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CSF1

gene
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Also known as M-CSFMCSFMGC31930

Summary

CSF1 (colony stimulating factor 1, HGNC:2432) is a protein-coding gene on chromosome 1p13.3, encoding Macrophage colony-stimulating factor 1 (P09603). Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes.

The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 1435 — RefSeq curated summary.

At a glance

  • GWAS associations: 25 (top 5% of genes corpus-wide)
  • Clinical variants (ClinVar): 103 total
  • GTEx eGene: eQTL in 22 tissues, sQTL in 3 (q < 0.05)
  • Drug target: yes — 2 curated mechanism-of-action drugs
  • Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.34 (highly constrained)
  • MANE Select transcript: NM_000757
  • Interaction hub: 3,416 STRING partners (top 2% of genes corpus-wide)
  • Notable: 103 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:2432
Approved symbolCSF1
Namecolony stimulating factor 1
Location1p13.3
Locus typegene with protein product
StatusApproved
AliasesM-CSF, MCSF, MGC31930
Ensembl geneENSG00000184371
Ensembl biotypeprotein_coding
OMIM120420
Entrez1435

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000329608

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 3: 2, TSL 4: 3, TSL 5: 1

ENST00000329608, ENST00000357302, ENST00000369801, ENST00000369802, ENST00000420111, ENST00000488198, ENST00000525659, ENST00000526001, ENST00000527192, ENST00000875282, ENST00000875283, ENST00000875284, ENST00000875285, ENST00000875286, ENST00000875287, ENST00000913371, ENST00000958976, ENST00001012642, ENST00001012643, ENST00001012644, ENST00001142243

RefSeq mRNA: 4 — MANE Select: NM_000757 NM_000757, NM_172210, NM_172211, NM_172212

CCDS: CCDS30797, CCDS816, CCDS817

Canonical transcript exons

ENST00000329608 — 9 exons

ExonStartEnd
ENSE00001291595109924776109924828
ENSE00001304095109915634109915696
ENSE00001310214109925147109925202
ENSE00001321883109923166109924190
ENSE00001933966109910849109911062
ENSE00001937307109928852109930992
ENSE00003576195109917293109917463
ENSE00003586257109921847109921994
ENSE00003669519109914259109914381

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 94.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.5367 / max 1625.0135, expressed in 1560 samples.

Highest expression (Bgee): omental fat pad, peritoneum, adipose tissue of abdominal region, gall bladder, subcutaneous adipose tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CSF1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

TissueQTLq-valueSlopeLead variant
Artery Tibialeqtl3.7e-20+0.401:109928142:G:A
Cells Cultured fibroblastssqtl1.4e-18+0.581:109923716:C:A
Nerve Tibialeqtl7.9e-18+0.371:109928142:G:A
Breast Mammary Tissueeqtl9.5e-09+0.281:109928142:G:A
Esophagus Musculariseqtl6.6e-07+0.201:109928142:G:A
Skin Sun Exposed Lower legeqtl2.5e-06+0.171:109928142:G:A
Brain Cerebellar Hemisphereeqtl6.5e-06+0.451:109941642:G:T
Muscle Skeletaleqtl8.4e-06+0.201:109928142:G:A
Adipose Subcutaneouseqtl1.0e-04+0.231:109928142:G:A
Artery Aortaeqtl1.5e-04+0.221:109928142:G:A
Cells Cultured fibroblastseqtl1.9e-04+0.081:109821653:T:G
Esophagus Mucosaeqtl6.2e-04-0.111:109960674:T:C
Lungeqtl6.2e-04+0.161:109927970:G:A
Thyroideqtl4.0e-03+0.171:109928142:G:A
Heart Left Ventricleeqtl5.4e-03+0.141:109927970:G:A
Small Intestine Terminal Ileumeqtl6.6e-03+3.391:109929951:G:A
Skin Not Sun Exposed Suprapubiceqtl6.6e-03+0.141:109928142:G:A
Brain Cortexeqtl8.2e-03-1.051:110117816:C:T
Esophagus Gastroesophageal Junctioneqtl1.2e-02+0.161:109928142:G:A
Brain Hypothalamuseqtl1.5e-02+1.791:110234735:T:C

FANTOM5 promoters

9 alternative TSS:

Promoter IDTPM avgSamples expressed
446218.96581383
44611.84991002
44601.4640817
44631.1077608
44590.5560309
44690.3023148
44700.147552
44650.080720
44640.062710

Top tissues by expression

showing 100 of 271 tissues by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
omental fat padUBERON:001041494.58gold quality
peritoneumUBERON:000235894.52gold quality
adipose tissue of abdominal regionUBERON:000780893.68gold quality
gall bladderUBERON:000211093.05gold quality
subcutaneous adipose tissueUBERON:000219092.98gold quality
right coronary arteryUBERON:000162592.82gold quality
apex of heartUBERON:000209892.67gold quality
left adrenal glandUBERON:000123492.60gold quality
left coronary arteryUBERON:000162692.54gold quality
cartilage tissueUBERON:000241892.54gold quality
right adrenal glandUBERON:000123392.43gold quality
right adrenal gland cortexUBERON:003582792.42gold quality
left adrenal gland cortexUBERON:003582592.40gold quality
endometrium epitheliumUBERON:000481192.27silver quality
coronary arteryUBERON:000162192.07gold quality
adrenal cortexUBERON:000123591.77gold quality
left uterine tubeUBERON:000130391.58gold quality
pancreatic ductal cellCL:000207991.26silver quality
upper lobe of left lungUBERON:000895291.24gold quality
spleenUBERON:000210690.82gold quality
adrenal glandUBERON:000236990.73gold quality
tibial nerveUBERON:000132390.47gold quality
adipose tissueUBERON:000101390.41gold quality
upper lobe of lungUBERON:000894890.37gold quality
ascending aortaUBERON:000149690.18gold quality
thoracic aortaUBERON:000151590.14gold quality
descending thoracic aortaUBERON:000234589.98gold quality
connective tissueUBERON:000238489.92gold quality
synovial jointUBERON:000221789.31gold quality
mucosa of stomachUBERON:000119989.15gold quality
lymph nodeUBERON:000002989.04gold quality
C1 segment of cervical spinal cordUBERON:000646988.96gold quality
right atrium auricular regionUBERON:000663188.96gold quality
aortaUBERON:000094788.90gold quality
right ovaryUBERON:000211888.67gold quality
esophagogastric junction muscularis propriaUBERON:003584188.64gold quality
layer of synovial tissueUBERON:000761688.58gold quality
lower esophagus muscularis layerUBERON:003583388.48gold quality
colonic epitheliumUBERON:000039788.44gold quality
lower esophagusUBERON:001347388.43gold quality
muscle layer of sigmoid colonUBERON:003580588.37gold quality
spinal cordUBERON:000224088.08gold quality
tibial arteryUBERON:000761088.07gold quality
popliteal arteryUBERON:000225088.06gold quality
right lungUBERON:000216787.70gold quality
right lobe of thyroid glandUBERON:000111987.63gold quality
cardiac atriumUBERON:000208187.59gold quality
vermiform appendixUBERON:000115487.27gold quality
body of stomachUBERON:000116187.14gold quality
small intestine Peyer’s patchUBERON:000345487.12gold quality
caecumUBERON:000115387.01gold quality
heart left ventricleUBERON:000208486.81gold quality
heartUBERON:000094886.80gold quality
body of uterusUBERON:000985386.76gold quality
cardiac ventricleUBERON:000208286.73gold quality
fundus of stomachUBERON:000116086.70gold quality
smooth muscle tissueUBERON:000113586.69gold quality
ectocervixUBERON:001224986.65gold quality
transverse colonUBERON:000115786.63gold quality
rectumUBERON:000105286.61gold quality
vena cavaUBERON:000408786.61gold quality
endocervixUBERON:000045886.52gold quality
left lobe of thyroid glandUBERON:000112086.43gold quality
sigmoid colonUBERON:000115986.28gold quality
sural nerveUBERON:001548886.11gold quality
metanephros cortexUBERON:001053386.09gold quality
olfactory bulbUBERON:000226486.07silver quality
stromal cell of endometriumCL:000225585.95gold quality
left ovaryUBERON:000211985.92gold quality
small intestineUBERON:000210885.88gold quality
colonUBERON:000115585.68gold quality
stomachUBERON:000094585.66gold quality
thyroid glandUBERON:000204685.60gold quality
minor salivary glandUBERON:000183085.59gold quality
saliva-secreting glandUBERON:000104485.45gold quality
esophagusUBERON:000104385.26gold quality
large intestineUBERON:000005985.18gold quality
intestineUBERON:000016085.10gold quality
mucosa of transverse colonUBERON:000499185.10gold quality
heart right ventricleUBERON:000208085.07silver quality
skin of legUBERON:000151185.03gold quality
lungUBERON:000204885.00gold quality
corpus callosumUBERON:000233684.72gold quality
type B pancreatic cellCL:000016984.71gold quality
substantia nigraUBERON:000203884.56gold quality
calcaneal tendonUBERON:000370184.54gold quality
myometriumUBERON:000129684.49gold quality
right uterine tubeUBERON:000130284.36gold quality
mouth mucosaUBERON:000372984.31gold quality
urinary bladderUBERON:000125584.16gold quality
cardia of stomachUBERON:000116284.08silver quality
midbrainUBERON:000189184.04gold quality
pericardiumUBERON:000240783.91gold quality
vaginaUBERON:000099683.83gold quality
mammary ductUBERON:000176583.75silver quality
body of pancreasUBERON:000115083.24gold quality
middle frontal gyrusUBERON:000270283.22silver quality
right lobe of liverUBERON:000111483.17gold quality
epithelium of mammary glandUBERON:000324483.16silver quality
skin of abdomenUBERON:000141683.12gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

ExperimentMarker?Max mean expression
E-HCAD-6yes46.66
E-CURD-122yes8.69
E-ANND-3no0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cellAxisnTPM
Adipose tissuetissue57.4
Choroid plexustissue50.3
Placentatissue38.8
Spleentissue38.6
Locus coeruleustissue35.0
Spinal cordtissue30.8
Vaginatissue30.1
Gallbladdertissue29.9
Hippocampustissue28.6
Adrenal glandtissue28.4
Corpus callosumtissue28.0
Lungtissue26.7
Lymph nodetissue26.4
Urinary bladdertissue24.9
Nucleus accumbenstissue24.6
Appendixtissue23.1
Substantia nigratissue19.6
Medulla oblongatatissue19.5
Colontissue18.7
Breasttissue18.4
Fallopian tubetissue17.9
Salivary glandtissue17.8
Bone marrowtissue17.4
Superior colliculitissue17.0
Small intestinetissue16.6
Pancreastissue16.5
Smooth muscletissue16.4
Midbraintissue16.2
Seminal vesicletissue15.7
Cervixtissue15.4
Rectumtissue15.3
Livertissue15.1
Esophagustissue14.7
Postcentral gyrustissue14.0
Stomach 1tissue13.8
Thalamustissue13.7
Periaqueductal graytissue13.7
Heart muscletissue12.8
Thymustissue12.6
Duodenumtissue12.5
Endometrium 1tissue12.3
Ponstissue11.9
Ovarytissue11.7
Hypothalamustissue11.7
Tonsiltissue11.4
Skin 1tissue11.3
Tonguetissue10.5
Putamentissue10.2
Prostatetissue10.1
Ventral forebraintissue10.1
Septumtissue10.0
Parathyroid glandtissue9.9
Basal gangliatissue9.7
Hippocampal formationtissue9.1
Pituitary glandtissue8.8
Frontal cortextissue8.6
Olfactory bulbtissue8.0
Caudate putamentissue8.0
Amygdalatissue7.4
Kidneytissue7.3

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Parieto-temporal junction (white matter) (75.1), Area postrema (71.0), Corpus callosum, genu (white matter) (68.0), Dorsal funiculus (white matter) (66.4), Nucleus gracilis (63.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

TargetRegulation
CCL2Activation
ITGAXActivation

Upstream regulators (CollecTRI, top): ABL1, AP1, ATF3, BCL6, CCL2, CEBPA, EGR1, ETS2, FOS, FOXC1, GFI1, HLX, JUN, MITF, MYC, NCOA1, NFIA, NFIC, NFKB1, NFKB, NOTCH1, PHF5A, PPARG, RBPJ, REL, RELA, RUNX1, SMAD1, SMAD4, SMAD5, SMARCB1, SP1, SP3, SPI1, STAT1, TBP, TBX3, TFAP2A, TP63, TXK

miRNA regulators (miRDB)

Targeting CSF1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 138 miRNAs:

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-4795-3P100.0074.624024
HSA-MIR-126-5P100.0072.713180
HSA-MIR-3163100.0077.238605
HSA-MIR-4283100.0066.422097
HSA-MIR-4673100.0066.641490
HSA-MIR-7110-3P100.0073.182486
HSA-MIR-656-3P100.0072.152788
HSA-MIR-4692100.0067.322066
HSA-MIR-4533100.0069.482758
HSA-MIR-451499.9967.101870
HSA-MIR-3667-3P99.9967.171636
HSA-MIR-27A-3P99.9872.132955
HSA-MIR-27B-3P99.9872.132955
HSA-MIR-998599.9872.112939
HSA-MIR-4645-5P99.9865.811284
HSA-MIR-426799.9666.532368
HSA-MIR-128-3P99.9571.172484
HSA-MIR-216A-3P99.9571.192505
HSA-MIR-6721-5P99.9368.922981
HSA-MIR-454-3P99.9174.011925
HSA-MIR-429599.9073.111838
HSA-MIR-130A-3P99.9073.311861
HSA-MIR-130B-3P99.9073.271850
HSA-MIR-301A-3P99.9073.151839
HSA-MIR-301B-3P99.9073.191836
HSA-MIR-366699.9073.241833
HSA-MIR-15A-5P99.9072.802787
HSA-MIR-15B-5P99.9072.782798
HSA-MIR-16-5P99.9072.802780
HSA-MIR-195-5P99.9072.812805

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.338, missense Z 0.493 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000329608 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)Missense obs / expo/eConstrained
1:109,911,024–109,914,32753 / 45.51.17no
1:109,914,328–109,917,32328 / 58.80.48no
1:109,917,324–109,925,186591 / 593.61.00no

Literature-anchored findings (GeneRIF, showing 40)

  • Macrophage colony-stimulating factor and receptor activator NF-kappaB ligand fail to rescue osteoclast-poor human malignant infantile osteopetrosis in vitro. (PMID:11792569)
  • High M-CSF levels may correlate with cellular or organ damage in patients treated with peripheral blood stem cell transplantation for hematologic diseases. (PMID:11843897)
  • Opposite effects of different doses of MCSF on ERK phosphorylation and cell proliferation in macrophages. (PMID:12032835)
  • CSF-1 and its receptor are regulated by 1,25(OH)(2)D(3) and its analogue tacalcitol in human monocytes which parallels the inhibition of differentiation into dendritic cells without altering survival (PMID:12372416)
  • IFN-gamma shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. (PMID:12393446)
  • in human tumor cells, HGF and M-CSF stimulate osteopontin production (which is subsequently used as a substrate for cell adhesion) (PMID:12456016)
  • Time-dependent folding events reveal that recombinant MCSF beta molecules pass through both monomeric and dimeric intermediate states, suggesting that the denatured and dimeric bond-reduced protein folds via multiple pathways. (PMID:12501178)
  • macrophage colony-stimulating factor increased platelet-activating factor acetylhydrolase secretion by decidual macrophages (PMID:12548211)
  • Results suggest that macrophage colony-stimulating factor may autoregulate functional cellular subpopulations of human endometrial stromal cells in an autocrine or a paracrine manner. (PMID:12684699)
  • findings directly support the conclusion that membrane-bound colony stimulating factor-1 is functionally active in bone in vivo (PMID:12865350)
  • Serum VEGF concentration was increased in arteriosclerosis obliterans (ASO) and thromboangitis obliterans, but increased concentration of M-CSF was seen only in ASO. (PMID:12890905)
  • CSF1 has a role in regulating macrophage activation [review] (PMID:12894871)
  • Monocytes promote angiogenesis via M-CSF-induced vascular endothelial growth factor production. (PMID:12928417)
  • sCSF-1 is a key determinant of bone cell activity in the corticoendosteal envelope (PMID:12929928)
  • increased levels of serum macrophage colony stimulating factor markedly precede the development of clinical manifestations of preeclampsia (PMID:14605992)
  • Increase in serum M-CSF levels precedes development of preeclampsia. Elevation of serum M-CSF supports M-CSF elevation in placenta. This elevation at 18 weeks of gestation may be related to placental hypoxia, considered cause of preeclampsia. (PMID:14634568)
  • findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation. (PMID:14654075)
  • The serum M-CSF concentration could be of interest as a tumor marker in squamous cell carcinomas of the head and neck. (PMID:15001836)
  • red blood cells from diabetic patients induced an increase in MCSF and VCAM1 expression in HUVEC cells, mediated by AGE-RAGE interaction (PMID:15116247)
  • Expreeeion of macrophage colony-stimulating factor in human osteoblast-like cells is suppressed by arginine-vasopressin. (PMID:15256272)
  • results suggest that nuclear actin plays a role in regulating CSF-1 gene transcription, and this role does not depend on actin polymerization (PMID:15261158)
  • In vitro human osteoclastogenesis is dependent on M-CSF and the stimulatory effects of GM-CSF are mediated by M-CSF. (PMID:15358207)
  • Crystal structures of HLA-B*3501 in complex with 14-mer macrophage-colony stimulating factor peptide reveal that the antigenic peptide follows the general rules of major histocompatibility complex binding. (PMID:15494511)
  • The MGFS mRNA expression in these cell lines and recent studies have demonstrated that HCs can stimulate tumor progression. (PMID:15576295)
  • Interferon-gamma stimulates transcription of the CSF-1 gene through this sequence, which binds STAT1 (PMID:15624698)
  • A significant serum tumor marker in head and neck squamous cell carcinoma. (PMID:15640942)
  • Serum M-CSF levels are markedly increased in Langerhans cell histiocytosis patients who, in addition to bone disease, also show skin or lymph node involvement. (PMID:15728521)
  • indicate novel roles of M-CSF in articular cartilage metabolism in collaboration with CTGF/CCN2, particularly during an inflammatory response (PMID:15820145)
  • The M-CSF gene was cloned into baculovirus transfer vector pVL1392 under the control of polyhedrin promoter and expressed in the Sf9 cells (Spodoptera frugiperda). (PMID:15866728)
  • Uncreased macrophage colony stimulating factor is associated with the process of atherosclerosis in hemodialysis patients (PMID:15919699)
  • M-CSF enhances tumor growth in mice by increasing endothelial progenitor cells and activating angiogenesis; the effects of M-CSF are largely based on the induction of systemic VEGF from skeletal muscles. (PMID:15944252)
  • catalase has a critical role in CSF-independent survival of human macrophages via regulation of the expression of BCL-2 and BCL-XL (PMID:16204228)
  • INI1/hSNF5/BAF47 functions in activation of the colony stimulating factor 1 (CSF1) promoter in HeLa cells. (PMID:16267391)
  • MCP-1 and M-CSF, critical for monocyte recruitment, activation, and differentiation, differentially regulate VEGF-A expression and may play an important role in monocyte/macrophage- mediated tumor angiogenesis (PMID:16318581)
  • Nurse-like cells are involved in rheumatoid arthritis-induced bone destruction by maintaining osteoclast precursors via production of M-CSF. (PMID:16320327)
  • Fusion with COL6A3 overexpresses CSF1, found in some but not all cells in tenosynovial giant-cell tumor and pigmented villonodular synovitis. (PMID:16407111)
  • at 35 and 38 weeks, the Macrophage colony-stimulating factor (M-CSF) levels were significantly higher in twin pregnancy than in singleton pregnancy (PMID:16673212)
  • three polymorphisms located in the colony stimulating factor 1 (CSF1) gene showed a positive association with aggressive periodontitis (PMID:16844084)
  • IL-10 may contribute to the inflammatory process by facilitating monocyte differentiation into TNF-alpha-responsive macrophages in the presence of M-CSF in rheumatoid arthritis. (PMID:16859503)
  • Different individual CSF-1 isoforms regulate the frequency of activated macrophages in the kidney during experimental unilateral ureteral obstruction. (PMID:16951369)

Cross-species orthologs

4 orthologs

OrganismSymbolGene ID
danio_reriocsf1bENSDARG00000068263
danio_reriocsf1aENSDARG00000075343
mus_musculusCsf1ENSMUSG00000014599
rattus_norvegicusCsf1ENSRNOG00000018659

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1339753) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 133 distinct phenotype terms.

Mouse phenotype (MP)Records
decreased macrophage cell number6
decreased body weight4
abnormal bone marrow morphology4
decreased osteoclast cell number4
abnormal bone marrow cavity morphology3
domed cranium3
abnormal osteoclast differentiation3
increased bone trabecula number3
osteopetrosis2
abnormal trabecular bone morphology2
abnormal microglial cell morphology2
decreased monocyte cell number2
decreased bone marrow cell number2
postnatal growth retardation2
abnormal ovulation2
abnormal spleen red pulp morphology2
abnormal bone remodeling2
abnormal bone structure2
abnormal osteoclast morphology2
abnormal Kupffer cell morphology2
abnormal visual evoked potential2
absent teeth2
fragile skeleton1
osteoporosis1
abnormal parietal bone morphology1

+108 more (showing top 25).

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

SymbolTypeEntrez
LINC01768ncRNA107985167
GSTM3protein-coding2947
EPS8L3protein-coding79574
LINC01397ncRNA104355139
AHCYL1protein-coding10768
ALX3protein-coding257
STRIP1protein-coding85369

Protein

Protein identifiers

Macrophage colony-stimulating factor 1 — P09603 (reviewed: P09603)

Alternative names: Lanimostim, Proteoglycan macrophage colony-stimulating factor

All UniProt accessions (5): E9PJA2, E9PKP4, E9PQ08, P09603, H7BY18

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone development. Required for normal male and female fertility. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. Plays a role in lipoprotein clearance.

Subunit / interactions. Homodimer or heterodimer; disulfide-linked. Likely to exist in multiple forms: homodimer consisting of 2 identical 150-200 kDa proteoglycan subunits, heterodimer consisting of a 150-200 kDa proteoglycan subunit and a truncated 43 kDa subunit, and homodimer consisting of 2 identical 43 kDa subunits. Interacts with CSF1R.

Subcellular location. Cell membrane Secreted. Extracellular space.

Post-translational modifications. N-glycosylated. N-glycosylated. N-glycosylated. O-glycosylated; contains chondroitin sulfate. O-glycosylated with core 1 or possibly core 8 glycans. O-glycosylated.

Disease relevance. Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers. Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.

Isoforms (3)

UniProt IDNamesCanonical?
P09603-11yes
P09603-22
P09603-33

RefSeq proteins (4): NP_000748, NP_757349, NP_757350, NP_757351 (=MANE)

Domains & families (InterPro)

IDNameType
IPR008001MCSF-1Family
IPR0090794_helix_cytokine-like_coreHomologous_superfamily

Pfam: PF05337

UniProt features (59 total): sequence conflict 9, helix 9, disulfide bond 6, sequence variant 6, glycosylation site 5, compositionally biased region 4, mutagenesis site 4, chain 3, region of interest 3, splice variant 2, topological domain 2, strand 2, signal peptide 1, modified residue 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDBTitleMethodResolution (Å)
5LXFCrystal structure of the human Macrophage Colony Stimulating Factor M- CSF_C31S variantX-RAY DIFFRACTION2
4FA8Multi-pronged modulation of cytokine signalingX-RAY DIFFRACTION2.2
1HMCTHREE-DIMENSIONAL STRUCTURE OF DIMERIC HUMAN RECOMBINANT MACROPHAGE COLONY STIMULATING …X-RAY DIFFRACTION2.5
3UF2Crystal structure of the human Colony-Stimulating Factor 1 (hCSF-1) cytokineX-RAY DIFFRACTION2.75
4WRLStructure of the human CSF-1:CSF-1R complexX-RAY DIFFRACTION2.8
3UEZCrystal structure of the human Colony-Stimulating Factor 1 (hCSF-1) cytokine in complex …X-RAY DIFFRACTION3.41
4ADFCRYSTAL STRUCTURE OF THE HUMAN COLONY-STIMULATING FACTOR 1 (hCSF-1) CYTOKINE IN COMPLEX …X-RAY DIFFRACTION4.4
4WRMStructure of the human CSF-1:CSF-1R complexX-RAY DIFFRACTION6.85

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P09603-F158.620.26

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, RAS pathway related proteins, Cancer-related genes, Candidate cancer biomarkers, Candidate cardiovascular disease genes, Disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; nuclear bodies

Antibody reliability (HPA): IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1)

TypePositions
Phosphothreonine266

Disulfide bonds (6)

TypePositions
Disulfide bond39–122, 80–171, 134–178
Interchain63, 189, 191

Glycosylation sites (5)

TypePositions
N-linked (glcnac…) asparagine154, 172
O-linked (xyl…) (chondroitin sulfate) serine309
O-linked (galnac…) threonine363, 365

Mutagenesis-validated functional residues (4)

PositionPhenotype
252loss of 43 kda subunit.
309loss of chondroitin sulfate attachment.
444does not affect production of 150-200 kda subunit.
489–554produces biologically active protein which is secreted.

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 14; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

14 pathways:

IDPathwayEvidence
R-HSA-9968734Differentiation of Circulating Monocytescurated
R-HSA-6783783Interleukin-10 signalingcurated
R-HSA-449836Other interleukin signalingcurated
R-HSA-8957275Post-translational protein phosphorylationcurated
R-HSA-381426Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)curated
R-HSA-9856649Transcriptional and post-translational regulation of MITF-M expression and activitycurated
R-HSA-1280215Cytokine Signaling in Immune system—
R-HSA-1266738Developmental Biology—
R-HSA-168256Immune System—
R-HSA-9730414MITF-M-regulated melanocyte development—
R-HSA-392499Metabolism of proteins—
R-HSA-597592Post-translational protein modification—
R-HSA-9680350Signaling by CSF1 (M-CSF) in myeloid cellselectronic
R-HSA-449147Signaling by Interleukins—

MSigDB gene sets: 582 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_GLAND_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255

GO Biological Process (28): positive regulation of cell-matrix adhesion (GO:0001954), response to ischemia (GO:0002931), developmental process involved in reproduction (GO:0003006), inflammatory response (GO:0006954), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), regulation of macrophage derived foam cell differentiation (GO:0010743), positive regulation of macrophage derived foam cell differentiation (GO:0010744), positive regulation of macrophage chemotaxis (GO:0010759), macrophage differentiation (GO:0030225), osteoclast differentiation (GO:0030316), positive regulation of cell migration (GO:0030335), positive regulation of mononuclear cell proliferation (GO:0032946), macrophage colony-stimulating factor signaling pathway (GO:0038145), monocyte activation (GO:0042117), innate immune response (GO:0045087), positive regulation of macrophage differentiation (GO:0045651), positive regulation of monocyte differentiation (GO:0045657), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of protein metabolic process (GO:0051247), microglial cell proliferation (GO:0061518), positive regulation of macrophage colony-stimulating factor signaling pathway (GO:1902228), positive regulation of microglial cell migration (GO:1904141), positive regulation of macrophage migration (GO:1905523), immune system process (GO:0002376), positive regulation of leukocyte migration (GO:0002687), signal transduction (GO:0007165)

GO Molecular Function (6): cytokine activity (GO:0005125), macrophage colony-stimulating factor receptor binding (GO:0005157), growth factor activity (GO:0008083), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), CSF1-CSF1R complex (GO:1990682)

Reactome top-level categories

8 top-level categories:

CategoryPathways
Metabolism of proteins2
Signaling by Interleukins2
Cytokine Signaling in Immune system2
Post-translational protein modification1
MITF-M-regulated melanocyte development1
Developmental Cell Lineages1
Immune System1
Developmental Biology1

GO top-level categories

56 GO namespaces:

CategoryTerms
positive regulation of myeloid leukocyte differentiation3
cellular anatomical structure3
macrophage derived foam cell differentiation2
myeloid leukocyte differentiation2
receptor ligand activity2
regulation of cell-matrix adhesion1
cell-matrix adhesion1
positive regulation of cell-substrate adhesion1
response to stress1
reproductive process1
developmental process1
defense response1
enzyme-linked receptor protein signaling pathway1
cell population proliferation1
regulation of cell population proliferation1
positive regulation of cellular process1
gene expression1
regulation of gene expression1
positive regulation of macromolecule biosynthetic process1
regulation of cell differentiation1
regulation of macrophage derived foam cell differentiation1
positive regulation of cell differentiation1
positive regulation of leukocyte chemotaxis1
regulation of macrophage chemotaxis1
macrophage chemotaxis1
regulation of granulocyte chemotaxis1
positive regulation of macrophage migration1
mononuclear cell differentiation1
cell migration1
regulation of cell migration1
positive regulation of cell motility1
mononuclear cell proliferation1
regulation of mononuclear cell proliferation1
positive regulation of leukocyte proliferation1
cytokine-mediated signaling pathway1
cellular response to macrophage colony-stimulating factor stimulus1
myeloid leukocyte activation1
immune response1
defense response to symbiont1
macrophage differentiation1
regulation of macrophage differentiation1
monocyte differentiation1
regulation of monocyte differentiation1
osteoclast differentiation1
regulation of osteoclast differentiation1
cytokine receptor binding1
protein binding1
identical protein binding1
protein dimerization activity1
binding1
endoplasmic reticulum1
intracellular organelle lumen1
membrane1
cell periphery1
cytoplasm1
protein-containing complex1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 20 of 41 annotations. The rest are phylogenetic / computational / electronic (IEA).

20 experimentally-supported GO terms:

GO termNSEvidence
cell surface receptor protein tyrosine kinase signaling pathwayBPdirect assay
osteoclast differentiationBPdirect assay
positive regulation of cell population proliferationBPdirect assay
positive regulation of gene expressionBPdirect assay
positive regulation of macrophage chemotaxisBPdirect assay
positive regulation of macrophage colony-stimulating factor signaling pathwayBPdirect assay
positive regulation of macrophage derived foam cell differentiationBPdirect assay
positive regulation of macrophage differentiationBPdirect assay
positive regulation of macrophage migrationBPmutant phenotype
positive regulation of microglial cell migrationBPdirect assay
positive regulation of mononuclear cell proliferationBPdirect assay
positive regulation of osteoclast differentiationBPdirect assay
positive regulation of protein metabolic processBPdirect assay
response to ischemiaBPdirect assay
perinuclear region of cytoplasmCCdirect assay
plasma membraneCCdirect assay
cytokine activityMFdirect assay
growth factor activityMFdirect assay
identical protein bindingMFphysical interaction
protein homodimerization activityMFdirect assay

Protein interactions and networks

STRING

showing 15 of 3,416 interactions by confidence (×1000):

Protein AProtein BPartner UniProtScore
CSF1CSF1RP07333967
CSF1CSF2P04141944
CSF1IL34Q6ZMJ4907
CSF1TNFSF11O14788881
CSF1IL3P08700856
CSF1CSF3P09919852
CSF1IL6P05231794
CSF1IL10P22301790
CSF1IL1BP01584787
CSF1IFNGP01579785
CSF1IL4P05112785
CSF1CCL2P13500779
CSF1TNFP01375779
CSF1OSCARQ8IYS5758
CSF1ITGAMP11215751

IntAct

Human interaction partners of CSF1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

PartnerInteraction typeMIscoreRecords
CSF1Rdirect interaction0.92014
SGTAphysical association0.7206
BARF1direct interaction0.6203
CYSRT1physical association0.5603
FHL3physical association0.5603
KRTAP1-1physical association0.5603
KRTAP10-8physical association0.5603
MTUS2physical association0.5603
NOTCH2NLAphysical association0.5603
AMIGO1physical association0.4001

BioGRID (16 interactions; top human partners by supporting records): SGTA (Two-hybrid; 2 records), AMIGO1 (Affinity Capture-MS), CBL (Affinity Capture-Western), CSF1R (Reconstituted Complex), CYSRT1 (Two-hybrid), FHL3 (Two-hybrid), KIAA1429 (Affinity Capture-RNA), KRTAP1-1 (Two-hybrid), KRTAP10-8 (Two-hybrid), MTUS2 (Two-hybrid), NOTCH2NL (Two-hybrid), SLA2 (Reconstituted Complex), SOCS1 (Affinity Capture-MS), TRIM25 (Affinity Capture-RNA)

SIGNOR signaling

showing 5 of 6 signaling interactions:

AEffectBMechanism
SMARCB1“up-regulates quantity by expression”CSF1“transcriptional regulation”
CSF1up-regulatesCSF3Rbinding
CSF1“up-regulates activity”CSF1Rbinding
CSF1up-regulatesM2_polarization
CSF1up-regulatesCSF2RAbinding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

ComplexSubunitsMembers
★ CSF1-CSF1R complex2CSF1, CSF1R

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

PartnerThis gene’s roleSignaling class
CSF1RligandSignaling by Colony-Stimulating factor

Disease & clinical

Genetic variants

Variant evidence for CSF1: 103 ClinVar records (0 pathogenic / likely pathogenic); 25 GWAS associations.

ClinVar

103 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance80
Likely benign7
Benign3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 766):

Position(s)EffectΔscoreSites
1:109917291–109917292acceptor_loss1.00006
1:109917464–109917465donor_loss1.00004
1:109921995donor_loss1.00002
1:109924191–109924192donor_loss1.00005
1:109911064donor_loss0.99002
1:109914382–109914383donor_loss0.99005
1:109917464donor_loss0.9900
1:109924774–109924775acceptor_loss0.99006
1:109924829–109924830donor_loss0.99005
1:109928850–109928851acceptor_loss0.99004

AlphaMissense

449 missense substitutions predicted likely pathogenic (of 3,625 scored), across 135 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

ResidueLikely-pathogenic substitutionsMean am_pathogenicityMax am_pathogenicity
F9980.9370.995
F16780.9240.989
F15380.9100.982
H4780.8140.912
C8070.9840.992
C17170.9840.994
C13470.9790.990
C12270.9690.980
F6970.9650.992
C17870.9610.986
C6370.9580.975
C3970.9460.966
C18970.9260.956
C19170.9160.950
M5970.9080.958
F6770.9080.988
F13870.8710.982
F17570.8690.978
D5670.8650.906
F12370.8470.964

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

CancerPrognosticp-value
Liver Hepatocellular Carcinoma (TCGA)unfavorable2.14e-05

Disease associations

OMIM: gene MIM:120420 | disease phenotypes:

GWAS associations

25 associations:

StudyTraitp-value
GCST90011899_28Aspartate aminotransferase levels2e-64
GCST006014_1Creatine kinase levels1e-40
GCST001086_6Paget’s disease7e-35
GCST90002393_576Monocyte count1e-33
GCST011351_1Aspartate aminotransferase levels3e-26
GCST005999_1Aspartate aminotransferase levels1e-25
GCST000672_4Paget’s disease5e-24
GCST006013_6Lactate dehydrogenase levels3e-23
GCST004625_137Monocyte count9e-17
GCST90002402_506Platelet count5e-16
GCST90002400_425Plateletcrit1e-15
GCST90002388_453Lymphocyte count3e-14
GCST90002394_442Monocyte percentage of white cells6e-14
GCST90002407_16White blood cell count1e-13
GCST005989_1Serum total protein levels5e-13
GCST009731_66Blood protein levels in cardiovascular risk1e-12
GCST008839_337Height1e-10
GCST005348_120Total body bone mineral density2e-10
GCST004610_105White blood cell count3e-9
GCST011348_25High density lipoprotein cholesterol levels6e-9
GCST010175_1Adult onset Still’s disease1e-8
GCST010726_4Periventricular white matter hyperintensities1e-7
GCST001762_466Obesity-related traits2e-7
GCST011681_1Cryptococcosis in HIV infection3e-7
GCST002090_3Sensory disturbances after bilateral sagittal split ramus osteotomy3e-6

EFO canonical traits (from GWAS)

12 canonical traits:

EFO IDTrait name
EFO:0004471insulin sensitivity measurement
EFO:0005324post-operative sensory disturbance
EFO:0005091monocyte count
EFO:0004736aspartate aminotransferase measurement
EFO:0004808L lactate dehydrogenase measurement
EFO:0004534creatine kinase measurement
EFO:0005665white matter hyperintensity measurement
EFO:0004612high density lipoprotein cholesterol measurement
EFO:0004587lymphocyte count
EFO:0007989monocyte percentage of leukocytes
EFO:0007985platelet crit
EFO:0004309platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3989382 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CSF1 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

DrugModalityMax phase
MCS-110Unknown2
PD-360324Unknown2

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

118 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Lipopolysaccharidesincreases reaction, increases expression, decreases reaction, affects cotreatment, increases chemical synthesis (+3 more)4
sodium arsenitedecreases expression, affects cotreatment, increases abundance, increases expression3
Cyclosporineaffects cotreatment, increases expression, decreases expression3
Cadmium Chloridedecreases expression, increases abundance, increases expression3
Particulate Matterdecreases expression, increases abundance, affects expression3
(+)-JQ1 compounddecreases expression2
Zoledronic Aciddecreases expression, increases expression2
Fulvestrantincreases methylation, increases expression, affects cotreatment2
Acetaminophenincreases expression, affects cotreatment2
Air Pollutantsincreases abundance, increases expression, decreases expression2
Arsenicaffects methylation, affects cotreatment, increases abundance, increases expression2
Asbestosincreases expression2
Benzeneincreases chemical synthesis, increases reaction, decreases expression, increases response to substance, affects cotreatment2
Benzo(a)pyreneincreases expression, affects methylation2
Calcitrioldecreases expression, increases expression, affects cotreatment2
Chenodeoxycholic Acidaffects cotreatment, increases expression2
Deoxycholic Acidaffects cotreatment, increases expression2
Glycochenodeoxycholic Acidaffects cotreatment, increases expression2
Glycocholic Acidaffects cotreatment, increases expression2
Glycodeoxycholic Acidaffects cotreatment, increases expression2
Nickelincreases expression2
Ozoneincreases abundance, increases expression, affects cotreatment2
Phenylmercuric Acetateaffects cotreatment, increases expression2
Tobacco Smoke Pollutiondecreases expression2
Triclosanincreases expression2
Gold Compoundsincreases expression, affects cotreatment2
aristolochic acid Iincreases expression1
pexidartinibdecreases secretion1
bisphenol Fdecreases methylation1
2-anisidineincreases expression1

Cellosaurus cell lines

15 cell lines: 12 cancer cell line, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_63585/9 m a3-18Transformed cell lineFemale
CVCL_A9YZNCC-TGCT1-C1Cancer cell lineFemale
CVCL_B8E4Abcam HCT 116 CSF1 KOCancer cell lineMale
CVCL_B9GCAbcam A-549 CSF1 KOCancer cell lineMale
CVCL_D1S0Abcam U-87MG CSF1 KOCancer cell lineMale
CVCL_D2ELAbcam MCF-7 CSF1 KOCancer cell lineFemale
CVCL_D7MWUbigene A-549 CSF1 KOCancer cell lineMale
CVCL_D8JDUbigene HCT 116 CSF1 KOCancer cell lineMale
CVCL_D9CEUbigene HEK293 CSF1 KOTransformed cell lineFemale
CVCL_E0B2Ubigene HeLa CSF1 KOCancer cell lineFemale

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.