Affinage

CSF3

Granulocyte colony-stimulating factor · UniProt P09919

Round 2 corrected
Length
207 aa
Mass
22.3 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSF3 (G-CSF) is a secreted four-α-helix bundle glycoprotein that functions as the principal cytokine driving granulopoiesis, neutrophil mobilization, and emergency myelopoiesis. It signals through a homodimeric receptor (G-CSFR) in a 2:2 stoichiometry, activating Jak2/STAT3 and Lyn/c-Cbl/PI3K pathways for proliferation and differentiation, with SOCS3-mediated ubiquitination of G-CSFR at K632 routing the receptor to lysosomes as a negative-feedback brake (PMID:14975238, PMID:17363902, PMID:12149655). G-CSF mobilizes hematopoietic stem/progenitor cells by indirectly suppressing osteoblast-derived CXCL12, directly down-regulating CXCR4 on myeloid cells through the transcriptional repressor Gfi-1, and triggering a TPO/CXCL1/CXCR2-dependent neutrophil motility cascade that requires autophagy (PMID:16037394, PMID:17596540, PMID:21224471, PMID:25788702). Beyond hematopoiesis, G-CSF signals through its receptor on cardiomyocytes (Jak/STAT3-dependent anti-apoptosis), dopaminergic neurons (ERK-dependent survival), and regenerating myoblasts, and serves as the principal pathogenic cytokine in APLAID driven by PLCG2 gain-of-function mutations (PMID:15723072, PMID:16839644, PMID:21422169, PMID:36997670).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1986 High

    Cloning of the CSF3 gene and expression of recombinant G-CSF established it as a single-gene product sufficient for neutrophil colony stimulation and leukemia cell differentiation, resolving the molecular identity of a previously purified activity.

    Evidence cDNA cloning from CHU-2 cells, COS cell expression, CFU-GM assays, WEHI-3B differentiation assays

    PMID:2420009 PMID:2423327 PMID:3484805

    Open questions at the time
    • Receptor identity unknown at this point
    • Signal transduction mechanism undefined
    • In vivo relevance of leukemia differentiation not tested
  2. 1993 High

    Determination of the four-α-helix bundle crystal structure placed G-CSF in the helical cytokine superfamily and provided a structural framework for understanding receptor engagement.

    Evidence X-ray crystallography at 2.2 Å resolution with multiple isomorphous replacement

    PMID:7685117

    Open questions at the time
    • No co-crystal with receptor
    • Stoichiometry of ligand–receptor complex not yet resolved
    • Disulfide bond roles in folding vs. function not fully mapped
  3. 2002 Medium

    Identification of the Jak2/Lyn/c-Cbl/PI3K signaling axis downstream of G-CSFR established that proliferative signaling requires PI3K engagement beyond Jak-STAT activation alone, partitioning receptor outputs into distinct functional modules.

    Evidence Yeast two-hybrid, antisense c-Cbl knockdown in DT40-G-CSFR cells, PI3K activity and DNA synthesis assays

    PMID:12149655

    Open questions at the time
    • Lyn–c-Cbl coupling demonstrated in a single cell system
    • Relative contributions of PI3K vs. ERK to proliferation unresolved
    • In vivo validation lacking
  4. 2005 High

    Genetic deletion of SOCS3 and STAT3 in hematopoietic cells revealed a STAT3→SOCS3 negative-feedback circuit that limits G-CSF signaling amplitude and duration, with SOCS3 loss producing sustained STAT3 activation and neutrophilia, and STAT3 loss de-repressing ERK signaling.

    Evidence Conditional Socs3-KO and Stat3-KO bone marrow, phospho-STAT3/ERK Western blot, MEK inhibitor epistasis, colony assays

    PMID:14975238 PMID:15671148

    Open questions at the time
    • Mechanism of SOCS3 binding to G-CSFR not yet mapped to specific residues
    • Whether SOCS3 controls receptor degradation or only signal attenuation unknown
  5. 2005 High

    G-CSF was shown to mobilize hematopoietic progenitors by indirectly suppressing osteoblast function and CXCL12 expression in bone marrow, establishing the niche-disruption model of mobilization.

    Evidence G-CSFR transgenic mouse series with graded mobilization capacity, osteoblast histomorphometry, CXCL12 mRNA/protein quantification

    PMID:16037394

    Open questions at the time
    • Intermediate cell type relaying signal from G-CSFR+ cells to osteoblasts unidentified
    • Mechanism of osteoblast suppression unknown
  6. 2006 High

    The mobilization mechanism was refined: G-CSF directly down-regulates CXCR4 on myeloid cells via the transcriptional repressor Gfi-1 (shown by ChIP at the CXCR4 promoter), while also operating a parallel TPO→CXCL1→CXCR2 cascade for neutrophil motility, revealing two complementary mobilization arms.

    Evidence Flow cytometry of CXCR4, SDF-1 migration assays, Gfi-1 ChIP at CXCR4 promoter, intravital 2-photon microscopy, CXCR2-KO and TPO-receptor-KO mice

    PMID:16537807 PMID:17596540 PMID:21224471

    Open questions at the time
    • How G-CSF induces Gfi-1 expression mechanistically not defined
    • Whether Gfi-1 and CXCL1 pathways are redundant or additive not established
  7. 2006 Medium

    Receptor stoichiometry was established as a 2:2 G-CSF:G-CSFR complex with site II and site III interfaces analogous to IL-6/gp130, and G-CSF was shown to promote E-selectin ligand expression on mobilized myeloid cells by upregulating specific glycosyltransferases.

    Evidence Antibody epitope mapping, mutagenesis, receptor fragment solution binding, parallel-plate flow assay, intravital microscopy, glycosyltransferase transcript analysis

    PMID:16720384 PMID:16980970

    Open questions at the time
    • No crystal structure of the G-CSF:G-CSFR complex
    • Functional contribution of each glycosyltransferase not individually tested
  8. 2007 High

    SOCS3-mediated ubiquitination of G-CSFR at K632 was identified as the mechanism routing the receptor from early endosomes to lysosomes; K632 mutation caused sustained STAT5/ERK activation and disrupted the proliferation-to-differentiation switch, connecting receptor trafficking to lineage fate decisions.

    Evidence K632 point mutagenesis, endosomal fractionation, ubiquitination assays, phospho-STAT5/ERK Western blot, myeloid differentiation assays

    PMID:17363902

    Open questions at the time
    • E3 ligase recruited by SOCS3 for K632 ubiquitination not identified
    • Whether additional ubiquitination sites exist on G-CSFR unknown
  9. 2010 High

    Gfi-1 was positioned upstream of Ras/ERK signaling through its transcriptional target RasGRP1: Gfi1-null cells fail to activate ERK in response to G-CSF, and RasGRP1 re-expression rescues both ERK activation and neutrophil differentiation, linking the Gfi-1 transcriptional program to a specific kinase cascade.

    Evidence Gfi1-KO mice, phospho-ERK Western blot, RasGRP1 re-expression rescue, neutrophil differentiation assays

    PMID:20203268

    Open questions at the time
    • Whether RasGRP1 is sufficient or only necessary for full ERK activation by G-CSF
    • Other Gfi-1 targets contributing to neutrophil differentiation not catalogued
  10. 2005 High

    G-CSF receptor expression and direct signaling on cardiomyocytes and dopaminergic neurons established extra-hematopoietic cytoprotective roles: Jak/STAT3 in heart and ERK/Bad/Bcl-xL in neurons, broadening G-CSF biology beyond the myeloid lineage.

    Evidence G-CSFR immunostaining on cardiomyocytes and substantia nigra neurons, dominant-negative STAT3 transgenic mice, MEK/ERK inhibitor epistasis, apoptosis assays, 6-OHDA neurotoxicity model

    PMID:15723072 PMID:16839644

    Open questions at the time
    • Source of endogenous G-CSF reaching neurons in vivo not identified
    • Whether neuronal G-CSFR signaling is physiologically relevant or pharmacological only
  11. 2015 High

    Autophagy was identified as specifically required for G-CSF-dependent (but not AMD3100-dependent) mobilization of neutrophils and HSCs, adding a cell-autonomous metabolic requirement to the mobilization pathway.

    Evidence Autophagy-deficient mice, G-CSF vs. AMD3100 mobilization comparison, autophagy flux assays in human and mouse cells

    PMID:25788702

    Open questions at the time
    • Molecular target of autophagy in mobilization (cargo identity) unknown
    • Whether autophagy acts on the progenitor or the niche side not determined
  12. 2021 Medium

    MLKL-dependent endosomal membrane pore formation was shown to control unconventional G-CSF release from leukemic progenitors, revealing a necroptosis-pathway component repurposed for cytokine secretion and myeloid differentiation.

    Evidence Mlkl-KO mice, intracellular G-CSF quantification, endosomal colocalization, membrane pore assay, myeloid differentiation assays

    PMID:34079078

    Open questions at the time
    • Whether MLKL-dependent G-CSF release operates in non-leukemic progenitors unknown
    • Signal that activates MLKL for secretion vs. necroptosis not defined
    • Single-lab finding
  13. 2023 High

    G-CSF was identified as the principal pathogenic driver of autoinflammation in APLAID (PLCG2 p.Ser707Tyr): anti-G-CSF antibody completely reversed established disease, demonstrating that excess G-CSF is both necessary and sufficient for the inflammatory phenotype.

    Evidence APLAID knock-in mouse, anti-G-CSF antibody therapy, bone marrow transplantation, cytokine profiling, immune cell flow cytometry

    PMID:36997670

    Open questions at the time
    • How PLCG2 gain-of-function drives G-CSF overproduction mechanistically not established
    • Non-hematopoietic cellular source of G-CSF in APLAID not identified
    • Relevance to human APLAID patients not yet tested therapeutically

Open questions

Synthesis pass · forward-looking unresolved questions
  • No crystal structure of the G-CSF:G-CSFR signaling complex exists, the molecular basis of differential pathway activation (STAT3 vs. ERK) in different cell types remains unexplained, and the intermediate cell type that relays G-CSF signals to suppress osteoblasts during mobilization is unidentified.
  • Co-crystal of G-CSF:G-CSFR complex needed
  • Cell-type-specific pathway selection mechanism unknown
  • Identity of intermediate niche cell suppressing osteoblasts undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 9 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 1
Partners
CSF3RGFI1JAK2LYNMLKLRASGRP1SOCS3STAT3

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 The gene encoding human G-CSF (CSF3) was cloned from a squamous carcinoma cell line (CHU-2); the cDNA expressed in COS cells produced a protein with authentic G-CSF activity. Two mRNA isoforms arise from alternative splicing of the second intron. The mature secreted protein is O-glycosylated (Thr-133) with MW ~19,600 Da. cDNA cloning, COS cell expression, competitive radioligand binding assay, biochemical characterization Nature / EMBO Journal High 2423327 3484805
1986 Recombinant human G-CSF (expressed in E. coli) supports neutrophil colony formation (CFU-GM assay), induces terminal differentiation of WEHI-3B(D+) myelomonocytic leukemia cells, and supports early erythroid and mixed colonies. Leukemic cells bearing G-CSF receptors (demonstrated by 125I-labeled ligand binding) undergo terminal differentiation to macrophages and granulocytes. Recombinant protein expression, CFU-GM colony assay, competitive radioligand binding, cell differentiation assays Science High 2420009
1990 Natural and recombinant human G-CSF both contain a free Cys-17 and two intramolecular disulfide bonds (Cys-36/Cys-42 and Cys-64/Cys-74), with O-glycosylation at Thr-133; both forms exhibit equivalent biological activity in vitro and in vivo. Protein purification, amino acid sequencing, biochemical disulfide mapping, CD spectroscopy, colony-forming and in vivo bioassays Journal of biochemistry High 1692828
1991 Two alternatively spliced forms of the G-CSF receptor (G-CSFR) both transduce G-CSF proliferative signals when expressed in IL-3-dependent BAF/BO3 or IL-6-dependent B9 cells. A cytoplasmic-domain deletion mutant fails to confer G-CSF responsiveness, indicating that the first 96 amino acids of the cytoplasmic domain are required for signal transduction. cDNA transfection into cytokine-dependent cell lines, growth assays, radioligand binding The New biologist High 1725961
1993 X-ray crystal structure of recombinant human G-CSF at 2.2 Å resolution reveals a four-α-helix bundle with up-up-down-down connectivity, placing it in the same structural superfamily as growth hormone, GM-CSF, interferon-β, IL-2, and IL-4, suggesting a conserved receptor-binding mechanism. X-ray crystallography (multiple isomorphous replacement, 2.2 Å resolution) Proceedings of the National Academy of Sciences of the United States of America High 7685117
1995 G-CSF is cleared from the body primarily via receptor-mediated endocytosis in bone marrow; elimination is saturable with a Km (~107 pM) matching the receptor dissociation constant (Kd), and receptor downregulation after excess G-CSF reduces tissue uptake clearance, which recovers as receptors are replenished. Steady-state infusion pharmacokinetics in rats, 125I-labeled ligand tissue uptake assays, cyclophosphamide and repeated-dosing receptor modulation experiments The American journal of physiology High 7543246
2002 rhG-CSF aggregation under physiological conditions (pH 6.9, 37°C) proceeds through a reversible dimer intermediate that does not itself participate in irreversible aggregation; sucrose stabilizes the native monomeric state by thermodynamic preferential exclusion, reducing the population of structurally expanded intermediates that seed aggregation. Biochemical aggregation assays, hydrogen-deuterium exchange, thermal unfolding, sucrose stabilization experiments Biochemistry High 12009905
2002 G-CSF receptor (G-CSFR) engages the Jak2 and Lyn non-receptor tyrosine kinases upon ligand binding. Lyn phosphorylates c-Cbl, which couples to PI3-kinase; the c-Cbl/PI3-kinase pathway is required for G-CSF-induced proliferative (DNA synthesis) signaling, whereas Jak-STAT activation alone is insufficient for proliferation. Yeast two-hybrid (Lyn–c-Cbl–PI3K coupling), antisense knockdown of c-Cbl in DT40 cells expressing G-CSFR, Jak-STAT and PI3-kinase activity assays, DNA synthesis measurement Oncogene Medium 12149655
2004 SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells: hematopoietic-specific Socs3-knockout mice display prolonged STAT3 activation and enhanced cellular responses to G-CSF (increased cloning frequency, survival, proliferation, neutrophilia, and progenitor mobilization), demonstrating that SOCS3 normally limits the amplitude and duration of G-CSF/STAT3 signaling. Conditional Socs3 gene knockout (hematopoietic cells), in vitro G-CSF stimulation assays, in vivo G-CSF injection, phospho-STAT3 Western blot Immunity High 14975238
2005 G-CSF acts directly on cardiomyocytes (which express G-CSF receptor) and activates the Jak/STAT3 pathway; this signaling induces anti-apoptotic proteins, reduces cardiomyocyte and endothelial cell apoptosis, and increases vascularization after myocardial infarction. Overexpression of dominant-negative STAT3 in cardiomyocytes abolishes all these protective effects. Dominant-negative STAT3 transgenic mice, G-CSF receptor immunostaining on cardiomyocytes, Jak/STAT phosphorylation assays, apoptosis assays, cardiac function measurement, vascularization histology Nature medicine High 15723072
2005 Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression: Stat3-deficient hematopoietic cells have near-absent SOCS3, sustained ERK1/2 activation (not STAT3) in response to G-CSF, and augmented G-CSF-driven proliferation that is abolished by MEK1 inhibition. Conditional Stat3-knockout bone marrow cells, G-CSF stimulation, phospho-ERK/STAT3 Western blot, MEK1 inhibitor (PD98059), colony proliferation assays Stem cells High 15671148
2005 G-CSF potently suppresses osteoblast activity and reduces CXCL12 (SDF-1) mRNA/protein expression in bone marrow via an indirect mechanism (G-CSF receptor is not expressed on osteoblasts); the degree of CXCL12 reduction correlates with the degree of hematopoietic progenitor cell (HPC) mobilization across transgenic G-CSFR mouse lines with different mobilization capacities. G-CSFR transgenic mouse series with variable mobilization, cell sorting, osteoblast histomorphometry, osteocalcin expression, CXCL12 mRNA/protein quantification Blood High 16037394
2006 G-CSF directly down-regulates CXCR4 expression on myeloid (Gr1+) bone marrow cells in a time-dependent manner, reducing their responsiveness to SDF-1 in attachment and migration assays, thereby promoting their mobilization to peripheral blood; non-myeloid cells show no CXCR4 change. Flow cytometry of CXCR4 surface expression, SDF-1 migration/attachment assays, in vivo G-CSF mobilization in mice Blood High 16537807
2006 G-CSF induces the transcriptional repressor Gfi-1 in myeloid cells; Gfi-1 binds to DNA sequences upstream of the CXCR4 gene and represses CXCR4 transcription, thereby reducing SDF-1 responsiveness and facilitating granulocytic cell mobilization from bone marrow. In vitro and in vivo G-CSF treatment, Gfi-1 expression analysis, chromatin immunoprecipitation (ChIP) at CXCR4 promoter, migration assays Blood High 17596540
2006 G-CSF promotes expression of E-selectin ligands (HCELL and a ~65 kDa ligand) on mobilized human myeloid cells by upregulating glycosyltransferases (ST3GalIV, FucT-IV, FucT-VII), resulting in heightened E-selectin-mediated adhesion to inflamed endothelium under physiological flow conditions. Parallel-plate flow assay, intravital microscopy, flow cytometry, enzymatic treatments, glycosyltransferase transcript quantification, in vitro G-CSF treatment of bone marrow Nature medicine High 16980970
2006 G-CSF receptor is expressed on dopaminergic neurons in the substantia nigra; G-CSF activates the ERK pathway (not JAK/STAT) in these neurons, increases phospho-Bad and Bcl-xL, inhibits 6-OHDA-induced caspase-3 activation, and protects dopaminergic neurons from 6-OHDA neurotoxicity; ERK inhibition abrogates all neuroprotective effects. Immunostaining for G-CSFR in substantia nigra and mesencephalic cultures, 6-OHDA neurotoxicity model, phospho-ERK/Bad/Bcl-xL Western blot, caspase-3 activity, MEK/ERK inhibitor epistasis Neurobiology of aging Medium 16839644
2006 The G-CSF receptor has a 2:2 stoichiometry with G-CSF, with two binding sites on both the ligand and receptor equivalent to sites II and III of the IL-6/gp130 receptor complex, as established by mapping of neutralizing antibody binding sites, solution studies of receptor fragments, and mutagenesis, validated against the crystal structure of gp130 bound to viral IL-6. Neutralizing antibody epitope mapping, solution binding studies with receptor fragments, site-directed mutagenesis, comparative structural modeling Frontiers in bioscience Medium 16720384
2007 SOCS3 controls lysosomal routing of G-CSFR: a juxtamembrane lysine residue (K632) is required for SOCS3-mediated ubiquitination and routing of G-CSFR to lysosomes. Mutation of K632 causes G-CSFR accumulation in early endosomes and sustained activation of STAT5 and ERK (but not PKB/Akt), and perturbs the proliferation/differentiation balance in myeloid progenitors. K632 point mutagenesis of G-CSFR, endosomal fractionation/localization, phospho-STAT5/ERK/Akt Western blot, ubiquitination assays, myeloid differentiation assays The EMBO journal High 17363902
2008 SAA (serum amyloid A) induces G-CSF expression and neutrophilia via TLR2: SAA stimulates G-CSF mRNA and protein in macrophages, activates NF-κB binding to the CK-1 element of the G-CSF promoter, and this induction is blocked by anti-TLR2 antibody, absent in TLR2-deficient macrophages, and abolished in vivo in G-CSF- or TLR2-deficient mice. Anti-TLR2 antibody blocking, TLR2-KO macrophages, in vitro reconstitution, G-CSF KO mice, NF-κB EMSA, in vivo neutrophilia measurement Blood High 18952897
2010 Transcription factor Gfi1 promotes expression of RasGRP1 (a Ras guanine nucleotide exchange factor) in myeloid cells; RasGRP1 is required for G-CSF to activate Ras/MEK/ERK signaling. Gfi1-null cells fail to activate ERK in response to G-CSF and cannot differentiate into neutrophils; re-expression of RasGRP1 in Gfi1-deficient cells rescues ERK activation and neutrophil maturation by G-CSF. Gfi1-knockout mice, G-CSF stimulation with phospho-ERK/STAT1/STAT3 Western blot, RasGRP1 re-expression rescue, neutrophil differentiation assays Blood High 20203268
2011 G-CSF receptor (G-CSFR) is expressed on myoblasts during embryonic somite development and transiently on regenerating myocytes in injured adult muscle; neutralization of endogenous G-CSF impairs skeletal muscle regeneration, exogenous G-CSF promotes regeneration by stimulating myoblast proliferation, and G-CSFR-knockout mice show markedly impaired muscle regeneration. G-CSFR immunostaining in developing and regenerating muscle, G-CSF neutralizing antibody, recombinant G-CSF administration, G-CSFR-KO mice, BrdU myoblast proliferation assay The Journal of experimental medicine High 21422169
2011 G-CSF induces rapid induction of CXCL1 (KC) in bone marrow via a thrombopoietin (TPO)-mediated pathway: G-CSF rapidly increases BM TPO levels, TPO stimulates megakaryocytes and endothelial cells to release KC, KC then activates CXCR2 on neutrophils to induce their motility and vascular entry; mice lacking CXCR2 or the TPO receptor show impaired G-CSF-driven neutrophil mobilization. Intravital 2-photon microscopy, CXCR2-KO and TPO-receptor-KO mice, CXCR2-blocking antibody, intravital chemokine spike measurement, megakaryocyte isolation and KC secretion assays Blood High 21224471
2011 G-CSF improves G6PC3-deficient neutrophil function in vivo by normalizing PI3K/Akt signaling, reducing caspase-3 activity, and restoring energy homeostasis (increased glucose uptake, elevated G6P, lactate, and ATP), thereby correcting both neutropenia and functional deficits. G6pc3-KO mice, in vivo G-CSF therapy, flow cytometric apoptosis (caspase-3, PI3K/Akt), metabolic assays (glucose uptake, G6P, lactate, ATP), neutrophil functional assays Blood High 21292774
2015 G-CSF activates autophagy in neutrophils and hematopoietic stem cells (HSCs); G-CSF-induced neutrophil and HSC mobilization is impaired in autophagy-deficient animals, whereas direct HSC mobilization by AMD3100 (CXCR4 antagonist) is autophagy-independent, demonstrating that autophagy is specifically required for G-CSF-dependent mobilization. Autophagy-deficient mice, G-CSF and AMD3100 mobilization assays, autophagy flux assays in human and mouse neutrophils and HSCs Blood High 25788702
2015 ERK2 (but not ERK1) specifically mediates LPS-induced G-CSF expression in macrophages: shRNA knockdown of ERK2 (not ERK1) reduces LPS-stimulated G-CSF promoter activity, mRNA, and protein; ERK2 synergizes with C/EBPβ to activate the G-CSF promoter, and ERK2 is required for LPS-induced chromatin remodeling (DNase I accessibility) and NF-κB/C/EBPβ binding at the G-CSF promoter. shRNA knockdown (ERK1 vs ERK2), G-CSF promoter reporter assay, ChIP for NF-κB p50/p65 and C/EBPβ, DNase I sensitivity assay, MEK1/2 inhibitor (U0126) PloS one Medium 26114754
2019 Trauma-induced emergency hematopoiesis is driven by an IL-1/MyD88-dependent pathway that increases G-CSF production; G-CSF then expands hematopoietic stem cells and multipotent progenitors and increases myeloid-skewed progenitor frequency. Mouse polytrauma model, MyD88-KO and IL-1-pathway-KO mice, G-CSF ELISA, hematopoietic progenitor flow cytometry Journal of immunology Medium 30988118
2020 Cancer-associated adipocyte (CAA)-derived G-CSF promotes breast cancer cell epithelial-mesenchymal transition, migration, and invasion via STAT3 activation; G-CSF upregulates MMP2 and MMP9 as STAT3 target genes; these effects are abrogated by G-CSF-neutralizing antibody, chemical STAT3 inhibitor, or STAT3 siRNA. Co-culture of primary CAAs with TNBC cell lines, recombinant G-CSF treatment, G-CSF neutralizing antibody, STAT3 siRNA/inhibitor, migration/invasion assays, MMP2/MMP9 Western blot Journal of molecular cell biology Medium 32242230
2021 MLKL controls the release of G-CSF from leukemic hematopoietic progenitor cells by associating with early endosomes and mediating plasma membrane pore formation to release intracellularly stored G-CSF; Mlkl-knockout cells retain G-CSF mRNA expression and protein translation but release significantly less G-CSF, impairing myeloid differentiation. Mlkl-knockout gene-targeted mice, intracellular G-CSF protein quantification, G-CSF secretion assay, endosomal co-localization (MLKL/early endosome markers), plasma membrane pore formation assay, myeloid differentiation assays Cell death and differentiation Medium 34079078
2021 M2 macrophage-derived G-CSF promotes trophoblast EMT, migration, and invasion via activation of the PI3K/Akt/ERK1/2 signaling pathway; knockdown or inhibition of these pathways abolishes G-CSF-stimulated trophoblast invasiveness. Co-culture of macrophages with trophoblast cell lines, recombinant G-CSF treatment, PI3K/Akt/ERK1/2 pathway inhibitors, migration/invasion assays, EMT marker Western blot Journal of cellular and molecular medicine Medium 33393205
2023 G-CSF is the principal driver of autoinflammation in APLAID (PLCG2 p.Ser707Tyr mutation): APLAID mice show markedly elevated G-CSF levels (the most distinct cytokine feature); anti-G-CSF antibody treatment completely reverses established disease, normalizes myelopoiesis, and restores lymphocyte numbers; bone marrow transplantation from healthy donors rescues APLAID mice and reduces G-CSF predominantly from non-hematopoietic cells. APLAID knock-in mouse model, anti-G-CSF antibody therapeutic intervention, bone marrow transplantation, cytokine profiling, flow cytometry of immune populations Nature immunology High 36997670

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1986 Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science (New York, N.Y.) 1334 2420009
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1986 Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 808 3484805
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nature medicine 473 15723072
2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature genetics 406 20139978
2005 G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 403 16037394
2015 G-CSF and GM-CSF in Neutropenia. Journal of immunology (Baltimore, Md. : 1950) 285 26254266
2014 G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine & growth factor reviews 250 25131807
2002 Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha, and granulocyte-colony-stimulating factor by human airway epithelial cells. American journal of respiratory cell and molecular biology 243 12034575
2004 SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 231 14975238
1986 The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor. The EMBO journal 228 2423327
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
1993 The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors. Proceedings of the National Academy of Sciences of the United States of America 213 7685117
2008 Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology (Baltimore, Md.) 189 18537187
2006 G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood 186 16537807
2003 G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases. Blood 176 12676791
2011 G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands. Blood 175 21224471
2010 Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization. Leukemia 172 21079612
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2003 Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood 161 12576320
2002 Aggregation of granulocyte colony stimulating factor under physiological conditions: characterization and thermodynamic inhibition. Biochemistry 151 12009905
2010 Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma. Blood 140 20435882
2008 Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood 140 18952897
2009 G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nature reviews. Rheumatology 134 19798030
2015 The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Scientific reports 133 26666576
2010 G-CSF and its receptor in myeloid malignancy. Blood 126 20237318
2006 G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 118 16735597
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2008 Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. International journal of medical sciences 113 18219369
2006 Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor promote malignant growth of cells from head and neck squamous cell carcinomas in vivo. Cancer research 111 16912178
1990 Structural characterization of natural and recombinant human granulocyte colony-stimulating factors. Journal of biochemistry 109 1692828
2002 Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocyte-macrophage colony-stimulating factor on dendritic cell subsets in mice. Blood 106 11877288
2021 G-CSF - A double edge sword in neutrophil mediated immunity. Seminars in immunology 105 34728120
2005 Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. Diabetes 105 15616013
2021 M2 macrophage-derived G-CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy. Journal of cellular and molecular medicine 104 33393205
2005 Endogenous G-CSF and CD34+ cell mobilization after acute myocardial infarction. International journal of cardiology 103 16051386
2007 Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF? Bone marrow transplantation 92 17369869
2002 G-CSF therapy of ongoing experimental allergic encephalomyelitis via chemokine- and cytokine-based immune deviation. Journal of immunology (Baltimore, Md. : 1950) 91 11823538
2002 G-CSF: function and modes of action (Review). International journal of molecular medicine 85 12060844
2001 Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 84 11687616
2021 G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation. Cytokine 82 33677228
2002 Molecular aspects of anti-inflammatory action of G-CSF. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 80 12005202
2022 Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF. Journal of hepatology 79 35843375
2006 The role of G-CSF in adaptive immunity. Cytokine & growth factor reviews 76 16807060
2011 G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation. The Journal of experimental medicine 73 21422169
2007 Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. The EMBO journal 73 17363902
2005 Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation. Blood 70 16239431
2021 G-CSF, the guardian of granulopoiesis. Seminars in immunology 69 34772606
2006 CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation. The Journal of clinical investigation 69 16964312
2006 Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection. Blood 59 17185469
2011 G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist. Blood 58 21685373
2013 G-CSF in Healthy Allogeneic Stem Cell Donors. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 56 24179471
2009 Optimal use of G-CSF administration after hematopoietic SCT. Bone marrow transplantation 54 19363527
2005 Roles of Stat3 and ERK in G-CSF signaling. Stem cells (Dayton, Ohio) 53 15671148
2003 Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction. Current pharmaceutical design 53 12769752
2007 Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells. Blood 52 17596540
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