Journal of experimental medicine High 18794338
2011 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. Fgr siRNA knockdown in mast cells and mice, Fgr overexpression, co-immunoprecipitation with FcεRI, phospho-immunoblotting, degranulation assay, anaphylaxis model Journal of immunology High 21746961
2014 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. Fgr knockout cells and mice, FpSDH tyrosine point mutant, Complex II activity assay, supercomplex analysis, H2O2 activation of Fgr, metabolic assays Cell metabolism High 24856931
2015 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. Triple KO cells (Lck/Hck/Fgr), ectopic kinase expression, phospho-TBK1 antibodies, TBK1 dimerization assay, zebrafish and mouse viral infection models Cell host & microbe High 28618271
2015 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. Reporter gene assays, FCRL4 palmitoylation-defective mutant, overexpression of HCK/FGR in B cells, phospho-tyrosine immunoblotting Journal of immunology Medium 25972488
2016 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. Primary macrophages from single and combined SFK KO mice, small-molecule Src/Arg inhibitors, phagocytosis assay, Leishmania mouse infection model with bosutinib Journal of cell science Medium 27358479
2018 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. Soft agar colony formation assay in Rat-2 fibroblasts, activation loop mutagenesis, hydrogen-deuterium exchange mass spectrometry, SH3-SH2 ligand activation assays Science signaling High 30352950
2018 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. Kinome-wide target profiling, in vitro kinase assay, AML patient bone marrow samples, xenograft mouse model, oral drug administration ACS chemical biology High 29763550
2020 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. Fgr knockout mice, BM transplantation chimeras, HFD feeding model, mitochondrial peroxide scavenging, flow cytometry for macrophage polarization Nature metabolism High 32943786
2020 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. Collagenase/autologous blood thalamic hemorrhage model, Fgr siRNA knockdown, Fgr inhibitor, NF-κB and ERK1/2 phospho-immunoblotting, cytokine ELISA, behavioral pain tests JCI insight Medium 33055425
2005 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. Mouse erythrocyte cell-free system, peroxynitrite treatment, Fgr immune complex kinase assay, PP1α activity assay, fgr/hck KO erythrocytes Free radical biology & medicine Medium 15917191

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. The Journal of experimental medicine 354 9151903
2004 Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nature genetics 327 15098032
1996 Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions. The Journal of cell biology 306 8666673
1984 Gene product of v-fgr onc: hybrid protein containing a portion of actin and a tyrosine-specific protein kinase. Science (New York, N.Y.) 233 6318314
2000 Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn. The Journal of experimental medicine 201 10684859
1994 Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity. Genes & development 201 8125254
2008 PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling. The Journal of experimental medicine 168 18794338
1999 Adhesion-dependent degranulation of neutrophils requires the Src family kinases Fgr and Hck. Journal of immunology (Baltimore, Md. : 1950) 164 9916742
2000 Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary. Endocrinology 163 10830308
1994 Beta 2 integrin-dependent protein tyrosine phosphorylation and activation of the FGR protein tyrosine kinase in human neutrophils. The Journal of cell biology 151 7519620
1998 Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr. Proceedings of the National Academy of Sciences of the United States of America 139 9636192
1993 Association of immunoglobulin G Fc receptor II with Src-like protein-tyrosine kinase Fgr in neutrophils. Proceedings of the National Academy of Sciences of the United States of America 137 8327512
2008 Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science (New York, N.Y.) 136 19039140
1990 The level of c-fgr RNA is increased by EBNA-2, an Epstein-Barr virus gene required for B-cell immortalization. Journal of virology 135 2159528
1999 Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages. Journal of cell science 129 10547366
2014 The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment. The Journal of experimental medicine 116 25225462
1986 fgr proto-oncogene mRNA induced in B lymphocytes by Epstein-Barr virus infection. Nature 109 3003578
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1996 Lyn and Fgr protein-tyrosine kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells. The Journal of biological chemistry 71 8626717
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2011 Functional roles of Src and Fgr in ovarian carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 62 21300758
1996 Activation of SRC family kinases in human neutrophils. Evidence that p58C-FGR and p53/56LYN redistributed to a Triton X-100-insoluble cytoskeletal fraction, also enriched in the caveolar protein caveolin, display an enhanced kinase activity. FEBS letters 62 8603737
1987 Differential expression and regulation of the c-src and c-fgr protooncogenes in myelomonocytic cells. Proceedings of the National Academy of Sciences of the United States of America 60 2440024
2020 Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity. Nature metabolism 59 32943786
2006 Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3. The Journal of investigative dermatology 56 17082781
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2023 An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway. Journal of translational medicine 53 37475042
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2015 SRC2-1 is required in PcINF1-induced pepper immunity by acting as an interacting partner of PcINF1. Journal of experimental botany 48 25922484
2007 Identification of the flavoprotein of succinate dehydrogenase and aconitase as in vitro mitochondrial substrates of Fgr tyrosine kinase. FEBS letters 47 17997986
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2011 The Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis in mice. Journal of immunology (Baltimore, Md. : 1950) 44 21746961
2015 Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2). Scientific reports 43 26548416
2020 Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency. Cell death & disease 42 32703931
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2019 Src family kinases, HCK and FGR, associate with local inflammation and tumour progression in colorectal cancer. Cellular signalling 41 30684564
1999 Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase. The Journal of biological chemistry 40 10066823
1999 Novel association of the src family kinases, hck and c-fgr, with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. Biochemical and biophysical research communications 40 10527858
2018 Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo. ACS chemical biology 39 29763550
2017 Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses. Cell host & microbe 39 28618271
2011 Homeostatic levels of SRC-2 and SRC-3 promote early human adipogenesis. The Journal of cell biology 38 21220509
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2008 Molecular characterization of a pepper C2 domain-containing SRC2 protein implicated in resistance against host and non-host pathogens and abiotic stresses. Planta 36 18204857
2015 The Src-Family Kinases Hck and Fgr Regulate Early Lipopolysaccharide-Induced Myeloid Cell Recruitment into the Lung and Their Ability To Secrete Chemokines. Journal of immunology (Baltimore, Md. : 1950) 34 26232427
2015 miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation. Molecular endocrinology (Baltimore, Md.) 33 26066330
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2019 Human sFLT1 Leads to Severe Changes in Placental Differentiation and Vascularization in a Transgenic hsFLT1/rtTA FGR Mouse Model. Frontiers in endocrinology 31 30949132
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2009 cAMP enhances estrogen-related receptor alpha (ERRalpha) transcriptional activity at the SP-A promoter by increasing its interaction with protein kinase A and steroid receptor coactivator 2 (SRC-2). Molecular endocrinology (Baltimore, Md.) 30 19264843
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2021 PFKFB4 promotes lung adenocarcinoma progression via phosphorylating and activating transcriptional coactivator SRC-2. BMC pulmonary medicine 21 33593309
2016 Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology. Journal of biological rhythms 21 27432117
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2020 Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury. Acta pharmaceutica Sinica. B 19 33643819
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2021 Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis. Cell death discovery 18 34772919
2023 SRC2 controls CD4+ T cell activation via stimulating c-Myc-mediated upregulation of amino acid transporter Slc7a5. Proceedings of the National Academy of Sciences of the United States of America 17 37094160
2005 Protein phosphatase 1alpha is tyrosine-phosphorylated and inactivated by peroxynitrite in erythrocytes through the src family kinase fgr. Free radical biology & medicine 17 15917191
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