Affinage

FES

Tyrosine-protein kinase Fes/Fps · UniProt P07332

Length
822 aa
Mass
93.5 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FES (c-Fps/Fes) is a cytoplasmic non-receptor protein-tyrosine kinase expressed predominantly in myeloid hematopoietic cells (monocyte/macrophage and granulocyte lineages) that acts as a signaling effector downstream of hematopoietic growth factor and immune receptors (PMID:2426571, PMID:2986115). The mature protein autophosphorylates and phosphorylates exogenous tyrosine substrates in vitro, and its catalytic activity resides in a C-terminal kinase domain while its SH2 domain selects Group I phosphopeptide motifs (phospho-Tyr-hydrophilic-hydrophilic-hydrophobic) (PMID:7511210, PMID:2449646). Although intrinsically active in vitro, FES kinase activity is restrained in normal cells, and this restraint is relieved in oncogenic v-fps/fes forms that drive cellular transformation (PMID:6605429, PMID:3352601). FES is activated by GM-CSF, IL-3, and EPO and physically associates with the GM-CSF receptor beta chain, with kinase-inactivating knock-in mice revealing a non-redundant requirement for FES in GM-CSF-induced Stat3/Stat5A phosphorylation (PMID:7682176, PMID:10523632). Downstream, FES phosphorylates BCR to nucleate a GRB2/SOS complex and signals through Ras to ERK and through Ras plus Rac/Cdc42 to JNK (PMID:7529874, PMID:9593727). FES also phosphorylates the PDGFbeta receptor, plexinA1/CRMP2 in semaphorin3A-induced growth cone collapse, and PECAM-1 ITIMs downstream of FcepsilonRI to restrain mast cell degranulation (PMID:9620549, PMID:12093729, PMID:16731527). In innate immunity it limits TLR4 signaling by promoting receptor internalization, accounting for endotoxin hypersensitivity of FES-null mice (PMID:11909942, PMID:16959897). Beyond signaling, FES localizes to Golgi and Rab-marked vesicular compartments and, via its FCH domain, associates with microtubules and gamma-tubulin to promote microtubule bundling and centrosomal nucleation (PMID:11339827, PMID:14551201). FES is an essential effector of oncogenic KIT and FLT3-ITD in leukemic cells, yet functions as a tumor suppressor in epithelial cancers and protects against atherosclerosis by restraining monocyte and smooth muscle cell migration (PMID:15867340, PMID:17595334, PMID:20111072, PMID:36321446).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1983 Medium

    Established that the transforming activity of the fps/fes oncogene resides in a tyrosine kinase encoded by a single conserved cellular locus, defining the gene's core biochemical identity.

    Evidence Cloned viral DNA transfection, immunoprecipitation/in vitro kinase assay, tumor induction, and cross-species molecular hybridization

    PMID:6301150 PMID:6605429

    Open questions at the time
    • Did not define the cellular substrates or physiological regulators of the normal c-fps/fes product
    • Transformation readouts used viral oncogene, not the proto-oncogene
  2. 1985 High

    Defined the human proto-oncogene product p92c-fes as a myeloid-restricted tyrosine kinase, linking the kinase to a specific hematopoietic lineage.

    Evidence Anti-peptide antibody immunoprecipitation, in vitro kinase/enolase phosphorylation, lineage analysis of hematopoietic cells and gene structure determination

    PMID:2426571 PMID:2986115 PMID:2987674 PMID:4065096

    Open questions at the time
    • Did not identify activating receptors or physiological substrates
    • Mechanism of lineage-restricted expression unresolved at this stage
  3. 1987 High

    Mapped the minimal catalytic domain, showing the C-terminal kinase region alone is sufficient for autophosphorylation and substrate phosphorylation.

    Evidence E. coli expression of trpE-v-fps deletion constructs with in vitro kinase assays

    PMID:2449646

    Open questions at the time
    • Used viral v-fps, not the regulated cellular protein
    • Did not address how N-terminal/SH2 regions regulate activity in cells
  4. 1988 High

    Revealed that the normal kinase is intrinsically active yet held in check in vivo, distinguishing the proto-oncogene from its transforming viral counterpart.

    Evidence Stable overexpression in Rat-2 fibroblasts with soft agar, in vivo phosphotyrosine immunoblot, and in vitro kinase controls

    PMID:3352601

    Open questions at the time
    • Molecular basis of the in vivo restraint not defined
    • Did not identify the cellular context where restraint is physiologically relieved
  5. 1993 High

    Placed c-fps/fes downstream of hematopoietic cytokine receptors by demonstrating receptor-induced activation and physical receptor association.

    Evidence Immunoprecipitation/kinase assay and co-IP with GM-CSF receptor beta chain in TF-1 cells; EPO-induced activation

    PMID:7682176 PMID:7685196

    Open questions at the time
    • EPO receptor interaction not demonstrated directly
    • Downstream substrates of receptor-activated FES not yet defined
  6. 1995 High

    Identified BCR as a FES substrate that couples the kinase to Ras signaling and showed the N-terminal BCR-binding domain is required for transformation.

    Evidence Co-expression in Sf-9 cells, co-IP, SH2/domain deletion mutagenesis, and transformation assay

    PMID:7529874

    Open questions at the time
    • Interaction mapped in heterologous insect cells
    • Physiological role of BCR-FES complex in myeloid cells not established
  7. 1998 High

    Dissected the GTPase/MAPK architecture downstream of FES, separating Ras-dependent ERK activation from Ras/Rac/Cdc42-dependent JNK activation.

    Evidence Dominant-negative small G protein co-expression with soft agar and ERK/JNK kinase assays; PDGFbeta receptor phosphorylation/downregulation experiments

    PMID:9593727 PMID:9620549

    Open questions at the time
    • Used activated Fps/Fes transformation context, not normal signaling
    • Direct linkage between FES substrates and GTPase activation incompletely defined
  8. 1999 High

    Demonstrated a non-redundant, kinase-dependent requirement for FES in GM-CSF receptor signaling in vivo via a knock-in mouse.

    Evidence Kinase-inactivating knock-in mouse, immunoblot of Stat3/Stat5A and Erk1/2 in bone marrow-derived macrophages

    PMID:10523632

    Open questions at the time
    • Specificity to GM-CSF over IL-3/IL-6 mechanistically unexplained
    • Direct STAT phosphorylation by FES not shown
  9. 2001 Medium

    Localized FES to Golgi and Rab-marked vesicular compartments, implicating it in vesicular trafficking and distinguishing it from diffusely cytoplasmic Fer.

    Evidence GFP-fusion confocal imaging, colocalization with TGN38 and Rab markers, brefeldin A perturbation

    PMID:11339827

    Open questions at the time
    • Functional consequence of vesicular localization for trafficking not tested
    • Single-lab imaging without orthogonal biochemical fractionation
  10. 2002 High

    Extended FES function beyond hematopoiesis into innate immunity and axon guidance, defining roles in endotoxin response and semaphorin signaling.

    Evidence Fps/fes-null mice with LPS challenge and signaling panels; co-IP and growth cone collapse assays for the PlexA1/Sema3A pathway

    PMID:11909942 PMID:12093729

    Open questions at the time
    • Mechanism connecting FES to endotoxin sensitivity not yet defined in 2002
    • PlexA1 interaction characterized in COS-7 overexpression
  11. 2003 Medium

    Uncovered cytoskeletal and platelet functions and established functional redundancy with Fer in hematopoiesis.

    Evidence Microtubule bundling/gamma-tubulin colocalization with FCH deletion in MEFs; platelet aggregometry and P-selectin assays; compound Fps/Fer kinase-inactivating knock-in mice

    PMID:12871378 PMID:12901971 PMID:14551201

    Open questions at the time
    • Microtubule and platelet substrates of FES not identified
    • Mechanism of FCH-mediated microtubule nucleation incompletely defined
  12. 2005 High

    Revealed a context-dependent tumor suppressor role in epithelial cancers, with cancer-associated mutations inactivating rather than activating the kinase.

    Evidence Biochemical kinase assays of colorectal cancer-derived mutants, structural modeling, breast cancer mouse model with null/knock-in alleles and transgene rescue

    PMID:15867340

    Open questions at the time
    • Epithelial substrates mediating tumor suppression not identified
    • Reconciliation of suppressor versus oncogenic roles mechanistically open
  13. 2006 High

    Provided mechanistic basis for FES control of innate immunity and immune-receptor signaling via TLR4 internalization and PECAM-1 phosphorylation.

    Evidence Fps/fes-null macrophages with TLR4 internalization assays, NF-kB readouts; FcepsilonRI-activated mast cells with in vitro PECAM-1 phosphorylation and degranulation assays

    PMID:16731527 PMID:16959897

    Open questions at the time
    • How FES promotes TLR4 internalization at the molecular level unresolved
    • Lyn-to-FES activation step in mast cells not fully mapped
  14. 2010 High

    Established FES (with FER) as a non-redundant effector of oncogenic receptor tyrosine kinases in leukemia.

    Evidence RNAi knockdown with proliferation/survival/cell-cycle assays in KIT(D816V) and FLT3-ITD cells, with kinase activation status and GM-CSF rescue

    PMID:17595334 PMID:20111072

    Open questions at the time
    • Direct FES substrates downstream of KIT/FLT3 not defined
    • Whether FES is directly phosphorylated by these receptors versus indirectly activated unclear
  15. 2022 High

    Linked a human CAD risk locus to reduced FES expression and a protective role against atherosclerosis through restraint of cell migration.

    Evidence CRISPR genotype editing, siRNA, phosphoproteomics, migration assays, scRNA-seq, and Fes knockout in ApoE-deficient atherosclerosis model

    PMID:36321446

    Open questions at the time
    • Specific FES substrates governing migration not pinpointed
    • Cell-type-specific contributions of monocyte versus smooth muscle FES not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for the in vivo restraint of FES kinase activity and how the same kinase functions as both an oncogenic effector and a tumor/atherosclerosis suppressor across cell types remains unresolved.
  • No unifying structural mechanism for context-dependent activation/restraint
  • Physiological direct substrates in epithelial and vascular settings not catalogued
  • Vesicular and microtubule functions not connected to a defined signaling output

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005794 Golgi apparatus 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 1
Partners
BCRCSF2RBFLT3KITPDGFRBPECAM1PLEXINA1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 The SH2 domain of fps/fes selects phosphopeptides with the optimal motif phospho-Tyr-hydrophilic-hydrophilic-hydrophobic (Group I SH2 specificity), established using a degenerate phosphopeptide library screen. Degenerate phosphopeptide library binding assay Molecular and cellular biology Medium 7511210
1983 The v-fps transforming gene (without gag sequences) encodes a ~91 kDa protein with associated protein kinase activity and is sufficient for cell transformation and tumor induction, demonstrating that the gag portion of gag-fps fusion is not required for transformation. Transfection of cloned viral DNA, immunoprecipitation, in vitro kinase assay, tumor induction in chicks Journal of virology Medium 6605429
1983 The avian v-fps and mammalian v-fes transforming genes correspond to a single conserved cellular locus (c-fps/fes), with translational products exhibiting protein-tyrosine kinase activity. Molecular hybridization, sequence comparison, biochemical characterization of kinase activity Virology Medium 6301150
1985 The human c-fps/fes product p92c-fes is a 92 kDa protein with tyrosine-specific kinase activity in vitro, capable of autophosphorylation and phosphorylation of exogenous substrate enolase; expression is largely confined to myeloid hematopoietic cells. Immunoprecipitation with anti-fps antiserum, in vitro kinase assay with enolase substrate, cell fractionation Molecular and cellular biology High 2426571
1985 NCP92 (p92c-fes) expression is restricted to cells of the monocyte/macrophage and granulocyte lineages in bone marrow and is not found in B-lymphocytic, T-lymphocytic, or erythroid cells; NCP92 has associated tyrosine kinase activity. Anti-peptide antibody immunoprecipitation, kinase activity assay, analysis of hematopoietic tumors by lineage Proceedings of the National Academy of Sciences of the United States of America High 2986115
1987 The minimal catalytic domain of v-fps (P130gag-fps) begins at the predicted N-terminus of the ATP-binding site (residue 922); polypeptides containing ≥263 C-terminal residues are enzymatically active, autophosphorylate at physiological sites, and phosphorylate exogenous substrates (enolase, poly(glu,tyr)). Expression of trpE-v-fps hybrid proteins in E. coli, in vitro kinase assay, deletion mapping Oncogene High 2449646
1985 The c-fps gene product NCP98 (chicken) and its mammalian counterpart NCP92 show highest expression in macrophages and granulocytic cells; NCP98 kinase activity per cell correlates with peak granulopoiesis in bone marrow, spleen, and bursa. BSA density gradient fractionation of bone marrow cells, kinase activity measurement, complement-mediated lysis depletion Molecular and cellular biology Medium 2987674
1985 The human c-fps/fes gene has a 13 kb genomic locus with 18 exons encoding a 93,390 Da protein (NCP92), deduced from nucleotide sequence; the gene architecture resembles the chicken c-fps locus. Nucleotide sequencing, Southern blot analysis, sequence deduction The EMBO journal Medium 4065096
1988 Human p92c-fes expressed ectopically in Rat-2 fibroblasts is non-transforming despite ~50-fold overexpression; its kinase activity is restrained in vivo (no increase in cellular phosphotyrosine), even though the isolated protein is catalytically active in vitro. This in vivo restraint is lifted for v-fps/fes oncoproteins. Stable transfection, soft agar assay, immunoprecipitation/kinase assay, phosphotyrosine immunoblot, E. coli expression of kinase fragment Molecular and cellular biology High 3352601
1989 FER (the human counterpart of rat flk) encodes a widely expressed 94 kDa protein-tyrosine kinase antigenically and structurally related to fps/fes; FER and fps/fes define a new subfamily of non-receptor PTKs sharing domain structure. cDNA cloning, sequencing, immunoblot with anti-fps antiserum, evolutionary conservation analysis Molecular and cellular biology Medium 2685575
1990 A 13 kb genomic fragment of human c-fps/fes is sufficient for integration-independent, myeloid-specific expression in transgenic mice; expression is proportional to transgene copy number and recapitulates the endogenous myeloid expression pattern. Transgenic mouse generation, RNase protection, tissue distribution analysis Molecular and cellular biology Medium 2188092
1992 v-Fps induces Egr-1 promoter activation as a primary response (without protein synthesis); this responsiveness is mediated by serum response elements (SREs/CArG boxes) in the Egr-1 promoter, linking v-Fps tyrosine kinase activity to SRE-dependent transcription. Transient transfection with CAT reporter, deletion mutagenesis of Egr-1 promoter, co-transfection with v-Fps expression vector Nucleic acids research Medium 1594452
1993 GM-CSF and IL-3 induce tyrosine phosphorylation and kinase activation of p92c-fes in TF-1 cells, and GM-CSF induces physical association between p92c-fes and the beta chain of the GM-CSF receptor, placing c-fps/fes downstream of these hematopoietic growth factor receptors. Immunoprecipitation, in vitro kinase assay, co-immunoprecipitation of p92c-fes with GM-CSF receptor beta chain The EMBO journal High 7682176
1993 Erythropoietin (EPO) induces tyrosine phosphorylation and enhanced kinase activity of p92c-fes in human erythroleukemia TF-1 cells, implicating c-fps/fes in EPO receptor signaling. Immunoprecipitation, in vitro kinase assay, anti-phosphotyrosine immunoblot Blood Medium 7685196
1994 Activated (myristylated) Fps/Fes transforms Rat-2 fibroblasts and drives widespread hypervascularity progressing to multifocal hemangiomas in transgenic mice; fps/fes transcripts localize to endothelial cells of vascular tumors and normal blood vessels, indicating a direct role in angiogenesis regulation. Retroviral transformation assay, transgenic mouse model, in situ RNA hybridization, RNase protection Molecular and cellular biology High 7523858
1995 Spi-1/PU.1 and Spi-B transcription factors bind a site in the c-fes/c-fps promoter and activate c-fes transcription; Spi-1 binds this site in vivo in HL-60 cells, suggesting Spi-1 regulates myeloid-specific c-fes expression. PCR-mediated random site selection, in vitro binding/transcription assay, transfection in HeLa cells, gel shift with HL-60 nuclear extracts Oncogene Medium 7624145
1995 FES phosphorylates BCR on tyrosine residues upon co-expression in Sf-9 cells, forming a stable BCR-FES complex; this interaction involves the FES SH2 domain and a novel N-terminal BCR-binding domain (first 347 aa of FES). Tyrosine-phosphorylated BCR then associates with GRB-2/SOS, linking FES to RAS signaling. Deletion of the N-terminal BCR-binding domain from v-fps abolished transforming activity. Co-expression in Sf-9 insect cells, co-immunoprecipitation, deletion mutagenesis, transformation assay Molecular and cellular biology High 7529874
1996 Endothelial cells from hypervascular fps/fes transgenic mouse yolk sacs show a growth advantage and express high levels of the fps/fes tyrosine kinase, supporting a role in vasculogenesis and angiogenesis. Cell cloning from transgenic yolk sac, Southern blot genotyping, immunoblot for fps/fes expression, Matrigel tube formation assay In vitro cellular & developmental biology. Animal Medium 8792159
1997 fps-transformed fibroblasts show approximately 2-fold elevated concentrations of phosphatidate and diacylglycerol compared to controls, resulting from enhanced phospholipid turnover; ceramide concentrations are also elevated ~2.5-fold, linking fps tyrosine kinase activity to bioactive lipid second messenger pathways. Lipid extraction and quantification, phospholipid turnover assay, phosphatase/kinase activity measurements Oncogene Low 9129148
1998 Fps/Fes-induced fibroblast transformation requires Ras, Rac, and Cdc42; ERK activation by v-Fps/Myr-Fes occurs exclusively downstream of Ras, while JNK activation requires both Ras and Rho-family GTPases (Rac and Cdc42), defining the small G protein/MAPK cascades through which Fps/Fes signals. Dominant-negative small G protein co-expression, soft agar transformation assay, ERK and JNK kinase activity measurements The Journal of biological chemistry High 9593727
1998 v-Fps induces tyrosine phosphorylation and activation of the PDGFbeta receptor within minutes of kinase activation; sustained v-Fps expression causes >100-fold downregulation of PDGF receptor protein. Kinase activity of v-Fps is required for both PDGF receptor phosphorylation and downregulation. A kinase-inactive PDGF receptor cannot mediate transformation even when phosphorylated by v-Fps. Immunoprecipitation/kinase assay, immunoblot, soft agar colony formation assay, kinase-inactive PDGF receptor mutant co-expression Oncogene Medium 9620549
1999 Kinase-inactivating missense mutation in murine fps/fes results in dramatically reduced Stat3 and Stat5A tyrosine phosphorylation in response to GM-CSF (but not IL-3 or IL-6) in bone marrow-derived macrophages, and reduced LPS-induced Erk1/2 activation, demonstrating a non-redundant role for Fps/Fes kinase activity in GM-CSF receptor signaling. Knock-in mouse model, flow cytometry, signaling analysis by immunoblot, bone marrow colony-forming assays Molecular and cellular biology High 10523632
2001 Fps/Fes localizes to cytoplasmic vesicles and a perinuclear Golgi region (colocalizing with TGN38), and also colocalizes with Rab proteins involved in both endocytosis (Rab5B, Rab7) and exocytosis (Rab1A, Rab3A); this localization is disrupted by brefeldin A. Fer is diffusely cytoplasmic. This distinct vesicular localization suggests a role for Fps/Fes in vesicular trafficking. GFP fusion proteins, confocal fluorescence microscopy, colocalization with TGN38 and Rab markers, brefeldin A perturbation Experimental cell research Medium 11339827
2002 Fps/Fes-null mice are more sensitive to LPS-induced endotoxicity; fps/fes kinase is involved in but not required for myelopoiesis; phenotypes are rescued by fps/fes transgene. Fps/Fes-null macrophages show no defects in GM-CSF-, IL-6-, or IL-3-induced Stat3/Stat5A activation or LPS-induced IκB degradation, p38, JNK, ERK, or Akt activation. Fps/fes-null mouse model, LPS challenge, flow cytometry, signaling analysis by immunoblot, transgene rescue Molecular and cellular biology High 11909942
2002 Fes/Fps tyrosine kinase interacts with plexinA1 (PlexA1) and phosphorylates PlexA1 on tyrosine; neuropilin-1 (NP-1) attenuates this interaction in resting conditions but semaphorin3A (Sema3A) enhances Fes-PlexA1 association and Fes-mediated phosphorylation of PlexA1, CRAM, and CRMP2. Fes kinase-negative mutants suppress Sema3A-induced growth cone collapse, placing Fes in the Sema3A signaling pathway. Co-immunoprecipitation in COS-7 cells, cell morphology assay, dominant-negative kinase mutant, DRG neuron growth cone collapse assay The EMBO journal High 12093729
2003 Fps/Fes and Fer are expressed in platelets and are activated following collagen/CRP stimulation (GPVI pathway); Fer is also activated by thrombin/PAR4. Fps/Fes-null platelets show increased collagen-induced aggregation and elevated P-selectin surface expression; Fer-deficient platelets disaggregate more rapidly in response to ADP, demonstrating roles for these kinases in platelet aggregation regulation. Immunoprecipitation/kinase assay from platelet lysates, platelet aggregometry, P-selectin flow cytometry, targeted knockout mouse models Journal of thrombosis and haemostasis : JTH Medium 12871378
2003 Fes tyrosine kinase associates with microtubules and promotes microtubule bundling in a kinase-dependent manner; the FCH (Fes/CIP4 homology) domain of Fes colocalizes with gamma-tubulin at microtubule nucleation sites. FCH-deleted Fes blocks centrosome formation, and Fes-deficient mouse embryonic fibroblasts display aberrant microtubule nucleation and centrosome structure. Confocal microscopy, co-localization with gamma-tubulin, microtubule regeneration assay, FCH deletion mutants, Fes-deficient MEFs The Journal of biological chemistry Medium 14551201
2003 Mice lacking both Fps and Fer kinase activities are viable but show reduced fertility, elevated circulating neutrophils/erythrocytes/platelets, reduced bone marrow cellularity, and elevated CD11b(hi)Ly-6G(lo) myeloid cells, demonstrating functional redundancy between Fps and Fer in regulating hematopoiesis. Compound knock-in mouse model, flow cytometry, peripheral blood counts, bone marrow colony-forming assays Experimental hematology Medium 12901971
2005 Three of four somatic fps/fes kinase domain mutations found in colorectal cancers result in kinase inactivation, not activation; a fourth compromises in vivo activity. Tumor onset is accelerated in mice with fps/fes null or kinase-inactivating mutations in a breast cancer model, and restored by fps/fes transgene, suggesting a tumor suppressor role for Fps/Fes in epithelial cells. Biochemical kinase assays of mutant proteins, structural modeling, transgenic/knock-in mouse tumor model, tumor onset kinetics Cancer research High 15867340
2006 Fps/Fes-null macrophages display prolonged LPS-induced IκBα degradation, increased NF-κB p65 phosphorylation, increased TNF-α production, and defective TLR4 internalization compared to wild-type macrophages. This provides a mechanistic basis for enhanced endotoxin sensitivity of Fps/Fes-null mice: Fps/Fes modulates innate immune responses partly by regulating TLR4 internalization. Fps/fes-null macrophage culture, ELISA for TNF-α, immunoblot for IκBα and phospho-p65, TLR4 internalization assay Journal of leukocyte biology High 16959897
2006 FcεRI aggregation in mast cells leads to increased Fer/Fps kinase activities in a Lyn-dependent manner (independent of Syk, Fyn, and Gab2). Activated Fer/Fps phosphorylate PECAM-1 ITIMs and Tyr700 in vitro and in transfected cells. Mast cells devoid of Fer/Fps kinase activities show reduced PECAM-1 phosphorylation and exaggerated degranulation at low antigen doses. Kinase activity assay, in vitro phosphorylation of PECAM-1, transfected cell phosphorylation, mast cells from kinase-deficient mice, degranulation assay The Journal of biological chemistry High 16731527
2007 FES is phosphorylated on tyrosine residues in cells harboring KIT(D816V) in a KIT-dependent manner; RNAi-mediated reduction of FES expression decreases cell proliferation in human and murine cells with KIT(D816V) or KIT(D814Y), and the growth defect is rescued by GM-CSF. FES knockdown alters signaling downstream of KIT(D816V), identifying FES as an essential effector of oncogenic KIT. RNAi knockdown, proliferation assay, phosphotyrosine immunoblot, GM-CSF rescue, signaling analysis Blood High 17595334
2010 Both FES and FER are activated in AML blasts and cell lines in a FLT3-dependent manner; RNAi knockdown of FES or FER inhibits proliferation downstream of FLT3-ITD, with FER required for cell cycle transitions and FES necessary for cell survival, demonstrating non-redundant functions of FES and FER downstream of oncogenic FLT3. RNAi knockdown, proliferation/cell cycle/survival assays in AML cell lines, activation status by immunoprecipitation/kinase assay Leukemia Medium 20111072
2022 CRISPR-engineered monocytic cell lines with 15q26.1 CAD risk genotype have reduced FES expression. FES knockdown promotes migration of monocytes and vascular smooth muscle cells and alters phosphorylation of migration-regulating proteins (phosphoproteomics). Fes knockout in ApoE-deficient mice increases atherosclerotic plaque size and monocyte/macrophage and smooth muscle cell content, identifying FES as a protective factor against atherosclerosis. CRISPR genome editing, siRNA knockdown, phosphoproteomics, migration assays, scRNA-seq, Fes knockout in ApoE-deficient mouse atherosclerosis model Circulation research High 36321446

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Molecular and cellular biology 840 7511210
2000 Maturation of cellular Fe-S proteins: an essential function of mitochondria. Trends in biochemical sciences 298 10916152
2003 The role of Fe-S proteins in sensing and regulation in bacteria. Current opinion in microbiology 280 12732309
2010 Building Fe-S proteins: bacterial strategies. Nature reviews. Microbiology 267 20467446
2008 Fe-S cluster assembly pathways in bacteria. Microbiology and molecular biology reviews : MMBR 262 18322036
2010 Structural basis for Fe-S cluster assembly and tRNA thiolation mediated by IscS protein-protein interactions. PLoS biology 217 20404999
2002 Closing in on the biological functions of Fps/Fes and Fer. Nature reviews. Molecular cell biology 203 11994747
2015 Emerging critical roles of Fe-S clusters in DNA replication and repair. Biochimica et biophysica acta 184 25655665
1993 c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3. The EMBO journal 178 7682176
1988 Novel protein-tyrosine kinase cDNAs related to fps/fes and eph cloned using anti-phosphotyrosine antibody. Oncogene 173 2485255
2009 Nanostructured FeS as a mimic peroxidase for biocatalysis and biosensing. Chemistry (Weinheim an der Bergstrasse, Germany) 164 19267381
2017 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. Nature communications 161 29097656
1985 Specific expression of the human cellular fps/fes-encoded protein NCP92 in normal and leukemic myeloid cells. Proceedings of the National Academy of Sciences of the United States of America 161 2986115
2005 In vitro characterization of salmochelin and enterobactin trilactone hydrolases IroD, IroE, and Fes. Journal of the American Chemical Society 154 16076215
2009 Iron-sulfur (Fe/S) protein biogenesis: phylogenomic and genetic studies of A-type carriers. PLoS genetics 146 19478995
1997 Superoxide-driven aconitase FE-S center cycling. Bioscience reports 146 9171919
2014 Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry. Biochemistry 134 24971490
1985 Expression of the mammalian c-fes protein in hematopoietic cells and identification of a distinct fes-related protein. Molecular and cellular biology 131 2426571
2017 Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proceedings of the National Academy of Sciences of the United States of America 127 28634302
2010 Frataxin and mitochondrial FeS cluster biogenesis. The Journal of biological chemistry 126 20522547
2014 Interplay between oxygen and Fe-S cluster biogenesis: insights from the Suf pathway. Biochemistry 119 25153801
1985 The structure of the human c-fes/fps proto-oncogene. The EMBO journal 113 4065096
2020 Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis. Trends in biochemical sciences 109 32311335
1995 DNA binding specificities of Spi-1/PU.1 and Spi-B transcription factors and identification of a Spi-1/Spi-B binding site in the c-fes/c-fps promoter. Oncogene 108 7624145
2002 Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling. The EMBO journal 98 12093729
2014 Alternative FeS cluster ligands: tuning redox potentials and chemistry. Current opinion in chemical biology 97 24463764
2014 Mössbauer spectroscopy of Fe/S proteins. Biochimica et biophysica acta 97 25498248
1993 Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. Blood 93 7685196
1994 The Fps/Fes protein-tyrosine kinase promotes angiogenesis in transgenic mice. Molecular and cellular biology 92 7523858
2014 Mammalian Fe-S cluster biogenesis and its implication in disease. Biochimie 89 24440636
2014 Assembly of Fe/S proteins in bacterial systems: Biochemistry of the bacterial ISC system. Biochimica et biophysica acta 81 25510311
2006 Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. The EMBO journal 81 16424901
2020 Fe-S cluster biogenesis by the bacterial Suf pathway. Biochimica et biophysica acta. Molecular cell research 77 32822728
1990 Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice. Molecular and cellular biology 73 2188092
2015 How Is Fe-S Cluster Formation Regulated? Annual review of microbiology 72 26488283
1997 Bovine-heart NADH:ubiquinone oxidoreductase is a monomer with 8 Fe-S clusters and 2 FMN groups. Biochimica et biophysica acta 69 9030258
1983 A fps gene without gag gene sequences transforms cells in culture and induces tumors in chickens. Journal of virology 63 6605429
1996 Isolation and propagation of yolk-sac-derived endothelial cells from a hypervascular transgenic mouse expressing a gain-of-function fps/fes proto-oncogene. In vitro cellular & developmental biology. Animal 61 8792159
2015 Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology 60 25609768
2014 Recent advances in the Suf Fe-S cluster biogenesis pathway: Beyond the Proteobacteria. Biochimica et biophysica acta 59 25447545
1998 The c-Fes family of protein-tyrosine kinases. Critical reviews in oncogenesis 59 9754447
2018 Mitochondrial complex III Rieske Fe-S protein processing and assembly. Cell cycle (Georgetown, Tex.) 58 29243944
2014 TtcA a new tRNA-thioltransferase with an Fe-S cluster. Nucleic acids research 56 24914049
1995 Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS. Molecular and cellular biology 55 7529874
2016 Roles of Fe-S proteins: from cofactor synthesis to iron homeostasis to protein synthesis. Current opinion in genetics & development 54 27061491
2011 Fe-S clusters, fragile sentinels of the cell. Current opinion in microbiology 54 21288764
1997 Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts. Oncogene 52 9129148
2021 Two stripe rust effectors impair wheat resistance by suppressing import of host Fe-S protein into chloroplasts. Plant physiology 51 34890460
2017 Fe-S Clusters Emerging as Targets of Therapeutic Drugs. Oxidative medicine and cellular longevity 51 29445445
1985 Preferential expression of the c-fps protein in chicken macrophages and granulocytic cells. Molecular and cellular biology 51 2987674
2023 Monitoring Fe-S cluster occupancy across the E. coli proteome using chemoproteomics. Nature chemical biology 50 36635565
1989 The FER gene is evolutionarily conserved and encodes a widely expressed member of the FPS/FES protein-tyrosine kinase family. Molecular and cellular biology 50 2685575
2002 Enhanced endotoxin sensitivity in fps/fes-null mice with minimal defects in hematopoietic homeostasis. Molecular and cellular biology 46 11909942
1983 Transforming genes of avian (v-fps) and mammalian (v-fes) retroviruses correspond to a common cellular locus. Virology 46 6301150
2006 RNA silencing of mitochondrial m-Nfs1 reduces Fe-S enzyme activity both in mitochondria and cytosol of mammalian cells. The Journal of biological chemistry 45 16787928
2019 The SUF system: an ABC ATPase-dependent protein complex with a role in Fe-S cluster biogenesis. Research in microbiology 43 31419582
1994 c-fes expression in ontogenetic development and hematopoietic differentiation. Oncogene 42 8108116
2024 METTL17 is an Fe-S cluster checkpoint for mitochondrial translation. Molecular cell 41 38199006
2022 16α-18F-fluoro-17β-Fluoroestradiol (FES): Clinical Applications for Patients With Breast Cancer. Seminars in nuclear medicine 41 35379454
2016 The DUF59 Containing Protein SufT Is Involved in the Maturation of Iron-Sulfur (FeS) Proteins during Conditions of High FeS Cofactor Demand in Staphylococcus aureus. PLoS genetics 41 27517714
2012 Mutation in the Fe-S scaffold protein Isu bypasses frataxin deletion. The Biochemical journal 41 21936771
2007 The tyrosine kinase FES is an essential effector of KITD816V proliferation signal. Blood 40 17595334
2022 The FES Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis. Circulation research 39 36321446
1999 Targeted disruption of the murine fps/fes proto-oncogene reveals that Fps/Fes kinase activity is dispensable for hematopoiesis. Molecular and cellular biology 39 10523632
2023 Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes. Molecular cell 38 36893757
2016 Reductive transformation of hexabromocyclododecane (HBCD) by FeS. Water research 38 27262547
1987 Catalytic and non-catalytic domains of the Fujinami sarcoma virus P130gag-fps protein-tyrosine kinase distinguished by the expression of v-fps polypeptides in Escherichia coli. Oncogene 38 2449646
2001 Subcellular localization analysis of the closely related Fps/Fes and Fer protein-tyrosine kinases suggests a distinct role for Fps/Fes in vesicular trafficking. Experimental cell research 36 11339827
1988 The human c-fps/fes gene product expressed ectopically in rat fibroblasts is nontransforming and has restrained protein-tyrosine kinase activity. Molecular and cellular biology 36 3352601
2018 The ErpA/NfuA complex builds an oxidation-resistant Fe-S cluster delivery pathway. The Journal of biological chemistry 35 29626095
1998 Fibroblast transformation by Fps/Fes tyrosine kinases requires Ras, Rac, and Cdc42 and induces extracellular signal-regulated and c-Jun N-terminal kinase activation. The Journal of biological chemistry 35 9593727
1986 Antipeptide antiserum identifies a widely distributed cellular tyrosine kinase related to but distinct from the c-fps/fes-encoded protein. Molecular and cellular biology 35 3023866
2012 FES/FER kinase signaling in hematopoietic cells and leukemias. Frontiers in bioscience (Landmark edition) 34 22201778
2010 Polysaccharide from fuzi (FPS) prevents hypercholesterolemia in rats. Lipids in health and disease 34 20109183
2006 Fer and Fps/Fes participate in a Lyn-dependent pathway from FcepsilonRI to platelet-endothelial cell adhesion molecule 1 to limit mast cell activation. The Journal of biological chemistry 34 16731527
2020 Structural insights into Fe-S protein biogenesis by the CIA targeting complex. Nature structural & molecular biology 33 32632277
2003 Role for Fes/Fps tyrosine kinase in microtubule nucleation through is Fes/CIP4 homology domain. The Journal of biological chemistry 33 14551201
2006 The Fps/Fes kinase regulates the inflammatory response to endotoxin through down-regulation of TLR4, NF-kappaB activation, and TNF-alpha secretion in macrophages. Journal of leukocyte biology 32 16959897
2007 Geranylgeranyl diphosphate synthase in fission yeast is a heteromer of farnesyl diphosphate synthase (FPS), Fps1, and an FPS-like protein, Spo9, essential for sporulation. Molecular biology of the cell 31 17596513
2000 Identification of the [Fe-S] cluster-binding residues of Escherichia coli biotin synthase. The Journal of biological chemistry 30 10788513
1987 Structure of the feline c-fes/fps proto-oncogene: genesis of a retroviral oncogene. Journal of virology 30 3553615
2022 Fe-S clusters masquerading as zinc finger proteins. Journal of inorganic biochemistry 29 35247854
2018 The NMR contribution to protein-protein networking in Fe-S protein maturation. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 29 29569085
2016 Mammalian Fe-S proteins: definition of a consensus motif recognized by the co-chaperone HSC20. Metallomics : integrated biometal science 28 27714045
1992 v-Fps-responsiveness in the Egr-1 promoter is mediated by serum response elements. Nucleic acids research 28 1594452
2021 A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation. Biomedicines 27 34440194
2017 RecQ and Fe-S helicases have unique roles in DNA metabolism dictated by their unwinding directionality, substrate specificity, and protein interactions. Biochemical Society transactions 27 29273621
2020 Inhibition of RAGE by FPS-ZM1 alleviates renal injury in spontaneously hypertensive rats. European journal of pharmacology 26 32502492
2014 Fe/S protein biogenesis in trypanosomes - A review. Biochimica et biophysica acta 26 25196712
2011 Iron chaperones for mitochondrial Fe-S cluster biosynthesis and ferritin iron storage. Current opinion in chemical biology 26 21288761
2010 FES kinases are required for oncogenic FLT3 signaling. Leukemia 26 20111072
2003 Fps/Fes and Fer protein-tyrosinekinases play redundant roles in regulating hematopoiesis. Experimental hematology 26 12901971
1992 Expression of truncated transcripts of the proto-oncogene c-fps/fes in human lymphoma and lymphoid leukemia cell lines. Oncogene 26 1373879
2021 Sulfur Administration in Fe-S Cluster Homeostasis. Antioxidants (Basel, Switzerland) 25 34829609
2018 Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis. The Journal of biological chemistry 24 29773647
2018 Fe-S Cluster Assembly in Oxymonads and Related Protists. Molecular biology and evolution 24 30184127
2005 An identity crisis for fps/fes: oncogene or tumor suppressor? Cancer research 24 15867340
2003 Fps/Fes and Fer non-receptor protein-tyrosine kinases regulate collagen- and ADP-induced platelet aggregation. Journal of thrombosis and haemostasis : JTH 24 12871378
1998 v-fps causes transformation by inducing tyrosine phosphorylation and activation of the PDGFbeta receptor. Oncogene 23 9620549
2023 The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth. Cell discovery 21 37488138

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