Affinage

CSF1

Macrophage colony-stimulating factor 1 · UniProt P09603

Round 2 corrected
Length
554 aa
Mass
60.2 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSF1 (M-CSF) is a disulfide-linked homodimeric cytokine that exists as membrane-bound, secreted glycoprotein, and secreted proteoglycan isoforms generated by alternative splicing and extracellular proteolytic processing; it signals exclusively through the CSF-1R (c-Fms) receptor tyrosine kinase to govern survival, proliferation, differentiation, and motility of mononuclear phagocytes and osteoclasts (PMID:2408759, PMID:3039346, PMID:3493529). Ligand-induced CSF-1R autophosphorylation activates divergent intracellular cascades: Y721 recruits PI3K for chemotaxis and macropinocytosis (via PLCγ/DAG/PKC/Ras), Y807/Y809 controls a proliferation-versus-differentiation switch through c-Myc induction and sustained Raf-1/MEK/ERK signaling, and MAPK-dependent phosphorylation of Mitf/TFE3 recruits p300 to drive osteoclast maturation (PMID:1833648, PMID:8981370, PMID:11684011, PMID:25688212). Paracrine CSF1 production by tissue-specific sources — bone marrow Adipoq-lineage progenitors for osteoclast and macrophage homeostasis, mesothelial cells for peritoneal macrophages, and injured sensory neurons for spinal microglial activation underlying neuropathic pain — establishes CSF1 as a locally regulated master signal for myeloid cell fate across diverse organs (PMID:36779851, PMID:31251389, PMID:26642091). CSF1 gene translocations causing overexpression drive tenosynovial giant cell tumor through a landscape effect of non-neoplastic CSF1R-positive cell recruitment (PMID:16407111).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1985 High

    Identification of CSF-1 as a cloneable cytokine and its receptor as the c-Fms proto-oncogene product established the molecular identity of the ligand–receptor pair governing mononuclear phagocyte biology.

    Evidence cDNA cloning with recombinant protein expression in COS cells confirmed biological activity; immunoprecipitation and radioligand binding demonstrated c-Fms is the CSF-1 receptor with intrinsic tyrosine kinase activity

    PMID:2408759 PMID:2996129

    Open questions at the time
    • No structural information on how CSF-1 engages its receptor
    • Downstream signaling pathways unknown
  2. 1987 High

    Discovery that CSF-1 is synthesized as a transmembrane homodimeric precursor that is proteolytically cleaved to release soluble forms, and that alternative splicing generates distinct isoforms, resolved how one gene produces functionally diverse ligand forms.

    Evidence cDNA cloning of 4-kb and 1.6-kb transcripts, genomic exon mapping, direct protein sequencing, and surface trypsin cleavage experiments in transfected cells

    PMID:3039346 PMID:3493529 PMID:3500041

    Open questions at the time
    • Functional differences among isoforms in vivo not yet defined
    • Identity of the physiological membrane protease unknown
  3. 1992 High

    The crystal structure of the M-CSF homodimer revealed the four-helix-bundle architecture and, together with mutagenesis, pinpointed His-9 and His-15 as critical receptor-contact residues on helix A.

    Evidence X-ray crystallography at 2.5 Å; site-directed mutagenesis (H9A/H15A) with radioreceptor binding and bioactivity assays confirmed direct involvement without structural perturbation

    PMID:1455231 PMID:7983059

    Open questions at the time
    • No co-crystal structure of CSF-1 bound to CSF-1R
    • Receptor dimerization mechanism not yet visualized
  4. 1997 High

    Systematic mutagenesis of individual CSF-1R autophosphorylation sites delineated a signaling architecture in which Y721 recruits PI3K for motility, Y807/Y809 controls a proliferation-versus-differentiation switch through c-Myc and sustained ERK, and the Raf-1/MEK/ERK cascade is required for macrophage differentiation.

    Evidence Site-directed mutagenesis of CSF-1R tyrosines in FDC-P1 myeloid cells, c-myc overexpression rescue, PI3K co-immunoprecipitation, chemotaxis assays, pharmacological ERK inhibition

    PMID:1833648 PMID:8981359 PMID:8981370 PMID:9261328

    Open questions at the time
    • Quantitative kinetics of phosphosite usage during physiological stimulation unknown
    • Downstream transcriptional programs beyond c-Myc and immediate-early genes not mapped
  5. 2001 High

    Identification of the M-CSF→MAPK→Mitf/TFE3→p300 axis explained how CSF-1 drives osteoclast maturation at the transcriptional level, connecting receptor signaling to a known osteoclast transcription factor.

    Evidence In vitro kinase assay, co-immunoprecipitation with p300, Mitf phospho-site mutagenesis, and osteoclast differentiation assay

    PMID:11684011

    Open questions at the time
    • Full repertoire of MAPK-phosphorylated transcription factors downstream of CSF-1 not catalogued
    • How Mitf phosphorylation cooperates with RANKL-induced NFATc1 unclear
  6. 2002 High

    The toothless rat frameshift mutation provided definitive genetic proof that loss of functional CSF-1 protein causes osteopetrosis due to osteoclast failure.

    Evidence Genomic sequencing of the Csf1 coding region in the toothless (tl) rat identifying a 10-bp insertion producing a truncated 41-aa non-functional product

    PMID:12074592

    Open questions at the time
    • Hematopoietic and extra-skeletal phenotypes of the tl rat incompletely characterized
  7. 2006 High

    CSF1 gene translocations in tenosynovial giant cell tumor established CSF1 as an oncogenic driver through a landscape effect, where minority neoplastic cells overexpressing CSF1 recruit CSF1R-positive bystander cells to form the tumor mass.

    Evidence FISH and array CGH identification of chromosome 1p13 translocation fusing CSF1 to COL6A3, expression profiling, and immunohistochemistry on TGCT/PVNS samples

    PMID:16407111

    Open questions at the time
    • Whether CSF1 overexpression alone is sufficient or requires additional cooperating events not tested
    • Non-tumor landscape effects not explored in other cancers at this point
  8. 2008 High

    Discovery of IL-34 as a second ligand for CSF-1R redefined the receptor's ligand landscape, raising the question of non-redundant versus overlapping functions of the two ligands.

    Evidence Functional proteome screen identifying IL-34; receptor identification by extracellular domain library screen; monocyte viability assays

    PMID:18467591

    Open questions at the time
    • Structural basis for dual ligand recognition by CSF-1R not resolved
    • Tissue-specific dominance of CSF-1 vs IL-34 only partially mapped
  9. 2011 High

    Isoform-specific knock-in mice demonstrated that the three CSF-1 protein isoforms (cell-surface glycoprotein, secreted proteoglycan, secreted glycoprotein) have distinct non-redundant in vivo roles, with the cell-surface form initiating local macrophage activation and the proteoglycan form dominating systemic circulation and monocyte recruitment during lupus nephritis.

    Evidence Isoform-specific mutant MRL-Fas(lpr) knock-in mice with flow cytometry, histology, and TUNEL analysis

    PMID:21885670

    Open questions at the time
    • Whether isoform-specific functions extend to other tissues/disease contexts not determined
    • Molecular basis for differential tissue distribution of isoforms unknown
  10. 2015 High

    Sensory neuron-derived CSF1 was established as a critical mediator of neuropathic pain: nerve injury induces de novo CSF1 expression in DRG neurons, and axonally transported CSF1 activates spinal microglial CSF1R→DAP12 signaling to drive mechanical hypersensitivity.

    Evidence Sensory-neuron-specific Csf1 conditional KO, intrathecal CSF1 gain-of-function, DAP12 epistasis, behavioral pain testing

    PMID:26642091

    Open questions at the time
    • Molecular trigger for Csf1 transcriptional induction in injured neurons not identified
    • Whether CSF1 vs IL-34 contributes differentially to central microglial activation unclear
  11. 2015 Medium

    M-CSF-driven macropinocytosis was mechanistically mapped to a PI3K→PLCγ→DAG→PKC/Ras pathway, extending the known signaling repertoire beyond proliferation and differentiation to include bulk fluid uptake.

    Evidence Live imaging with fluorescent lipid probes and sequential pharmacological inhibition (LY294002, U73122, FTS, Calphostin C) in macrophages

    PMID:25688212

    Open questions at the time
    • Entirely pharmacological approach; genetic confirmation of each node lacking
    • Physiological significance of M-CSF-driven macropinocytosis in vivo not tested
  12. 2023 High

    Two independent studies using Adipoq-Cre conditional Csf1 knockout mice identified bone marrow Adipoq-lineage progenitors (MALPs) as the dominant paracrine source of CSF1 for osteoclast and macrophage homeostasis in the skeletal niche, explaining why the bone compartment is so dependent on CSF1.

    Evidence Adipoq-Cre × Csf1-floxed conditional KO, single-cell RNA-seq, micro-CT, TRAP staining, hematopoietic progenitor analysis, ovariectomy and LPS-induced osteolysis models

    PMID:36779851 PMID:36779854

    Open questions at the time
    • Whether other mesenchymal populations compensate over long-term deletion not addressed
    • Relative contribution of CSF1 vs IL-34 from marrow stroma not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for CSF-1 vs IL-34 recognition by CSF-1R, the identity of the physiological protease(s) that cleave membrane-bound CSF-1 in vivo, and the full transcriptional programs downstream of distinct CSF-1R phosphorylation sites in tissue-specific macrophage populations.
  • No co-crystal structure of CSF-1 bound to CSF-1R ectodomain
  • Physiological sheddase for membrane CSF-1 not genetically identified
  • Single-cell transcriptomic profiling of CSF-1 vs IL-34 responses in tissue-resident macrophages lacking

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 GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 3 R-HSA-1640170 Cell Cycle 2
Partners
CSF1RDAP12EP300MAPK1MITFPI3KRAF1TFE3

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 The c-fms proto-oncogene product is the receptor for CSF-1 (M-CSF); the 165 kDa murine c-fms glycoprotein specifically binds CSF-1 and exhibits ligand-dependent tyrosine kinase activity and tyrosine autophosphorylation in membrane preparations. Immunoprecipitation with anti-v-fms antisera, radioligand binding with 125I-CSF-1, and in vitro tyrosine kinase assay Cell High 2408759
1985 Molecular cloning of a CSF-1 cDNA encoding a 224-amino-acid mature polypeptide (plus 32-aa leader) that directs synthesis of biologically active CSF-1 in COS cells; multiple mRNA species arise from a single-copy gene. cDNA cloning, COS-cell expression, radioreceptor assay, macrophage colony assay, antibody neutralization Science High 2996129
1987 A 4-kb CSF-1 cDNA encodes a longer 522-amino-acid precursor containing a C-terminal extension not found in the 1.6-kb cDNA product; both isoforms are structurally and functionally equivalent, arising from alternative splicing of the CSF-1 pre-mRNA. cDNA cloning, direct protein sequencing, mammalian cell expression Science High 3493529
1987 Human CSF-1 gene contains 10 exons spanning 20 kb; alternative splicing at exon 6 and alternative 3′ noncoding exons produce transcripts encoding either 224 or 522 amino-acid forms of CSF-1. Genomic cloning, RNA analysis, exon mapping The EMBO Journal High 3500041
1987 CSF-1 is synthesized as an integral transmembrane homodimeric glycoprotein (disulfide-linked) on the cell surface; extracellular proteolysis by trypsin-like proteases cleaves this membrane-bound precursor to release the soluble secreted form. Autocrine CSF-1/c-fms co-expression transforms NIH 3T3 cells. Cotransfection of CSF-1 and c-fms genes, surface trypsin cleavage, receptor downmodulation assays, transformation assay Molecular and Cellular Biology High 3039346
1986 CSF-1 regulates survival, proliferation, and differentiation of mononuclear phagocytes exclusively via a cell-surface receptor (165 kDa glycoprotein) that undergoes CSF-1-dependent tyrosine autophosphorylation; receptor levels increase on CFU-C just before differentiation to mononuclear phagocytes, marking lineage determination. Purified receptor characterization, tyrosine kinase assay, developmental receptor expression analysis Ciba Foundation symposium High 3015514
1992 X-ray crystal structure of recombinant human M-CSF dimer at 2.5 Å reveals two four-helix bundles laid end-to-end with an inter-chain disulfide bond; individual monomers share structural similarity with GM-CSF and growth hormone, suggesting common receptor-binding determinants. X-ray crystallography at 2.5 Å resolution Science High 1455231
1991 Mutation of autophosphorylation site Y809 (Phe substitution) in CSF-1R does not reduce kinase activity, PI3K binding, or immediate-early gene (c-fos, junB) induction, but abolishes CSF-1-dependent mitogenesis and c-myc induction; enforced c-myc expression rescues proliferation, demonstrating a bifurcation of signaling pathways at the receptor level with c-Myc as a central mitogenic mediator downstream of Y809. Site-directed mutagenesis of CSF-1R Y809, serum-free growth assay, colony assay, Northern blot for c-myc, c-myc overexpression rescue Nature High 1833648
1992 CSF-1 gene expression is induced in vascular endothelial and smooth muscle cells by IL-1α, TNF-α, and LPS; locally produced CSF-1 promotes macrophage scavenger receptor and apolipoprotein E mRNA accumulation in monocytes, linking vascular CSF-1 production to macrophage foam cell development in atherosclerosis. Northern blot, immunostaining, ELISA, PCR on human/rabbit atheromata, monocyte culture The American Journal of Pathology Medium 1739124
1994 Structure-function analysis of recombinant human M-CSF by site-directed mutagenesis identifies residues His-9 and His-15 in the N-terminal region (helix A) as critical for receptor binding; double mutation H9A/H15A reduces bioactivity 9,100-fold and receptor affinity equivalently; X-ray crystallography at 2.5 Å confirms no structural change, indicating direct involvement in receptor contact. Site-directed mutagenesis, radioreceptor binding assay, bioactivity assay, X-ray crystallography at 2.5 Å The Journal of Biological Chemistry High 7983059
1997 CSF-1 stimulates macrophage proliferation through signaling cascades that include PI3K, ERK1/2, cyclin D1/D2, cdk4, Rb phosphorylation, and E2F activation; IFN-α/β acts as an endogenous inhibitor of CSF-1-driven cell cycle progression in bone marrow-derived macrophages, acting at least partly via down-regulation of c-myc and cyclin D. Pharmacological inhibitors, cyclin/CDK immunoprecipitation kinase assays, Northern blot, knockout macrophages, cell-cycle analysis Molecular reproduction and development Medium 8981359
1997 CSF-1R autophosphorylation site Y807 (murine numbering) is essential for macrophage differentiation signaling and its mutation totally abrogates differentiation of FDC-P1 myeloid cells while increasing proliferation, suggesting Y807 controls a proliferation/differentiation switch; sites Y697, Y706, Y721 in the kinase insert augment but are not essential for differentiation. Site-directed mutagenesis of individual CSF-1R tyrosines, differentiation and proliferation assays in FDC-P1 myeloid cells Molecular reproduction and development Medium 8981370
1997 CSF-1R phosphorylation of Y721 in the kinase insert domain is the primary site mediating association with PI3K, which activates the major macrophage motility signaling pathways. Receptor mutagenesis, phosphotyrosine co-immunoprecipitation with p85 PI3K subunit, chemotaxis assays International journal of cell biology (review citing original data) Medium 22505929 9261328
1997 CSF-1 stimulates macrophage proliferation through the Raf-1/MEK/ERK pathway; downstream, ERK activation is required for macrophage differentiation. New myeloid-specific substrate p150 (Shc/Grb2 complex partner via PTB domain) is identified as a CSF-1R signaling component specific to hematopoietic cells. Co-immunoprecipitation, tyrosine phosphorylation assays, cDNA cloning of p150 Molecular reproduction and development Medium 8981370
1997 CSF-1 produced by estrogen-deficient stromal cells via an Egr-1-dependent mechanism is required for osteoclast formation; neutralizing anti-CSF-1 antibody in vivo completely prevents ovariectomy-induced increases in osteoclast number, bone resorption, and bone loss, establishing CSF-1 as a central mediator of estrogen deficiency-induced bone loss. In vivo antibody neutralization, ovariectomy model, histomorphometry, Egr-1 knockout mice The Journal of Clinical Investigation High 10792003
2001 M-CSF induces phosphorylation of transcription factors Mitf and TFE3 via a MAPK consensus site, triggering their recruitment of the co-activator p300; an unphosphorylatable serine mutant of Mitf fails to support multinucleated osteoclast formation, mimicking the Mitf(mi/mi) osteoclast defect, establishing a M-CSF→MAPK→Mitf/TFE3→p300 signaling axis for osteoclast maturation. Kinase assay, co-immunoprecipitation with p300, site-directed mutagenesis, osteoclast differentiation assay Molecular Cell High 11684011
2001 Iba1 (a macrophage/microglia-specific calcium-binding protein) is involved in Rac signaling downstream of M-CSF/CSF-1R; M-CSF activates Fms→PI3K or PLCγ→Rac pathway to drive actin cytoskeleton reorganization underlying microglial activation, proliferation, and migration. Signaling pathway dissection in microglia, kinase assays, Rac activation assay Glia Medium 12379904
2002 A 10-base insertion frameshift mutation in the rat Csf1 coding sequence (toothless/tl rat) produces a truncated 41-amino-acid non-functional protein and causes osteopetrosis, confirming that functional CSF-1 is essential for osteoclast differentiation and activation in vivo. Genomic sequencing of mutant rat Csf1 gene Biochemical and biophysical research communications High 12074592
2008 IL-34 was discovered as a second ligand for the CSF-1 receptor (CSF-1R) by functional screening of the extracellular proteome; IL-34 stimulates monocyte viability through the same receptor as CSF-1. Functional proteome screen, receptor identification by extracellular domain library screen, viability assay Science High 18467591
2009 DUSP5 (a dual-specificity phosphatase) is induced by M-CSF in myeloid cells in an ERK-dependent manner and acts as a negative-feedback regulator of ERK1/2; overexpression of DUSP5 increases M-CSF-dependent proliferation and strongly suppresses macrophage differentiation, demonstrating that sustained MAPK activation is required for commitment to macrophage differentiation. Subtractive hybridization, MEK inhibitor (U0126), DUSP5 overexpression, proliferation and differentiation assays Journal of Leukocyte Biology Medium 19801501
2010 IL-34 and CSF-1 both activate CSF-1R tyrosine phosphorylation and downstream signaling equivalently; transgenic IL-34 expression in a CSF-1-dependent pattern rescues bone, osteoclast, tissue macrophage, and fertility defects of Csf1(op/op) mice, demonstrating functional overlap but different spatiotemporal expression patterns (IL-34 predominates in brain and heart; CSF-1 in uterus and osteoblasts). CSF-1R phosphorylation assay, macrophage proliferation assay, transgenic rescue of op/op mice, in situ hybridization, qRT-PCR Journal of Leukocyte Biology High 20504948
2011 CSF-1 has three biologically active isoforms (cell-surface glycoprotein csCSF-1, secreted proteoglycan spCSF-1, secreted glycoprotein sgCSF-1) with distinct roles: csCSF-1 initiates local macrophage activation in the kidney; spCSF-1 is the dominant circulating isoform during advancing lupus nephritis and, together with csCSF-1, drives intrarenal recruitment of Ly6C(hi) monocytes that induce renal parenchymal apoptosis. Isoform-specific mutant MRL-Fas(lpr) knock-in mice, flow cytometry, histology, TUNEL Journal of the American Society of Nephrology High 21885670
2011 Conditional deletion of CSF-1 (Meox2Cre-driven) causes osteopetrosis, defective osteocyte maturation, reduced DMP1 expression, impaired bone mineralization, and loss of osteomacs from the endosteal surface, revealing a novel link between CSF-1 and osteocyte survival/function. Conditional gene knockout (Meox2Cre × CSF-1 floxed), histology, immunostaining, micro-CT Bone High 21958845
2006 A chromosomal translocation involving chromosome 1p13 fuses CSF1 to COL6A3 (or other partners) in tenosynovial giant cell tumor (TGCT), causing CSF1 overexpression in the minority of neoplastic cells and creating a 'landscape effect' whereby CSF1R-expressing non-neoplastic cells are recruited to form the tumor mass. FISH, array CGH, expression profiling, IHC on TGCT/PVNS tumor samples Proceedings of the National Academy of Sciences High 16407111
2015 After peripheral nerve injury, CSF1 is de novo expressed in injured sensory neurons and transported to the spinal cord, where it activates microglial CSF1R to induce microglial proliferation; sensory-neuron-specific Cre deletion of Csf1 completely prevents nerve injury-induced mechanical hypersensitivity and reduces spinal microglial activation; intrathecal CSF1 alone is sufficient to induce hypersensitivity and microglial proliferation; downstream, DAP12 is required for CSF1R-mediated upregulation of pain-related microglial genes but not proliferation. Conditional neuron-specific Csf1 KO, intrathecal CSF1 injection, behavioral pain testing, immunostaining, microglial proliferation quantification Nature neuroscience High 26642091
2015 M-CSF from cancer cells induces fatty acid synthase (FASN) expression in tumor myeloid cells, which activates PPARβ/δ; PPARβ/δ in turn drives IL-10 production that facilitates tumor cell invasion and angiogenesis; myeloid-cell-specific PPARβ/δ knockout impairs tumor growth and can be rescued by wild-type myeloid cell transfer. Myeloid-specific PPARβ/δ KO mice, adoptive transfer, in vitro M-CSF stimulation, FASN inhibition, IL-10 measurement Cell Reports Medium 25753425
2015 M-CSF signaling through CSF-1R drives macropinocytosis in macrophages via PI3K (producing PIP3) → PLCγ (generating DAG) → PKC and Ras → macropinosome closure; PLC inhibition blocks M-CSF-induced but not PMA-induced macropinocytosis, and Ras and PKC are required downstream of both stimuli. Fluorescent lipid probes (live imaging), pharmacological inhibitors (LY294002, U73122, FTS, Calphostin C), Akt inhibitor MK-2206 Frontiers in Physiology Medium 25688212
2017 Lymphatic endothelial cells (LECs) express high levels of M-CSF and promote osteoclast formation and bone resorption; LEC-derived M-CSF activity is neutralized by anti-M-CSF antibody or c-Fms inhibitor Ki20227, and intra-tibial LEC injection in mice causes massive osteolysis that is blocked by Ki20227, establishing M-CSF secretion by LECs as a mechanism of pathological bone destruction in Gorham-Stout disease. LEC/osteoclast co-culture, neutralizing antibody, small-molecule CSF1R inhibitor, intra-tibial LEC injection, micro-CT, histology Journal of Bone and Mineral Research High 28052488
2019 Mesothelial cells produce both membrane-bound and secreted CSF1, and this locally produced CSF1 sustains peritoneal macrophage proliferation and survival in the peritoneal cavity. Conditional CSF1 deletion in mesothelial cells, peritoneal macrophage enumeration, flow cytometry European Journal of Immunology Medium 31251389
2023 Bone marrow Adipoq-lineage progenitors (not mature adipocytes) are a major source of CSF1 in bone marrow, producing M-CSF at levels far exceeding osteoblast lineage cells; conditional deletion of Csf1 in Adipoq-lineage progenitors drastically reduces bone marrow macrophages and osteoclasts, causes severe osteopetrosis, and significantly alleviates ovariectomy-induced bone loss. Adipoq-Cre × Csf1-floxed conditional KO, single-cell RNA sequencing, histology, micro-CT, OVX model eLife High 36779851
2023 Marrow adipogenic lineage precursors (MALPs) are a major mesenchymal source of Csf1 in trabecular bone; MALP-specific Csf1 CKO (Adipoq-Cre) increases femoral trabecular bone mass, reduces osteoclasts in secondary spongiosa, reduces bone marrow macrophages/hematopoietic progenitors, and protects against LPS-induced calvarial osteolysis. MALP-specific Csf1 conditional KO, TRAP staining, micro-CT, hematopoietic progenitor analysis, LPS-induced osteolysis model eLife High 36779854
2006 Cyclophilin A is required for M-CSF-dependent macrophage proliferation; sanglifehrin A (SfA), a cyclophilin A-binding immunosuppressor, arrests macrophages in G1 by inactivating Cdk2, repressing c-myc, and inhibiting phosphorylation of Raf-1 and ERK1/2, demonstrating that the cyclophilin A/Raf-1/MEK/ERK axis is necessary for CSF-1-driven cell cycle progression. Pharmacological inhibition with SfA, ERK/Raf-1 phosphorylation assays, Cdk2 kinase assay, cell cycle analysis, c-myc Northern blot European Journal of Immunology Medium 16909430
2007 miR-17-5p, miR-20a, and miR-106a control monocytopoiesis by targeting AML1 (Runx1) mRNA 3′UTR; their downregulation during monocytic differentiation permits AML1 protein translation, which then drives M-CSF receptor (M-CSFR/CSF1R) transcription; AML1 also transcriptionally inhibits the miR-17-5p/92 cluster promoters, forming a mutual negative feedback loop. miRNA transfection/anti-miRNA, AML1 siRNA knockdown, luciferase reporter, ChIP for AML1 on miRNA cluster promoters Nature Cell Biology High 17589498
2018 Systemic administration of neutralizing anti-CSF-1R or anti-CSF-1 monoclonal antibodies inhibits development of inflammatory pain (zymosan, GM-CSF, TNF-induced) and prevents arthritic pain in mice; systemic CSF-1 administration rapidly induces pain and enhances arthritis, demonstrating a peripheral role for CSF-1 in inflammatory pain generation distinct from its central microglial role. In vivo antibody neutralization, recombinant CSF-1 administration, behavioral pain assays (von Frey), mouse arthritis models Journal of Immunology Medium 30120124
2017 Proteasome inhibitors (MG132, bortezomib) accelerate degradation of c-Fms (CSF-1R) in osteoclasts via p38/TACE-mediated regulated intramembrane proteolysis (RIPping), without affecting RANK levels; c-Fms degradation completely blocks M-CSF-mediated signaling and suppresses osteoclast differentiation and bone resorption in vitro and in vivo. Proteasome inhibitor treatment, p38/TACE inhibitors, immunoblot for c-Fms, M-CSF signaling assays, LPS-induced bone loss model International Journal of Molecular Sciences Medium 28946669
1993 M-CSF stimulates migration in isolated rat osteoclasts, increasing both the proportion of migrating cells and substrate area covered; this motility-promoting effect is inverse to its inhibitory effect on bone resorption, suggesting M-CSF controls a switch between migratory and resorptive states in osteoclasts. Time-lapse microscopy of isolated osteoclasts on substrate, M-CSF stimulation dose-response Biochemical and biophysical research communications Medium 8216275

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 1567 2408759
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
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
2014 CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor perspectives in biology 652 24890514
2008 Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science (New York, N.Y.) 635 18467591
1985 Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1). Science (New York, N.Y.) 614 2996129
2011 Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 603 22186992
1987 Human CSF-1: molecular cloning and expression of 4-kb cDNA encoding the human urinary protein. Science (New York, N.Y.) 467 3493529
2015 Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nature neuroscience 450 26642091
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2006 A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proceedings of the National Academy of Sciences of the United States of America 423 16407111
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2007 MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nature cell biology 372 17589498
2004 Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. The Journal of biological chemistry 351 15304486
1997 Biology and action of colony--stimulating factor-1. Molecular reproduction and development 334 8981357
2012 Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PloS one 312 23251661
2002 Intracellular signaling in M-CSF-induced microglia activation: role of Iba1. Glia 300 12379904
1992 Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. The American journal of pathology 298 1739124
2010 Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. Journal of leukocyte biology 289 20504948
1987 Human CSF-1: gene structure and alternative splicing of mRNA precursors. The EMBO journal 280 3500041
2000 The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 247 10666185
1987 Synthesis of membrane-bound colony-stimulating factor 1 (CSF-1) and downmodulation of CSF-1 receptors in NIH 3T3 cells transformed by cotransfection of the human CSF-1 and c-fms (CSF-1 receptor) genes. Molecular and cellular biology 236 3039346
2018 Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α. Nature communications 220 29422647
2008 Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. American journal of human genetics 215 18606301
2014 An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF-β yields a dominant immunosuppressive phenotype. Scandinavian journal of immunology 213 24521472
2010 Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nature genetics 211 20436471
2020 The M-CSF receptor in osteoclasts and beyond. Experimental & molecular medicine 184 32801364
2009 Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathology international 179 19432671
1997 CSF-1 signal transduction. Journal of leukocyte biology 173 9261328
1991 Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling. Nature 172 1833648
2002 Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood 171 12393446
1992 Three-dimensional structure of dimeric human recombinant macrophage colony-stimulating factor. Science (New York, N.Y.) 169 1455231
2019 Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer. Frontiers in immunology 147 31552020
2003 M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. Journal of immunology (Baltimore, Md. : 1950) 140 12928417
1995 CSF-1 and its receptor in ovarian, endometrial and breast cancer. Annals of medicine 140 7742005
2001 Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice. Molecular cell 129 11684011
1997 Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood cells, molecules & diseases 115 9236158
2021 The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis. Theranostics 113 33408768
2000 Early events in M-CSF receptor signaling. Growth factors (Chur, Switzerland) 111 10705574
2013 IL-34 and CSF-1: similarities and differences. Journal of bone and mineral metabolism 110 23740288
2001 Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. The Journal of surgical research 103 11516200
2021 Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair. Seminars in immunology 102 34742624
2001 Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. Journal of reproductive immunology 101 11600176
2012 Macrophage Migration and Its Regulation by CSF-1. International journal of cell biology 96 22505929
2015 Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer research 92 25667468
2003 High dose M-CSF partially rescues the Dap12-/- osteoclast phenotype. Journal of cellular biochemistry 92 14624447
1989 Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasms. International journal of radiation oncology, biology, physics 88 2663797
1988 Enhancement of human monocyte tumoricidal activity by recombinant M-CSF. Journal of immunology (Baltimore, Md. : 1950) 88 3053901
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