CSF2

Summary

CSF2 (colony stimulating factor 2, HGNC:2434) is a protein-coding gene on chromosome 5q31.1, encoding Granulocyte-macrophage colony-stimulating factor (P04141). Cytokine that stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes.

The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13. This gene plays a role in promoting tissue inflammation. Elevated levels of cytokines, including the one produced by this gene, have been detected in SARS-CoV-2 infected patients that develop acute respiratory distress syndrome. Mice deficient in this gene or its receptor develop pulmonary alveolar proteinosis.

Source: NCBI Gene 1437 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 20 total
• GTEx eGene: eQTL in 2 tissues, sQTL in 0 (q < 0.05)
• Drug target: yes — 6 curated mechanism-of-action drugs
• Constraint (gnomAD): pLI 0.85 (intermediate), LOEUF 0.62 (unconstrained)
• MANE Select transcript: NM_000758
• Interaction hub: 3,848 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2434
Approved symbol	CSF2
Name	colony stimulating factor 2
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	GM-CSF, GMCSF
Ensembl gene	ENSG00000164400
Ensembl biotype	protein_coding
OMIM	138960
Entrez	1437

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

MANE Select: ENST00000296871

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000296871, ENST00001131941

RefSeq mRNA: 1 — MANE Select: NM_000758 NM_000758

CCDS: CCDS4150

Canonical transcript exons

ENST00000296871 — 4 exons

Exon	Start	End
ENSE00001084066	132074081	132074122
ENSE00001084068	132074810	132074935
ENSE00001124346	132075745	132076170
ENSE00001124351	132073789	132073982

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 72.09.

FANTOM5 (CAGE): breadth broad, TPM avg 18.9773 / max 3544.2514, expressed in 483 samples.

Highest expression (Bgee): type B pancreatic cell, Brodmann (1909) area 10, endometrium epithelium, cartilage tissue, olfactory bulb.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CSF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 2 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

2 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	2.4e-03	-0.67	5:132086417:C:T
Lung	eqtl	1.6e-02	-0.66	5:131762094:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
58423	18.9662	483
58424	0.0111	4

Top tissues by expression

showing 100 of 261 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	72.09	gold quality
Brodmann (1909) area 10	UBERON:0013541	69.33	gold quality
endometrium epithelium	UBERON:0004811	68.66	silver quality
cartilage tissue	UBERON:0002418	67.74	gold quality
olfactory bulb	UBERON:0002264	67.59	gold quality
middle frontal gyrus	UBERON:0002702	65.29	gold quality
frontal pole	UBERON:0002795	62.94	gold quality
paraflocculus	UBERON:0005351	62.64	gold quality
tongue squamous epithelium	UBERON:0006919	58.81	gold quality
gluteal muscle	UBERON:0002000	58.80	gold quality
triceps brachii	UBERON:0001509	58.63	gold quality
upper lobe of left lung	UBERON:0008952	57.14	gold quality
upper lobe of lung	UBERON:0008948	57.04	gold quality
vastus lateralis	UBERON:0001379	56.74	gold quality
quadriceps femoris	UBERON:0001377	56.28	gold quality
metanephric glomerulus	UBERON:0004736	54.79	gold quality
lower lobe of lung	UBERON:0008949	53.99	silver quality
lung	UBERON:0002048	53.68	gold quality
thymus	UBERON:0002370	52.89	gold quality
gall bladder	UBERON:0002110	52.87	gold quality
stromal cell of endometrium	CL:0002255	52.66	gold quality
epithelial cell of pancreas	CL:0000083	51.63	gold quality
left ventricle myocardium	UBERON:0006566	51.25	gold quality
Brodmann (1909) area 46	UBERON:0006483	51.15	gold quality
deltoid	UBERON:0001476	50.72	gold quality
vermiform appendix	UBERON:0001154	49.94	gold quality
CA1 field of hippocampus	UBERON:0003881	49.85	gold quality
kidney epithelium	UBERON:0004819	49.84	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
myocardium	UBERON:0002349	49.15	gold quality
oviduct epithelium	UBERON:0004804	48.77	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
islet of Langerhans	UBERON:0000006	48.52	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
muscle tissue	UBERON:0002385	47.99	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
caecum	UBERON:0001153	47.69	gold quality
smooth muscle tissue	UBERON:0001135	47.41	gold quality
skeletal muscle tissue	UBERON:0001134	47.30	gold quality
nephron tubule	UBERON:0001231	47.30	gold quality
diaphragm	UBERON:0001103	47.05	gold quality
nasal cavity epithelium	UBERON:0005384	46.83	gold quality
buccal mucosa cell	CL:0002336	46.51	gold quality
layer of synovial tissue	UBERON:0007616	45.76	gold quality
granulocyte	CL:0000094	44.73	silver quality
epithelium of bronchus	UBERON:0002031	44.72	gold quality
rectum	UBERON:0001052	44.70	gold quality
bone marrow	UBERON:0002371	44.57	gold quality
bronchus	UBERON:0002185	44.53	gold quality
tibialis anterior	UBERON:0001385	44.44	silver quality
lymph node	UBERON:0000029	44.32	silver quality
squamous epithelium	UBERON:0006914	44.09	gold quality
oocyte	CL:0000023	44.03	gold quality
adult organism	UBERON:0007023	43.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
pancreatic ductal cell	CL:0002079	43.36	silver quality
dorsal plus ventral thalamus	UBERON:0001897	42.93	gold quality
amniotic fluid	UBERON:0000173	42.89	gold quality
epithelium of esophagus	UBERON:0001976	42.87	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
heart right ventricle	UBERON:0002080	42.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	42.27	gold quality
gingiva	UBERON:0001828	42.24	gold quality
biceps brachii	UBERON:0001507	41.86	gold quality
ileal mucosa	UBERON:0000331	41.69	silver quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
epithelium of mammary gland	UBERON:0003244	41.33	gold quality
male germ cell	CL:0000015	41.24	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
subthalamic nucleus	UBERON:0001906	41.08	gold quality
trachea	UBERON:0003126	41.02	gold quality
metanephros	UBERON:0000081	41.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
parotid gland	UBERON:0001831	40.95	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
tongue	UBERON:0001723	40.59	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
nasal cavity mucosa	UBERON:0001826	40.42	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
placenta	UBERON:0001987	40.28	silver quality
jejunum	UBERON:0002115	40.18	gold quality
mammary duct	UBERON:0001765	40.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
saphenous vein	UBERON:0007318	39.83	gold quality
oral cavity	UBERON:0000167	39.82	gold quality
urethra	UBERON:0000057	39.80	gold quality
pleura	UBERON:0000977	39.79	gold quality
pericardium	UBERON:0002407	39.77	gold quality
endothelial cell	CL:0000115	39.75	gold quality
bone marrow cell	CL:0002092	39.74	gold quality
synovial joint	UBERON:0002217	39.70	gold quality
dorsal root ganglion	UBERON:0000044	39.68	gold quality
nipple	UBERON:0002030	39.68	gold quality
bronchial epithelial cell	CL:0002328	39.65	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-10	yes	367.15
E-ANND-3	yes	5.20
E-HCAD-29	no	35043.55

HPA expression

RNA tissue specificity: Tissue enhanced

49 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Olfactory bulb	tissue	3.3
Prefrontal cortex	tissue	2.4
Cerebral cortex	tissue	2.4
Amygdala	tissue	2.4
Retrosplenial and cingulate cortex	tissue	2.4
Retrosplenial cortex	tissue	2.4
Basal ganglia	tissue	2.3
Temporal cortex	tissue	2.3
Insular cortex	tissue	2.3
Cerebellum	tissue	2.2
Occipital cortex	tissue	2.2
Hippocampal formation	tissue	2.0
Entorhinal cortex	tissue	2.0
Ventral forebrain	tissue	2.0
Somatosensory cortex	tissue	2.0
Motor cortex	tissue	1.9
Lung	tissue	1.9
Septum	tissue	1.7
Periaqueductal gray	tissue	1.5
Putamen	tissue	1.4
Corpus callosum	tissue	1.3
Hypothalamus	tissue	1.2
Spinal cord	tissue	1.1
Midbrain	tissue	1.0
Medulla oblongata	tissue	1.0
Thalamus	tissue	1.0
Pons	tissue	0.9
Superior colliculi	tissue	0.8
Substantia nigra	tissue	0.8
Urinary bladder	tissue	0.6
Hippocampus	tissue	0.5
Pancreas	tissue	0.4
Bone marrow	tissue	0.4
Gallbladder	tissue	0.3
Rectum	tissue	0.2
Smooth muscle	tissue	0.2
Endometrium 1	tissue	0.2
Nucleus accumbens	tissue	0.2
Choroid plexus	tissue	0.2
Locus coeruleus	tissue	0.2
Postcentral gyrus	tissue	0.2
Appendix	tissue	0.2
Skin 1	tissue	0.1
Lymph node	tissue	0.1
Spleen	tissue	0.1
Small intestine	tissue	0.1
Prostate	tissue	0.1
Thymus	tissue	0.1
Caudate putamen	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Subiculum (1.8), Ventral hippocampus (1.8), Dorsal hippocampus (1.5), White matter (1.3), Dorsal spinal cord (1.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
HBG2	Activation
VTCN1	Repression

Upstream regulators (CollecTRI, top): AHR, AP1, CEBPA, CEBPB, CEBPD, CREBBP, CREM, CTCF, EGR3, ELF1, ELF4, ETS1, ETS2, FOS, GATA2, HMGA1, HSF1, IRF6, JUN, JUNB, KAT5, KAT7, MAF, MYB, MYC, NFAM1, NFATC1, NFATC2, NFKB1, NFKB2, NFKB, NR3C1, NR4A3, PBRM1, PRDM1, REL, RELA, RELB, RUNX1, RUNX2

miRNA regulators (miRDB)

Targeting CSF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

19 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-1470	98.11	63.53	399
HSA-MIR-6514-3P	97.52	66.50	808
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-4281	92.91	63.60	271
HSA-MIR-4707-5P	90.95	65.69	110

Functional genomics

gnomAD constraint: pLI 0.854, LOEUF 0.619, missense Z 1.08 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000296871 — one region, missense o/e 0.78.

Literature-anchored findings (GeneRIF, showing 40)

• inhibition of signaling by antisense oligodeoxynucleotides targeting the common beta chain of receptors (PMID:11763346)
• GM-CSF-driven apoptosis, but not TNF-driven apoptosis was reversibly associated with bcl-2-expression (bcl-2-dependent mechanism)in acute lymphoblastic leukaemia and non-Hodgkin’s lymphoma in children. (PMID:11855781)
• Protection of peritoneal macrophages by granulocyte/macrophage colony-stimulating factor (GM-CSF) against dexamethasone suppression of killing of Aspergillus, and the effect of human GM-CSF. (PMID:11880043)
• Adenomyotic glandular epithelium had greater expression of the GM-CSF ligand compared with autologous endometrium from premenopausal women (PMID:11963838)
• Activated eosinophils release small amounts of anti-apoptotic GM-CSF by stabilizing its coding mRNA. Review. (PMID:12022701)
• secretion from acute myelogenous leukemia blasts was up-regulated by leptin (PMID:12031914)
• B-CLL patients with progressive disease had a significantly increased number of T cells spontaneously producing IL-2, IL-4 and GM-CSF, suggesting a role for T cells in the pathogenesis of B-CLL. (PMID:12144536)
• GM-CSF induced human myelopoiesis is regulated by transforming growth factor-beta isoforms (PMID:12171249)
• GMCSF is induced in bronchial epithelial cells by the MAP kinase signaling system in response to air pollutants (PMID:12356579)
• GM-CSF plays a critical role in lung homeostasis by regulating levels of MCSF, MCP-1 and IL-8. (PMID:12356582)
• Enhanced PMN survival was attributed to effects of epithelial G-CSF and granulocyte-macrophage colony-stimulating factor expression, which inhibit PMN apoptosis.Both CF and normal cells responded to bacteria with increased cytokine production (PMID:12397015)
• data indicate that granulocyte-macrophage colony stimulating factor regulates cell viability in human embryos (PMID:12444058)
• GM-CSF inhibits prolonged glucocorticoid-induced activation of eosinophil c-Jun NH2-terminal kinase and preserves the expression of eosinophil antiapoptotic protein X-linked inhibitor of apoptosis. (PMID:12496443)
• signals for increased glucose transport via phosphatidylinositol 3-kinase- and hydrogen peroxide-dependent mechanisms (PMID:12538575)
• Granulocyte-macrophage colony-stimulating factor inhibited the platelet-activating factor acetylhydrolase secretion by decidual macrophages (PMID:12548211)
• GM-CSF-mediated antiapoptosis is mediated through protein synthesis-independent mechanisms and involves the Janus kinase-STAT pathway. (PMID:12568301)
• IL-6 and GM-CSF may be involved in the autoimmune mechanism of non-segmental vitiligo. (PMID:12615367)
• functional studies demonstrated GMCSF-dependent activation of IkappaB kinase activity in endothelial cells, degradation of IkappaB, and activation of NF-kappaB (PMID:12637324)
• GM-CSF is up-regulated by ETS2, a target of protein kinase C (PMID:12646185)
• GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. (PMID:12663443)
• ICAM-3 is highly expressed on the surface of human eosinophils and has a role in the downregulation of GM-CSF production. (PMID:12743567)
• GMCSF is induced in lung fibroblasts by IL-beta, TNF-alpha, and macrophage contact. (PMID:12744771)
• Incubation of eosinophils with GMCSF leads to reduced expression of IL-5R alpha that is sustained for up to 5 days; in contrast, eosinophil IL-3R alpha expression is increased by GMCSF, whereas eosinophil GMCSF receptor alpha is down-regulated by GMCSF. (PMID:12759409)
• induces cell cycle progression via internal ribosome entry site-mediated translation of c-myc though the PI3K pathway in human factor-dependent leukemic cells (PMID:12855588)
• IL-10 is one of the cytokines up-regulating the GM-CSF expression in non-small cell lung cancer. (PMID:12926133)
• GM-CSF induces expression of surface and total class II major histocompatibility antigens crucial for antigen presentation in human monocytes. (PMID:12928384)
• immunolocalization studies confirmed the presence of granulocyte-macrophage colony stimulating factor(GM-CSF) in the germ cell line in bovine and human testes and addition of GM-CSF enhances several parameters of sperm motility (PMID:12935848)
• TNF, GM-CSF, and G-CSF induce actin depolymerization and morphological changes through activation of ERK and/or p38 MAPK, and cytokine-induced actin reorganization may affect inhibitory effect of these cytokines on neutrophil chemotaxis. (PMID:12954601)
• The GM-CSF genotype is an important genetic marker predicting an individual’s predisposition to atopic dermatitis. (PMID:13679820)
• GMCSF was highly expressed in dendritic cells with a bicistronic retroviral vector. (PMID:14503968)
• neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (PMID:14512323)
• GMCSF displays additive effects with TNF-alpha on the common p47phox phosphorylated site and on fMLP-induced NADPH oxidase activation in human neutrophils, which is evidence for a common priming pathway. (PMID:14530365)
• Hematopoietin receptor superfamily. Comprised of cytokine-specific alpha chain and common beta chain for signaling. Contributes to differentiation and function of leukocytes. Protective immunity and pathophysiology of immunologic diseases. Review. (PMID:14564341)
• results suggest that in pulmonary alveolar proteinosis, GM-CSF synthesis is deficient and associated with negative regulation by IL-10 (PMID:14567558)
• long-term exposure of primitive human hematopoietic cells to elevated levels of human IL-3, GM-CSF and SF in vivo may deleteriously affect the stem cell compartment, while expanding terminal myelopoiesis. (PMID:14628073)
• Results identify several transcriptional targets of interleukin-5 and granulocyte macrophage-colony-stimulating factor in human eosinophils and suggest that a number of protein products are critical to the responsiveness of airway eosinophils. (PMID:14630612)
• GM-CSF elicits chemotaxis and chemokinesis of neutrophils by a process correlated with activity of the ribosomal p70 S6 kinase signaling pathway. (PMID:14662891)
• the GM-CSF ARE controls translation and mRNA decay by interfering with poly(A)-binding protein-mediated mRNA circularization. (PMID:14726527)
• Local injection of recombinant human GM-CSF may improve the healing of ischemic and even normal colon anastomoses. (PMID:14730225)
• Data characterize recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) for glycosylation sites and the definition of the glycosidic moiety, including the degree of site occupancy. (PMID:15009203)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Csf2	ENSMUSG00000018916
rattus_norvegicus	Csf2	ENSRNOG00000026805

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1339752) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 61 distinct phenotype terms.

Mouse phenotype (MP)	Records
lymphoid hyperplasia	2
abnormal lung morphology	2
increased body weight	2
abnormal pulmonary alveolus morphology	2
increased susceptibility to bacterial infection	2
abnormal alveolar macrophage morphology	2
abnormal abdominal fat pad morphology	1
abnormal circulating glucose level	1
abnormal uterus morphology	1
absent mature ovarian follicles	1
decreased body size	1
abnormal lipid level	1
increased circulating triglyceride level	1
increased circulating free fatty acids level	1
abnormal placenta development	1
placental labyrinth hypoplasia	1
postnatal growth retardation	1
lung inflammation	1
reduced fertility	1
abnormal ovulation	1
decreased litter size	1
emphysema	1
abnormal fertility/fecundity	1
abnormal spleen size	1
abnormal leukocyte physiology	1

+36 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Chlorocebus aethiops	Q0MUT8	94.4%	Diamond
Ovis aries	P28773	91.7%	Diamond
Cervus elaphus	P51748	91.7%	Diamond
Bos taurus	P11052	86.1%	Diamond
Sus scrofa	Q29118	81.3%	Diamond
Felis catus	O62757	77.1%	Diamond
Cavia porcellus	Q60481	76.4%	Diamond
Canis lupus familiaris	P48749	75.0%	Diamond

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).

Symbol	Type	Entrez
MIR6830	ncRNA	102465498
IL3-AS1	ncRNA	105379174
IL3	protein-coding	3562
PDLIM4	protein-coding	8572
P4HA2	protein-coding	8974
P4HA2-AS1	ncRNA	100861518
ACSL6-AS1	ncRNA	101927693
ACSL6-AS2	ncRNA	124901062
ACSL6	protein-coding	23305
MEIKIN	protein-coding	728637
FNIP1	protein-coding	96459

Protein

Protein identifiers

Granulocyte-macrophage colony-stimulating factor — P04141 (reviewed: P04141)

Alternative names: Colony-stimulating factor, Molgramostin, Sargramostim

All UniProt accessions (1): P04141

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes.

Subunit / interactions. Monomer. The signaling GM-CSF receptor complex is a dodecamer of two head-to-head hexamers of two alpha, two beta, and two ligand subunits.

Subcellular location. Secreted.

Polymorphism. Variant Ile-117 may be a risk factor for atopic asthma.

Similarity. Belongs to the GM-CSF family.

RefSeq proteins (1): NP_000749* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000773	GM_colony-stim-fac	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF01109

UniProt features (28 total): helix 8, glycosylation site 6, turn 3, strand 3, sequence variant 2, sequence conflict 2, disulfide bond 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

11 structures by resolution:

PDB	Title	Method	Resolution (Å)
6BFS	The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies	X-RAY DIFFRACTION	2
5D70	Crystal structure of MOR03929, a neutralizing anti-human GM-CSF antibody Fab fragment in …	X-RAY DIFFRACTION	2.06
5D71	Crystal structure of MOR04302, a neutralizing anti-human GM-CSF antibody Fab fragment in …	X-RAY DIFFRACTION	2.25
2GMF	HUMAN GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR	X-RAY DIFFRACTION	2.4
5D72	Crystal structure of MOR04252, a neutralizing anti-human GM-CSF antibody Fab fragment in …	X-RAY DIFFRACTION	2.6
6BFQ	The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies	X-RAY DIFFRACTION	2.6
4RS1	Crystal structure of receptor-cytokine complex	X-RAY DIFFRACTION	2.68
1CSG	Three-dimensional structure of recombinant human granulocyte-macrophage …	X-RAY DIFFRACTION	2.7
5C7X	Crystal structure of MOR04357, a neutralizing anti-human GM-CSF antibody Fab fragment in …	X-RAY DIFFRACTION	2.95
4NKQ	Structure of a Cytokine Receptor Complex	X-RAY DIFFRACTION	3.3
9JKR	human GM-CSF with Fabs from autoantibodies, F1 and C.	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04141-F1	88.30	0.77

Antibody-complex structures (SAbDab)

7 antibodies co-crystallized with this protein: 5C7X, 5D70, 5D71, 5D72, 6BFQ, 6BFS, OTILIMAB

Human Protein Atlas

Protein class: Predicted secreted proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IF enhanced

Functional residue map

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

Disulfide bonds (2)

Type	Positions
Disulfide bond	71–113, 105–138

Glycosylation sites (6)

Type	Positions
O-linked (galnac…) serine	22, 24, 26
O-linked (galnac…) threonine	27
N-linked (glcnac…) asparagine	44, 54

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 16; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

16 pathways:

ID	Pathway	Evidence
R-HSA-912526	Interleukin receptor SHC signaling	curated
R-HSA-6783783	Interleukin-10 signaling	curated
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-8939246	RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	curated
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-168256	Immune System	—
R-HSA-451927	Interleukin-2 family signaling	—
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-8878171	Transcriptional regulation by RUNX1	—

MSigDB gene sets: 395 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GGGACCA_MIR133A_MIR133B, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_PODOSOME_ASSEMBLY, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (27): histamine secretion (GO:0001821), immune response (GO:0006955), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), positive regulation of macrophage derived foam cell differentiation (GO:0010744), myeloid cell differentiation (GO:0030099), macrophage differentiation (GO:0030225), positive regulation of cell migration (GO:0030335), positive regulation of interleukin-23 production (GO:0032747), response to silicon dioxide (GO:0034021), response to fluid shear stress (GO:0034405), granulocyte-macrophage colony-stimulating factor signaling pathway (GO:0038157), epithelial fluid transport (GO:0042045), myeloid dendritic cell differentiation (GO:0043011), regulation of circadian sleep/wake cycle, sleep (GO:0045187), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of leukocyte proliferation (GO:0070665), cellular response to lipopolysaccharide (GO:0071222), positive regulation of podosome assembly (GO:0071803), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), dendritic cell differentiation (GO:0097028), cell surface receptor signaling pathway via STAT (GO:0097696), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), signal transduction (GO:0007165), regulation of signal transduction (GO:0009966), regulation of developmental process (GO:0050793)

GO Molecular Function (4): cytokine activity (GO:0005125), granulocyte macrophage colony-stimulating factor receptor binding (GO:0005129), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), plasma membrane (GO:0005886)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Signaling by Interleukins	3
MAPK1/MAPK3 signaling	1
Transcriptional regulation by RUNX1	1
Interleukin-2 family signaling	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Immune System	1
RNA Polymerase II Transcription	1
Cytokine Signaling in Immune system	1
Signal Transduction	1
MAPK family signaling cascades	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

54 GO namespaces:

Category	Terms
myeloid leukocyte differentiation	2
receptor ligand activity	2
secretion	1
histamine transport	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway via STAT	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
macrophage derived foam cell differentiation	1
regulation of macrophage derived foam cell differentiation	1
positive regulation of cell differentiation	1
hemopoiesis	1
cell differentiation	1
mononuclear cell differentiation	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
positive regulation of cytokine production	1
interleukin-23 production	1
regulation of interleukin-23 production	1
response to oxygen-containing compound	1
response to stress	1
cytokine-mediated signaling pathway	1
fluid transport	1
transepithelial transport	1
myeloid dendritic cell activation	1
dendritic cell differentiation	1
regulation of circadian sleep/wake cycle	1
circadian sleep/wake cycle, sleep	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of cell population proliferation	1
leukocyte proliferation	1
regulation of leukocyte proliferation	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
positive regulation of protein-containing complex assembly	1
podosome assembly	1
regulation of podosome assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
cytokine receptor binding	1
growth factor receptor binding	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 16 of 34 annotations. The rest are phylogenetic / computational / electronic (IEA).

16 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via JAK-STAT	BP	direct assay
cell surface receptor signaling pathway via STAT	BP	direct assay
cellular response to granulocyte macrophage colony-stimulating factor stimulus	BP	direct assay
dendritic cell differentiation	BP	direct assay
granulocyte-macrophage colony-stimulating factor signaling pathway	BP	direct assay
macrophage differentiation	BP	direct assay
myeloid dendritic cell differentiation	BP	direct assay
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	BP	direct assay
positive regulation of cell population proliferation	BP	direct assay
positive regulation of gene expression	BP	direct assay
positive regulation of interleukin-23 production	BP	direct assay
positive regulation of leukocyte proliferation	BP	direct assay
positive regulation of macrophage derived foam cell differentiation	BP	direct assay
positive regulation of podosome assembly	BP	direct assay
cytokine activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,848 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSF2	IL3	P08700	966
CSF2	IL5	P05113	956
CSF2	IL4	P05112	954
CSF2	CSF1	P09603	944
CSF2	CSF3	P09919	942
CSF2	IL2	P01585	939
CSF2	IL6	P05231	934
CSF2	IFNG	P01579	929
CSF2	IL10	P22301	929
CSF2	TNF	P01375	926
CSF2	IL13	P35225	923
CSF2	IL1B	P01584	920
CSF2	CXCL8	P10145	918
CSF2	CSF2RA	P15509	905
CSF2	IL7	P13232	900

IntAct

Human interaction partners of CSF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
MEOX2	physical association	0.720	6
HTT	physical association	0.560	15
A2M	physical association	0.560	3
DNM2	physical association	0.560	3
CSF2RB	physical association	0.520	1
B4GALT5	physical association	0.400	1
CSF2RA	physical association	0.400	1

BioGRID (16 interactions; top human partners by supporting records): MEOX2 (Two-hybrid; 2 records), B4GALT5 (Affinity Capture-MS), CSF2RA (Reconstituted Complex), HNRNPA0 (Affinity Capture-RNA), HNRNPA1 (Affinity Capture-RNA), HNRNPA2B1 (Affinity Capture-RNA), IGF2BP2 (Affinity Capture-RNA), ILF2 (Affinity Capture-RNA), ILF3 (Affinity Capture-RNA), PABPC1 (Affinity Capture-RNA), S100A6 (Reconstituted Complex), S100P (Reconstituted Complex), SDC2 (Reconstituted Complex), SYNCRIP (Affinity Capture-RNA)

SIGNOR signaling

showing 5 of 7 signaling interactions:

A	Effect	B	Mechanism
CSF2	up-regulates	CSF3R	binding
CSF2	“up-regulates activity”	CSF2RA	binding
CSF2	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
CSF2	up-regulates	CSF2RA/CSF2RB	binding
CSF2	up-regulates	CSF2RA	binding

Protein complexes (CORUM) (1)

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

1 complexes by size:

Complex	Subunits	Members
★ GM-CSF receptor-CSF2 complex	3	CSF2RB, CSF2, CSF2RA

Ligand–receptor pairs (CellPhoneDB) (1)

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

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CSF2RB;CSF2RA	ligand	Signaling by Colony-Stimulating factor

Disease & clinical

Genetic variants

Variant evidence for CSF2: 20 ClinVar records (0 pathogenic / likely pathogenic); 12 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	6
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 90):

Position(s)	Effect	Δscore	Sites
5:132073983	donor_loss	1.0000
5:132074079–132074080	acceptor_loss	1.0000	5
5:132074123–132074124	donor_loss	1.0000	4
5:132074808–132074809	acceptor_loss	1.0000	4
5:132074936–132074937	donor_loss	1.0000	4
5:132075742–132075743	acceptor_gain	1.0000	2
5:132075744	acceptor_loss	1.0000
5:132073983–132073984	donor_loss	0.9900	3
5:132074078	acceptor_gain	0.9900
5:132074080	acceptor_loss	0.9900

AlphaMissense

129 missense substitutions predicted likely pathogenic (of 944 scored), across 42 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:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
C105	7	0.851	0.905
C71	7	0.850	0.909
F130	7	0.840	0.951
F123	7	0.826	0.922
C113	7	0.820	0.872
C138	6	0.784	0.852
F64	5	0.839	0.879
Y101	5	0.732	0.838
W2	4	0.803	0.889
K124	4	0.783	0.923
F120	4	0.763	0.777
R75	4	0.741	0.917
W139	4	0.740	0.874
L131	3	0.872	0.879
S15	3	0.859	0.859
L127	3	0.859	0.950
L76	3	0.799	0.865
L83	3	0.792	0.860
Y79	3	0.787	0.861
L90	3	0.786	0.854

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Head and Neck Squamous Cell Carcinoma)

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	favorable	0.000891

Disease associations

OMIM: gene MIM:138960 | disease phenotypes:

GWAS associations

12 associations:

Study	Trait	p-value
GCST001725_83	Inflammatory bowel disease	1e-52
GCST004132_104	Crohn’s disease	6e-36
GCST004131_32	Inflammatory bowel disease	4e-27
GCST010701_3	Cortical surface area (MOSTest)	1e-20
GCST001454_6	Rheumatoid arthritis	3e-10
GCST010703_310	Brain morphology (MOSTest)	3e-9
GCST010702_71	Subcortical volume (MOSTest)	2e-8
GCST002318_137	Rheumatoid arthritis	8e-7
GCST006959_23	Rheumatoid arthritis	1e-6
GCST004133_15	Ulcerative colitis	2e-6
GCST002318_50	Rheumatoid arthritis	6e-6
GCST006959_118	Rheumatoid arthritis	8e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712955 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CSF2 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.

6 curated-mechanism drugs:

Drug	Modality	Max phase
LENZILUMAB	Antibody	3
OTILIMAB	Antibody	3
PEXASTIMOGENE DEVACIREPVEC	Gene	3
GIMSILUMAB	Antibody	2
NAMILUMAB	Antibody	2
PLONMARLIMAB	Antibody	2

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

5 measured of 7 human assays (7 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CC-220 (Compound 6)	IC50	28 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	190 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione	IC50	300 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(R)-3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	450 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
19171-19-8	IC50	13000 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	decreases expression, increases chemical synthesis, increases reaction, affects reaction, increases phosphorylation (+5 more)	22
Particulate Matter	increases abundance, increases reaction, decreases expression, decreases reaction, increases secretion (+2 more)	20
Dexamethasone	increases secretion, increases expression, increases reaction, increases activity, affects cotreatment (+3 more)	10
Silicon Dioxide	increases expression	8
sodium arsenite	affects cotreatment, decreases reaction, increases expression, increases secretion	7
Vehicle Emissions	decreases reaction, increases secretion, increases expression, increases reaction, decreases expression	7
Tobacco Smoke Pollution	increases expression, increases secretion, decreases expression, decreases secretion	7
Resveratrol	increases secretion, decreases reaction, increases expression	6
Beclomethasone	affects cotreatment, decreases secretion, decreases reaction, increases expression, increases secretion (+1 more)	6
titanium dioxide	affects binding, increases secretion, increases expression	5
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment, increases secretion (+1 more)	5
Smoke	decreases reaction, increases secretion, decreases expression, increases abundance, increases expression	5
(+)-JQ1 compound	decreases reaction, increases expression, decreases expression	4
Acetylcysteine	decreases reaction, increases expression, increases secretion	4
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	4
Tetradecanoylphorbol Acetate	decreases reaction, affects expression, affects cotreatment, increases secretion, increases expression	4
Zymosan	increases secretion, increases expression, increases reaction	4
Budesonide	decreases reaction, increases secretion, decreases secretion, increases activity	4
Soot	increases expression, increases secretion	4
RTKI cpd	decreases reaction, increases secretion, affects binding, increases expression	3
Fluticasone	increases secretion, decreases secretion, increases activity, decreases reaction	3
Bleomycin	decreases reaction, increases expression	3
Histamine	increases expression, increases secretion, increases reaction	3
Peptidoglycan	increases reaction, increases secretion, increases expression	3
Quercetin	decreases reaction, increases secretion, decreases expression	3
Theophylline	increases secretion, increases expression, increases reaction, decreases expression, affects cotreatment (+1 more)	3
Ionomycin	affects cotreatment, decreases expression, increases expression, increases secretion, affects reaction (+1 more)	3
Asbestos, Crocidolite	increases expression	3
Cadmium Chloride	increases secretion, decreases reaction, increases expression	3
Antigens, Dermatophagoides	increases expression, increases secretion, decreases reaction	3

Cellosaurus cell lines

11 cell lines: 9 cancer cell line, 1 transformed cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4U13	SV-BR-1-GM	Cancer cell line	Female
CVCL_A8HT	K562/GM-CSF	Cancer cell line	Female
CVCL_B2VA	Abcam HEK293T CSF2 KO	Transformed cell line	Female
CVCL_B6KZ	Mel PG	Cancer cell line	Sex unspecified
CVCL_B6L1	Mel 26G	Cancer cell line	Sex unspecified
CVCL_B6L2	Mel IG	Cancer cell line	Female
CVCL_B6L4	Mel 31G	Cancer cell line	Sex unspecified
CVCL_B6LC	Mel ILG	Cancer cell line	Sex unspecified
CVCL_B6LQ	Mel KG	Cancer cell line	Sex unspecified
CVCL_C3LY	MVX-2	Telomerase immortalized cell line	Female

Clinical trials (associated diseases)

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