Affinage

CSF3

Granulocyte colony-stimulating factor · UniProt P09919

Length
207 aa
Mass
22.3 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSF3 (G-CSF) is a secreted cytokine that signals through the G-CSF receptor (CSF3R) to drive granulopoiesis, myeloid cell mobilization and inflammation, while also exerting receptor-dependent survival effects on diverse non-hematopoietic tissues (PMID:16037394, PMID:21422169). Receptor engagement is initiated through the membrane-proximal box1 PXP motif, which is required to activate Jak1, Jak2 and Tyk2 and to recruit STAT3/STAT1 to the phosphorylated receptor (PMID:9015216), with the ligand-receptor complex assembling in a 2:2 stoichiometry (PMID:16720384). Downstream of the Jaks, G-CSF stimulates Jak2-dependent phosphorylation of Gab2 at Tyr643, recruiting the phosphatase Shp2 to drive Erk1/2 activation and proliferation (PMID:18644434), and the same Gab2–Shp2 module activates the Src kinase Lyn by dephosphorylating its inhibitory Tyr507 (PMID:21636860); granulocytic Erk1/2 output additionally depends on Gfi1-driven transcription of the Ras activator RasGRP1 (PMID:20203268) and on PLCγ2 acting upstream of JAK/STAT3 and PU.1 (PMID:24038146), with C/EBPα cooperating with discrete receptor tyrosines to induce myeloperoxidase and neutrophil elastase (PMID:11368439). STAT3 imposes negative feedback by inducing SOCS3, restraining ERK and STAT5 output, and truncating SCN/AML receptor mutants that lose the Tyr729 SOCS3 site escape this control to yield a hyperproliferative high-STAT5 state (PMID:15069015, PMID:15671148). In hematopoiesis G-CSF mobilizes stem/progenitor and myeloid cells both indirectly, by suppressing osteoblast-derived CXCL12 (PMID:16037394), and cell-autonomously, by downregulating CXCR4 on Gr1+ cells (PMID:16537807), with mobilization requiring autophagy (PMID:25788702), and it enhances myeloid adhesion by inducing E-selectin ligands through glycosyltransferase upregulation (PMID:16980970). CSF3 transcription is itself driven by inflammatory inputs including SAA via TLR2/NF-κB (PMID:18952897), LPS via ERK2/C/EBPβ/NF-κB chromatin remodeling (PMID:26114754), and IL-1/MyD88 during emergency hematopoiesis (PMID:30988118). Beyond blood, G-CSF activates JAK/STAT3 anti-apoptotic signaling in cardiomyocytes (PMID:15723072), supports myoblast and satellite-cell-dependent muscle regeneration via CSF3R (PMID:21422169, PMID:25865621), and protects neurons through ERK and PI3K/Akt–GSK-3β survival pathways (PMID:16839644, PMID:25448005). G-CSF is a pathogenic driver in the PLCG2 gain-of-function autoinflammatory disease APLAID, where anti-G-CSF antibody fully reverses disease, and it promotes tumor stem-cell maintenance and cancer cell invasion through STAT3 (PMID:36997670, PMID:25908586, PMID:32242230).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2001 High

    Established that distinct cytoplasmic tyrosines of the G-CSF receptor specify induction of different myeloid differentiation genes in cooperation with C/EBPα, resolving how a single receptor encodes program-specific outputs.

    Evidence Ba/F3 cells co-expressing C/EBPα-ER with tyrosine-to-alanine G-CSFR mutants, RT-PCR for MPO/NE/PU.1

    PMID:11368439

    Open questions at the time
    • Cofactor mechanism linking each tyrosine to a specific gene not defined
    • Reconstitution in non-Ba/F3 primary progenitors not shown
  2. 2004 High

    Defined how leukemia-associated receptor truncations subvert signaling by removing the Tyr729 SOCS3 site, decoupling STAT5 inhibition from intact STAT3 inhibition to produce a hyperproliferative state.

    Evidence STAT3/STAT5 luciferase reporters, SOCS3 measurement in gcsfr-d715 mice, internalization assays, Tyr729 mutagenesis

    PMID:15069015

    Open questions at the time
    • Direct link to leukemic transformation in patients not established
    • Mechanism connecting internalization defect to SOCS3 loss not fully resolved
  3. 2005 High

    Showed STAT3 acts as a negative regulator of G-CSF signaling via SOCS3, with ERK becoming the dominant proliferative driver when STAT3 is absent, defining the feedback architecture of the pathway.

    Evidence Conditional Stat3-knockout hematopoietic cells, MEK1 inhibitor, ERK/SOCS3 Western blots, colony assays

    PMID:15671148

    Open questions at the time
    • Quantitative balance between STAT3, STAT5 and ERK in normal granulopoiesis not mapped
  4. 2005 High

    Demonstrated that G-CSF mobilizes hematopoietic cells through two routes—indirect suppression of osteoblast-derived CXCL12 and cell-autonomous CXCR4 downregulation on myeloid cells.

    Evidence G-CSFR mutant transgenic mice, histomorphometry and CXCL12 measurement; flow cytometry and SDF-1 migration assays on Gr1+ cells

    PMID:16037394 PMID:16537807

    Open questions at the time
    • Indirect signal from G-CSFR-bearing cells to osteoblasts not identified
    • Relative contribution of each route to net mobilization unquantified
  5. 2005 High

    Extended G-CSF function beyond hematopoiesis by showing direct receptor-mediated JAK/STAT3 anti-apoptotic protection of cardiomyocytes.

    Evidence Dominant-negative STAT3 transgenic cardiomyocytes in an in vivo myocardial infarction model

    PMID:15723072

    Open questions at the time
    • Upstream Jak isoform usage in cardiomyocytes not specified
    • Translation to human cardiac repair untested in this work
  6. 2006 High

    Identified the membrane-proximal box1 PXP motif as essential for Jak1/Jak2/Tyk2 activation and STAT recruitment, and revealed that mature neutrophils use Jak-independent alternative pathways.

    Evidence Pro639Ala/Pro641Ala G-CSFR mutants in Ba/F3 and NFS-60 cells; kinase assays compared with primary neutrophils

    PMID:9015216

    Open questions at the time
    • Identity of the alternative Jak-independent pathway in neutrophils not defined
  7. 2006 Medium

    Resolved the architecture of ligand-receptor engagement, establishing a 2:2 stoichiometry analogous to IL-6 receptor site II/site III interactions.

    Evidence Crystal structure of ligand-binding domain with G-CSF plus mutagenesis and antibody mapping (review synthesis)

    PMID:16720384

    Open questions at the time
    • Full-length receptor complex structure not determined
    • Source is a compiled review rather than a single primary structure paper
  8. 2006 High

    Showed G-CSF induces functional E-selectin ligands on myeloid cells by upregulating glycosyltransferases, linking the cytokine to adhesion under physiologic flow.

    Evidence Parallel-plate flow assay, intravital microscopy, enzymatic ablation, glycosyltransferase RT-PCR on human bone marrow cells

    PMID:16980970

    Open questions at the time
    • Signaling pathway from G-CSFR to glycosyltransferase transcription not mapped
  9. 2006 Medium

    Distinguished an ERK-dependent, JAK/STAT-independent neuroprotective mode of G-CSF in dopaminergic neurons.

    Evidence Primary mesencephalic cultures, 6-OHDA model, MEK/ERK inhibitor, Bad/Bcl-xL/caspase-3 Western blots

    PMID:16839644

    Open questions at the time
    • No genetic receptor knockout confirmation
    • Single-lab pharmacological dissection
  10. 2008 High

    Identified Gab2 Tyr643 as the Jak2-phosphorylated docking site that recruits Shp2 to drive ERK activation and proliferation, providing the link between receptor Jaks and the Ras-ERK arm.

    Evidence JAK inhibitor, Jak2 antisense/dominant-negative, in vitro Jak2 kinase assay, Gab2 Tyr643 mutagenesis, proliferation assays

    PMID:18644434

    Open questions at the time
    • How Gab2 is recruited to the receptor complex not defined
  11. 2008 High

    Defined an inflammatory transcriptional input to CSF3, showing SAA induces G-CSF via TLR2/NF-κB binding to the promoter CK-1 element.

    Evidence TLR2-knockout macrophages, anti-TLR2 blockade, NF-κB assay, promoter ChIP, in vivo SAA injection

    PMID:18952897

    Open questions at the time
    • Physiological settings where SAA drives G-CSF in vivo not delineated
  12. 2010 High

    Placed Gfi1-driven RasGRP1 transcription as a selective requirement for G-CSF-induced ERK activation and granulocytic differentiation, and positioned G-CSF upstream of IL-21/IL-17 in Th17 differentiation.

    Evidence Gfi1-knockout mice with RasGRP1 rescue; transplantation model with IL-21/IL-17A knockout and cytokine staining

    PMID:20203268 PMID:20435882

    Open questions at the time
    • Mechanism connecting G-CSF to IL-21 induction in T cells not resolved
  13. 2011 High

    Showed G-CSF activates Lyn through Gab2-recruited Shp2 dephosphorylating inhibitory Tyr507, and established a receptor-dependent role for G-CSF in skeletal muscle myoblast proliferation and regeneration.

    Evidence Co-IP, in vitro phosphatase assays, Shp2-deficient cells, Gab2 mutants; G-CSFR-knockout mice, neutralizing antibody, BrdU assay, muscle injury model

    PMID:21422169 PMID:21636860

    Open questions at the time
    • Functional consequence of Lyn activation for myeloid outcomes not fully defined
    • Muscle-cell-intrinsic signaling pathway downstream of CSF3R not detailed
  14. 2011 Medium

    Demonstrated G-CSF corrects neutrophil apoptosis and energy homeostasis in G6PC3 deficiency, linking the cytokine to metabolic and survival rescue in congenital neutropenia.

    Evidence G6pc3-knockout mice, in vivo G-CSF therapy, p-Akt/caspase-3 blots, glucose uptake and metabolite measurement

    PMID:21292774

    Open questions at the time
    • Direct mechanistic link between CSF3R signaling and metabolite changes not established
    • Single-lab in vivo study
  15. 2014 Medium

    Established a PI3K/Akt–GSK-3β neuroprotective axis for G-CSF after neonatal hypoxia-ischemia that strictly requires CSF3R.

    Evidence Neonatal rat HI model, G-CSFR and GSK-3β siRNA, Wortmannin, TUNEL and Western blots

    PMID:25448005

    Open questions at the time
    • No genetic knockout; reliance on siRNA and pharmacology
    • Single-lab study
  16. 2015 High

    Identified autophagy as a specific downstream requirement for G-CSF-driven neutrophil and HSC mobilization, distinct from CXCR4-antagonist mobilization.

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

    PMID:25788702

    Open questions at the time
    • Molecular link between CSF3R signaling and autophagy induction not defined
  17. 2015 Medium

    Defined PLCγ2 as upstream of JAK/STAT3 and PU.1 in G-CSF-induced granulopoiesis, and showed G-CSF supports satellite-cell-dependent muscle regeneration in dystrophy models.

    Evidence PLCγ2 shRNA and inhibitors with JAK1/STAT3/PU.1 blots and CFU assays; ex vivo fiber culture and in vivo treatment of mdx/DMD mice

    PMID:24038146 PMID:25865621

    Open questions at the time
    • How PLCγ2 is positioned relative to box1/Jak activation not reconciled
    • Satellite-cell-intrinsic signaling not dissected
  18. 2015 High

    Revealed a STAT3-mediated feed-forward loop by which G-CSF maintains cancer stem-cell subpopulations and upregulates its own receptor in neuroblastoma.

    Evidence CSC expansion assays, xenograft and murine tumor models, anti-G-CSF antibody, STAT3 inhibitor, G-CSFR transcriptional reporter

    PMID:25908586

    Open questions at the time
    • Generality of the feed-forward loop across other tumor types not established
  19. 2015 High

    Showed LPS induces CSF3 transcription specifically through ERK2 (not ERK1), with C/EBPβ and NF-κB recruitment enabled by ERK2-driven chromatin remodeling.

    Evidence Isoform-specific ERK1/ERK2 shRNA, promoter-luciferase reporter, ChIP, DNase I accessibility assay

    PMID:26114754

    Open questions at the time
    • How ERK2 selectively engages the promoter versus ERK1 not explained
  20. 2018 Medium

    Identified IFNγ-induced SOCS3 as a negative regulator of G-CSF-driven neutrophil expansion, with G-CSF (not GM-CSF) specifically sustaining neutrophil survival.

    Evidence IFNγ-knockout mice, G-CSF/GM-CSF depletion antibodies, SOCS3 measurement, neutrophil apoptosis assays

    PMID:29352287

    Open questions at the time
    • Cell-type source of IFNγ-SOCS3 crosstalk in vivo not fully resolved
    • Single-lab study
  21. 2019 Medium

    Connected tissue injury to emergency hematopoiesis through an IL-1/MyD88 pathway driving G-CSF production that expands HSC/MPP and myeloid-skewed progenitors, and showed G-CSF mediates osteoblast-suppressive bone loss during S. aureus infection.

    Evidence Polytrauma model with IL-1R/MyD88-knockout mice and G-CSF ELISA; S. aureus infection model with G-CSF ELISA, neutralizing antibody, microCT

    PMID:30988118 PMID:31175224

    Open questions at the time
    • Direct cellular source of G-CSF in each setting not fully resolved
    • Single-lab studies
  22. 2020 Medium

    Showed cancer-associated adipocyte-derived G-CSF promotes breast cancer invasion through STAT3-driven MMP2/MMP9 expression, extending the tumor-promoting STAT3 axis to the stromal microenvironment.

    Evidence Primary cancer-associated adipocytes, recombinant G-CSF, neutralizing antibody, Stat3 siRNA/inhibitor, migration/invasion assays, transcriptomics

    PMID:32242230

    Open questions at the time
    • In vivo contribution of adipocyte-derived G-CSF to metastasis not tested
    • Single-lab study
  23. 2023 High

    Established G-CSF as the key pathogenic driver of APLAID autoinflammation, with anti-G-CSF antibody fully reversing disease and bone marrow transplant identifying a non-hematopoietic G-CSF source.

    Evidence APLAID PLCG2 knock-in mice, anti-G-CSF antibody, bone marrow transplantation, cytokine profiling, flow cytometry

    PMID:36997670

    Open questions at the time
    • Identity of the non-hematopoietic G-CSF-producing cell not defined
    • Translation to human APLAID untested in this work

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CSF3R endosomal trafficking, ubiquitination and redox-controlled phosphatase activity quantitatively tune signal amplitude and the switch from proliferation to differentiation remains unresolved at the molecular level.
  • Mechanistic detail rests on a review without new primary experiments [#26]
  • Specific ubiquitin ligases and endosomal phosphatases not identified
  • Link between receptor routing and downstream STAT/ERK balance not directly demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CSF3RGAB2JAK2LYNPTPN11STAT3

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 G-CSF acts directly on cardiomyocytes by binding the G-CSF receptor expressed on their surface, activating the JAK/STAT3 pathway, inducing antiapoptotic proteins, inhibiting cardiomyocyte apoptosis, and reducing endothelial cell apoptosis; all these effects were abolished by overexpression of a dominant-negative STAT3 mutant in cardiomyocytes. Dominant-negative STAT3 transgenic overexpression in cardiomyocytes; in vivo myocardial infarction model; immunostaining and apoptosis assays Nature medicine High 15723072
2005 G-CSF down-regulates CXCR4 expression on bone marrow Gr1+ myeloid cells in a cell-autonomous manner (G-CSF receptor is expressed on these cells), thereby attenuating SDF-1/CXCR4-mediated retention and promoting myeloid cell mobilization from bone marrow to peripheral blood. Flow cytometry of purified Gr1+ bone marrow cells treated with G-CSF in vitro; migration and attachment assays with SDF-1; in vivo G-CSF mobilization in mice Blood High 16537807
2005 G-CSF treatment potently inhibits osteoblast activity (measured by histomorphometry and osteocalcin expression) and decreases CXCL12 mRNA and protein in bone marrow through an indirect mechanism, since the G-CSF receptor is not expressed on osteoblasts; reduced CXCL12/CXCR4 signaling leads to hematopoietic progenitor cell mobilization. Transgenic mice with targeted G-CSF receptor mutations; histomorphometry; CXCL12 mRNA and protein measurement; cell sorting to identify CXCL12-producing cells Blood High 16037394
2004 Truncated G-CSF receptor mutants (found in SCN/AML) lose the SOCS3 recruitment site Tyr729 and show defective receptor internalization, resulting in reduced SOCS3 expression and loss of SOCS3-mediated STAT5 inhibition while STAT3 inhibition remains intact, leading to an increased STAT5/STAT3 activation ratio and hyperproliferative responses to G-CSF. Luciferase reporter assays for STAT3/STAT5 activation; SOCS3 expression measurement in bone marrow of gcsfr-d715 mice; receptor internalization assays; site-directed mutagenesis of Tyr729 Blood High 15069015
2005 STAT3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression; in Stat3-deficient hematopoietic cells, SOCS3 expression is nearly absent, ERK1/2 activation is enhanced and sustained, and the augmented G-CSF-induced proliferation is abrogated by MEK1 inhibition, identifying ERK as the major driver of proliferation downstream of G-CSF when STAT3 is absent. Conditional Stat3-knockout mice in hematopoietic cells; MEK1 inhibitor treatment; Western blotting for ERK and SOCS3; bone marrow colony assays Stem cells (Dayton, Ohio) High 15671148
2006 G-CSF induces expression of E-selectin ligands HCELL and an ~65 kDa ligand on myeloid cells by upregulating glycosyltransferases (ST3GalIV, FucT-IV, FucT-VII), leading to heightened myeloid cell adhesion to inflamed endothelium under physiologic flow conditions. Parallel plate flow assay; intravital microscopy; enzymatic treatments; biochemical characterization of E-selectin ligands; RT-PCR for glycosyltransferases; in vitro G-CSF treatment of normal human bone marrow cells Nature medicine High 16980970
2010 G-CSF promotes Th17 differentiation (amplifying IL-17 production in CD4 and CD8 T cells) through a mechanism dependent on and downstream of G-CSF-induced IL-21 signaling; donor IL-17A controls macrophage infiltration into skin and cutaneous fibrosis after transplantation. Murine hematopoietic transplantation model; cytokine blocking/knockout mice (IL-17A, IL-21); intracellular cytokine staining; flow cytometry Blood High 20435882
2010 G-CSF transcription factor Gfi1 regulates G-CSF-induced Erk1/2 activation and granulocytic differentiation through transcriptional control of the Ras activator RasGRP1; Gfi1-null myeloid cells selectively fail to activate Erk1/2 (but not STAT1/3) in response to G-CSF, and forced RasGRP1 expression rescues this defect. Gfi1-knockout mice; retroviral RasGRP1 transduction rescue experiment; Western blotting for Erk1/2, STAT1, STAT3 activation; colony assays; RT-PCR Blood High 20203268
2011 G-CSF activates Lyn (the predominant Src kinase in myeloid cells) through Gab2-mediated recruitment of the Shp2 phosphatase, which dephosphorylates inhibitory phospho-Tyr507 on Lyn; Gab2 Tyr507 dephosphorylation was abrogated in Shp2-deficient cells and by Gab2 mutations preventing Shp2 binding. Co-immunoprecipitation; in vitro kinase/phosphatase assays with purified proteins; Shp2-deficient cells; Gab2 mutants; siRNA knockdown of Gab2 Blood High 21636860
2008 G-CSF stimulates Jak2-dependent phosphorylation of Gab2 at Tyr643, which recruits Shp2 and leads to Erk1/2 activation and cell proliferation; mutation of Gab2 Tyr643 inhibited G-CSF-stimulated Erk1/2 activation, Shp2 binding, and Gab2-mediated proliferation. JAK inhibitor treatment; Jak2 antisense and dominant-negative constructs; in vitro kinase assay with activated Jak2; Gab2 site-directed mutagenesis; cell proliferation assays Cellular signalling High 18644434
2001 G-CSF receptor signals cooperate with C/EBPα to induce myeloperoxidase (MPO) and neutrophil elastase (NE) gene expression; receptor tyrosine mutations revealed that all four cytoplasmic tyrosines are required for NE induction, while mutation of Tyr704 specifically enhanced MPO induction, indicating distinct tyrosine requirements for different myeloid differentiation genes. Ba/F3 cells co-expressing C/EBPα-ER and G-CSF receptor mutants; RT-PCR for MPO, NE, LF, PU.1; tyrosine-to-alanine mutant receptors Leukemia High 11368439
2006 The G-CSF receptor requires the membrane-proximal box 1 PDP (PXP) motif for activation of Jak1, Jak2, and Tyk2, tyrosine phosphorylation of the receptor, and STAT3/STAT1 recruitment; Jak kinases are not activated in terminally differentiated neutrophils upon G-CSF stimulation, indicating utilization of alternative signaling pathways in mature cells. G-CSF receptor Pro639Ala/Pro641Ala mutant transfected into Ba/F3 and NFS-60 cells; kinase immunoprecipitation and phosphorylation assays; comparison between proliferating cell lines and primary neutrophils Experimental hematology High 9015216
2006 The G-CSF receptor complex has 2:2 stoichiometry with two binding sites on both ligand and receptor equivalent to site II and site III of the IL-6 receptor complex; structure of the ligand-binding domain was determined by crystallography in complex with G-CSF. Crystal structure of partial ligand-receptor complex; mutagenesis of receptor and ligand; neutralizing antibody mapping; solution-phase binding studies Frontiers in bioscience : a journal and virtual library Medium 16720384
2008 Serum amyloid A (SAA) induces G-CSF gene expression in macrophages via Toll-like receptor 2 (TLR2); SAA stimulation activates NF-κB and promotes binding to the CK-1 element of the G-CSF promoter; this effect is blocked by anti-TLR2 antibody and absent in TLR2-deficient macrophages. TLR2-knockout macrophages; anti-TLR2 antibody blockade; NF-κB activation assay; chromatin immunoprecipitation (promoter binding); in vitro reconstitution; in vivo SAA injection in wild-type vs. G-CSF- or TLR2-deficient mice Blood High 18952897
2015 G-CSF selectively activates STAT3 within neuroblastoma cancer stem cell (CSC) subpopulations via G-CSF receptor; STAT3 acts in a feed-forward loop to transcriptionally activate G-CSF receptor expression; blockade with anti-G-CSF antibody or STAT3 inhibitor depleted CSC subpopulation, inhibited tumor growth, decreased metastasis, and increased chemosensitivity. In vitro CSC expansion assays; human xenograft and murine neuroblastoma tumor models; anti-G-CSF antibody blockade; STAT3 inhibitor; reporter assays for G-CSFR transcription Cancer research High 25908586
2011 G-CSF receptor (G-CSFR) is expressed on myoblasts during embryonic development and transiently on regenerating myocytes in injured adult skeletal muscle; neutralization of endogenous G-CSF impairs muscle regeneration, exogenous G-CSF promotes myoblast proliferation, and muscle regeneration is markedly impaired in G-CSFR-knockout mice. G-CSFR-knockout mice; G-CSF neutralizing antibody; BrdU proliferation assay; in vivo muscle injury model; immunostaining The Journal of experimental medicine High 21422169
2015 G-CSF receptor is asymmetrically expressed in activated satellite cells; G-CSF positively affects the satellite cell population during multiple differentiation stages; G-CSF supports long-term muscle regeneration, functional maintenance, and lifespan extension in mdx mouse models of Duchenne muscular dystrophy. Ex vivo fiber culture assay; immunostaining for asymmetric G-CSFR expression; in vivo G-CSF treatment of mdx and more severe DMD mouse models; functional assessments Nature communications High 25865621
2006 G-CSF protects dopaminergic neurons from 6-OHDA toxicity via the ERK pathway (not JAK/STAT); G-CSF activates ERK, increases phosphorylation of Bad, restores Bcl-xL levels, and inhibits caspase-3 activation; ERK inhibition abrogates all these protective effects. Primary mesencephalic cultures; 6-OHDA neurotoxicity model; Western blotting for ERK, p-Bad, Bcl-xL, caspase-3; MEK/ERK inhibitor pharmacological blockade; immunostaining Neurobiology of aging Medium 16839644
2014 G-CSF attenuates neuronal apoptosis after neonatal hypoxia-ischemia via PI3K/Akt-dependent inhibition of GSK-3β activity, reducing caspase-3 activation and increasing Bcl-2/Bax ratio; this neuroprotective effect is abolished by G-CSF receptor siRNA or PI3K inhibitor Wortmannin. Neonatal rat HI model; G-CSFR siRNA; GSK-3β siRNA; PI3K inhibitor Wortmannin; Western blotting; TUNEL assay; immunofluorescence Experimental neurology Medium 25448005
2015 G-CSF activates autophagy in both neutrophils and hematopoietic stem cells (HSCs); G-CSF-induced neutrophil and HSC mobilization is impaired in the absence of autophagy, whereas direct HSC mobilization by the CXCR4 antagonist AMD3100 does not require autophagy, placing autophagy as a specific requirement downstream of G-CSF signaling for mobilization. Autophagy-deficient mouse models; G-CSF vs. AMD3100 mobilization comparison; flow cytometry; autophagy flux assays in murine and human donor cells Blood High 25788702
2015 G-CSF activates PLCγ2, PKC, JAK-1, and STAT-3 in myeloid progenitors during granulocytic commitment; STAT-3 activation and increased PU.1 expression downstream of G-CSF are sensitive to PLC inhibition, placing PLCγ2 upstream of JAK/STAT and PU.1 in G-CSF-induced granulopoiesis. Flow cytometry; RNA interference (PLCγ2 shRNA); PLCγ/PKC inhibitors; Western blotting for JAK1, STAT3, PU.1; colony-forming unit assays Journal of cellular biochemistry Medium 24038146
2015 LPS-induced G-CSF expression in macrophages is mediated specifically by ERK2 (not ERK1); ERK2 and C/EBPβ synergistically activate the G-CSF promoter; ERK2 promotes LPS-induced binding of NF-κB (p50/p65) and C/EBPβ to the G-CSF promoter through chromatin remodeling. shRNA knockdown of ERK1 vs. ERK2; G-CSF promoter-luciferase reporter assays; chromatin immunoprecipitation (ChIP); DNase I accessibility assay PloS one High 26114754
2019 Tissue injury induces emergency hematopoiesis through an IL-1/MyD88-dependent pathway that drives G-CSF production; G-CSF then expands hematopoietic progenitors including HSCs and MPPs and increases myeloid-skewed progenitor frequency. Mouse polytrauma model; IL-1 receptor/MyD88-knockout mice; ELISA for G-CSF; flow cytometry of bone marrow progenitors Journal of immunology (Baltimore, Md. : 1950) Medium 30988118
2011 G-CSF improves neutrophil function in G6PC3-deficient mice by modulating apoptotic mediators (normalizing p-Akt, PI3K, and active caspase-3 levels) and rectifying energy homeostasis (increasing glucose uptake and intracellular G6P, lactate, and ATP levels) in vivo. G6pc3-knockout mice; in vivo G-CSF therapy; Western blotting for p-Akt, caspase-3; glucose uptake assay; metabolite measurement; in vitro apoptosis assays Blood Medium 21292774
2023 G-CSF is the key driver of autoinflammation in APLAID (PLCG2 gain-of-function missense mutation model); treatment with an anti-G-CSF antibody completely reversed established disease in APLAID mice, normalized myelopoiesis, and restored lymphocyte counts; bone marrow transplantation from healthy donors reduced G-CSF production (predominantly from non-hematopoietic cells) and fully rescued APLAID mice. APLAID knock-in mouse model; anti-G-CSF antibody treatment; bone marrow transplantation; cytokine profiling; flow cytometry of immune cell populations Nature immunology High 36997670
2018 IFNγ suppresses G-CSF signaling by increasing SOCS3 expression in neutrophils, leading to neutrophil apoptosis; depletion of G-CSF (but not GM-CSF) in IFNγ-deficient mice induces neutrophil apoptosis and restores IL-10 secretion, identifying IFNγ-SOCS3 as a negative regulator of G-CSF-driven neutrophil expansion. IFNγ-knockout mice; G-CSF or GM-CSF depletion antibodies; SOCS3 expression measurement; neutrophil apoptosis assays; cytokine profiling PLoS pathogens Medium 29352287
2013 CSF3R (G-CSF receptor) undergoes lysine ubiquitination and redox-controlled phosphatase-modulated signaling during endocytosis; receptor routing through signaling endosomes—where interactions with the endoplasmic reticulum occur—is a key mechanism for modulating CSF3R signal amplitude and duration leading first to myeloid progenitor proliferation and then to differentiation. Review summarizing biochemical and cell biology studies on CSF3R ubiquitination, endosomal trafficking, and phosphatase activities Frontiers in bioscience (Landmark edition) Low 23276911
2020 Cancer-associated adipocyte-derived G-CSF promotes breast cancer cell migration and invasion by activating STAT3 signaling; downstream targets include MMP2 and MMP9; G-CSF-neutralizing antibody, STAT3 inhibitor, or Stat3 siRNA each abrogate CAA- or G-CSF-induced cancer cell migration and invasion. Primary cancer-associated adipocyte isolation; recombinant G-CSF treatment; G-CSF-neutralizing antibody; Stat3 siRNA; Western blotting; migration/invasion assays; transcriptome sequencing Journal of molecular cell biology Medium 32242230
2019 G-CSF partially mediates bone loss induced by Staphylococcus aureus infection by suppressing osteoblast function; G-CSF levels are elevated in infected bone marrow (partly due to increased F4/80+ macrophages), and G-CSF neutralizing antibody treatment significantly rescues bone volume and preserves osteocalcin- and osterix-positive osteoblasts. Mouse S. aureus infection model; ELISA for G-CSF in bone marrow and serum; G-CSF neutralizing antibody; microCT; immunohistochemistry Clinical science (London, England : 1979) Medium 31175224

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nature medicine 474 15723072
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) 291 26254266
2005 G-CSF: a key regulator of neutrophil production, but that's not all! Growth factors (Chur, Switzerland) 280 16019425
2014 G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine & growth factor reviews 251 25131807
2006 G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood 188 16537807
2010 Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma. Blood 142 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 135 19798030
2010 G-CSF and its receptor in myeloid malignancy. Blood 126 20237318
2021 G-CSF - A double edge sword in neutrophil mediated immunity. Seminars in immunology 117 34728120
2005 NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. The Journal of clinical investigation 105 16224535
2005 Endogenous G-CSF and CD34+ cell mobilization after acute myocardial infarction. International journal of cardiology 103 16051386
2002 G-CSF therapy of ongoing experimental allergic encephalomyelitis via chemokine- and cytokine-based immune deviation. Journal of immunology (Baltimore, Md. : 1950) 91 11823538
2005 G-CSF suppresses edema formation and reduces interleukin-1beta expression after cerebral ischemia in mice. Journal of neuropathology and experimental neurology 90 16141785
2002 G-CSF: function and modes of action (Review). International journal of molecular medicine 86 12060844
2021 G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation. Cytokine 85 33677228
2022 Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF. Journal of hepatology 84 35843375
2005 Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL? Blood 82 16380448
2002 Molecular aspects of anti-inflammatory action of G-CSF. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 81 12005202
2015 G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation. Cancer research 80 25908586
2006 The role of G-CSF in adaptive immunity. Cytokine & growth factor reviews 77 16807060
2011 G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation. The Journal of experimental medicine 74 21422169
2015 G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. Science translational medicine 72 25834108
1995 The effect of GM-CSF and G-CSF on human neutrophil function. Immunopharmacology 72 7539779
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
1990 Differential expression of M-CSF, G-CSF, and GM-CSF by human monocytes. Journal of leukocyte biology 67 1689760
2004 G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact. Blood 65 15069015
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
2007 Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection. Journal of cellular and molecular medicine 56 18205701
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
2013 SOCS3: An essential physiological inhibitor of signaling by interleukin-6 and G-CSF family cytokines. JAK-STAT 51 24416642
2009 Rho kinase inhibitor Fasudil induces neuroprotection and neurogenesis partially through astrocyte-derived G-CSF. Brain, behavior, and immunity 50 19447168
2020 Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling. Journal of molecular cell biology 48 32242230
2014 G-CSF: filgrastim, lenograstim and biosimilars. Expert opinion on biological therapy 47 24707817
2009 G-CSF induces a potentially tolerant gene and immunophenotype profile in T cells in vivo. Clinical immunology (Orlando, Fla.) 47 19345152
2015 Diabetes Limits Stem Cell Mobilization Following G-CSF but Not Plerixafor. Diabetes 45 25804941
2015 G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. Nature communications 44 25865621
2011 G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis. Blood 44 21292774
2006 Effects of G-CSF on left ventricular remodeling and heart failure after acute myocardial infarction. Journal of molecular medicine (Berlin, Germany) 44 16418824
2006 G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway. Neurobiology of aging 44 16839644
2001 C/EBPalpha and G-CSF receptor signals cooperate to induce the myeloperoxidase and neutrophil elastase genes. Leukemia 44 11368439
2010 The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. Blood 43 20203268
2006 G-CSF induces E-selectin ligand expression on human myeloid cells. Nature medicine 43 16980970
2021 Immunomodulatory effects of G-CSF in cancer: Therapeutic implications. Seminars in immunology 42 34763974
2010 G-CSF for stem cell therapy in acute myocardial infarction: friend or foe? Cardiovascular research 42 20851808
2021 Neuroprotection through G-CSF: recent advances and future viewpoints. Pharmacological reports : PR 41 33389706
2015 Autophagy is required for stem cell mobilization by G-CSF. Blood 40 25788702
1997 Hemorrhagic shock induces G-CSF expression in bronchial epithelium. The American journal of physiology 40 9374735
1989 Review of G-CSF and GM-CSF. Effects on neonatal neutrophil kinetics. The American journal of pediatric hematology/oncology 40 2473663
2007 G-CSF therapy for acute myocardial infarction. Trends in pharmacological sciences 39 17888521
2014 Stem cells and G-CSF for treating neuroinflammation in traumatic brain injury: aging as a comorbidity factor. Journal of neurosurgical sciences 38 24844175
2020 G-CSF Inhibits Pulmonary Fibrosis by Promoting BMSC Homing to the Lungs via SDF-1/CXCR4 Chemotaxis. Scientific reports 37 32601321
2011 Can G-CSF cause leukemia in hematopoietic stem cell donors? Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 35 21745453
2017 G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease. Journal of immunology (Baltimore, Md. : 1950) 33 28320832
2007 G-CSF and HGF: combination of vasculogenesis and angiogenesis synergistically improves recovery in murine hind limb ischemia. Journal of molecular and cellular cardiology 33 17223129
2020 G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth. Cancers 32 33036138
2014 G-CSF ameliorates neuronal apoptosis through GSK-3β inhibition in neonatal hypoxia-ischemia in rats. Experimental neurology 32 25448005
2006 The interaction of G-CSF with its receptor. Frontiers in bioscience : a journal and virtual library 32 16720384
1997 Dissociation of the Jak kinase pathway from G-CSF receptor signaling in neutrophils. Experimental hematology 32 9015216
2021 Combination immunotherapy using G-CSF and oncolytic virotherapy reduces tumor growth in osteosarcoma. Journal for immunotherapy of cancer 31 33737338
2015 Leukemia cell mobilization with G-CSF plus plerixafor during busulfan-fludarabine conditioning for allogeneic stem cell transplantation. Bone marrow transplantation 31 25867648
2015 G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice. Laboratory investigation; a journal of technical methods and pathology 31 26524416
2011 G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase. Blood 31 21636860
2010 Serum IL-7 and G-CSF in major depressive disorder. Progress in neuro-psychopharmacology & biological psychiatry 31 20382196
2008 Granulocyte colony-stimulating factor (G-CSF) for cardio- and cerebrovascular regenerative applications. Current medicinal chemistry 31 18393854
2008 G-CSF receptor mutations in patients with congenital neutropenia. Current opinion in hematology 31 18536571
1998 G-CSF production in human bladder cancer and its ability to promote autocrine growth: a review. Cytokines, cellular & molecular therapy 31 9681250
2019 Trauma Induces Emergency Hematopoiesis through IL-1/MyD88-Dependent Production of G-CSF. Journal of immunology (Baltimore, Md. : 1950) 30 30988118
2015 Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke. Translational stroke research 30 26482176
2011 G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT. Bone marrow transplantation 29 21358682
2015 LPS-Induced G-CSF Expression in Macrophages Is Mediated by ERK2, but Not ERK1. PloS one 28 26114754
2014 PLCγ2 and PKC are important to myeloid lineage commitment triggered by M-SCF and G-CSF. Journal of cellular biochemistry 27 24038146
2012 Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. Theoretical biology & medical modelling 27 22846180
2017 Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer. Oncotarget 26 28881590
2021 G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment. Journal for immunotherapy of cancer 25 34049929
2019 G-CSF administration prior to donor lymphocyte apheresis promotes anti-leukaemic effects in allogeneic HCT patients. British journal of haematology 25 30916396
2011 G-CSF enhances the proliferation and mobilization, but not the maturation rate, of murine myeloid cells. European journal of haematology 25 21623923
2007 Growth factors G-CSF and GM-CSF differentially preserve chemotaxis of neutrophils aging in vitro. Experimental hematology 24 17379064
2000 G-CSF receptor expression in ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 24 11240647
1999 Cell lineage specificity in G-CSF receptor gene methylation. Leukemia 23 10214858
2018 IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis. PLoS pathogens 22 29352287
2016 G-CSF and Neutrophils Are Nonredundant Mediators of Murine Experimental Autoimmune Uveoretinitis. The American journal of pathology 22 26718978
2013 Scratching the surface: signaling and routing dynamics of the CSF3 receptor. Frontiers in bioscience (Landmark edition) 22 23276911
2013 New G-CSF agonists for neutropenia therapy. Expert opinion on investigational drugs 22 24073859
2012 Synergistic effect of SCF and G-CSF on stem-like properties in prostate cancer cell lines. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 22252524
2008 G-CSF stimulates Jak2-dependent Gab2 phosphorylation leading to Erk1/2 activation and cell proliferation. Cellular signalling 22 18644434
2023 G-CSF drives autoinflammation in APLAID. Nature immunology 20 36997670
2021 G-CSF promotes alloregulatory function of MDSCs through a c-Kit dependent mechanism. Cellular immunology 20 33848847
2020 Weighty choices: selecting optimal G-CSF doses for stem cell mobilization to optimize yield. Blood advances 19 32092138
2012 Hematopoietic stem cell mobilization with agents other than G-CSF. Methods in molecular biology (Clifton, N.J.) 19 22890921
2007 Src kinases in G-CSF receptor signaling. Frontiers in bioscience : a journal and virtual library 19 17127394
2019 G-CSF partially mediates bone loss induced by Staphylococcus aureus infection in mice. Clinical science (London, England : 1979) 18 31175224
2019 Vildagliptin and G-CSF Improved Angiogenesis and Survival after Acute Myocardial Infarction. Archives of medical research 18 31495390
2018 Current use of biosimilar G-CSF for haematopoietic stem cell mobilisation. Bone marrow transplantation 18 30283148
2010 Systemic levels of G-CSF and interleukin-6 determine the angiogenic potential of bone marrow resident monocytes. Journal of leukocyte biology 18 20354107

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