IL3

Summary

IL3 (interleukin 3, HGNC:6011) is a protein-coding gene on chromosome 5q31.1, encoding Interleukin-3 (P08700). Cytokine secreted predominantly by activated T-lymphocytes as well as mast cells and osteoblastic cells that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells.

The protein encoded by this gene is a potent growth promoting cytokine. This cytokine is capable of supporting the proliferation of a broad range of hematopoietic cell types. It is involved in a variety of cell activities such as cell growth, differentiation and apoptosis. This cytokine has been shown to also possess neurotrophic activity, and it may be associated with neurologic disorders.

Source: NCBI Gene 3562 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 22 total
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.43 (unconstrained)
• MANE Select transcript: NM_000588
• Interaction hub: 2,392 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6011
Approved symbol	IL3
Name	interleukin 3
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	IL-3, MULTI-CSF, MCGF, MGC79398, MGC79399
Ensembl gene	ENSG00000164399
Ensembl biotype	protein_coding
OMIM	147740
Entrez	3562

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

MANE Select: ENST00000296870

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

ENST00000296870

RefSeq mRNA: 1 — MANE Select: NM_000588 NM_000588

CCDS: CCDS4149

Canonical transcript exons

ENST00000296870 — 5 exons

Exon	Start	End
ENSE00001084061	132062312	132062401
ENSE00001084062	132062526	132062567
ENSE00001084064	132060967	132061008
ENSE00001124361	132062669	132063204
ENSE00001124369	132060655	132060868

Expression profiles

Bgee: expression breadth tissue_specific, 4 present calls, max score 77.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.5181 / max 7772.5406, expressed in 7 samples.

Highest expression (Bgee): epithelium of bronchus, thymus, vastus lateralis, quadriceps femoris, cerebellar vermis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

IL3 is not an eGene in any GTEx v10 tissue: no tissue shows a variant significantly associated with its expression or splicing (q < 0.05).

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
58421	4.5181	7

Top tissues by expression

showing 100 of 117 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelium of bronchus	UBERON:0002031	77.68	gold quality
thymus	UBERON:0002370	64.92	silver quality
vastus lateralis	UBERON:0001379	59.82	gold quality
quadriceps femoris	UBERON:0001377	59.78	gold quality
cerebellar vermis	UBERON:0004720	57.59	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
endometrium epithelium	UBERON:0004811	46.85	gold quality
calcaneal tendon	UBERON:0003701	43.89	gold quality
bone marrow	UBERON:0002371	38.31	silver quality
granulocyte	CL:0000094	38.13	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
corpus callosum	UBERON:0002336	35.20	gold quality
lymph node	UBERON:0000029	34.64	silver quality
skeletal muscle tissue	UBERON:0001134	34.29	gold quality
right uterine tube	UBERON:0001302	33.60	gold quality
vermiform appendix	UBERON:0001154	33.28	silver quality
superior frontal gyrus	UBERON:0002661	32.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
muscle tissue	UBERON:0002385	31.77	gold quality
leukocyte	CL:0000738	31.04	gold quality
prefrontal cortex	UBERON:0000451	30.93	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
monocyte	CL:0000576	30.71	gold quality
primary visual cortex	UBERON:0002436	30.38	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
placenta	UBERON:0001987	29.65	gold quality
frontal cortex	UBERON:0001870	29.62	gold quality
duodenum	UBERON:0002114	28.14	gold quality
urinary bladder	UBERON:0001255	27.87	gold quality
right coronary artery	UBERON:0001625	27.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	27.66	silver quality
blood	UBERON:0000178	27.28	gold quality
islet of Langerhans	UBERON:0000006	26.97	gold quality
adrenal tissue	UBERON:0018303	26.03	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
endometrium	UBERON:0001295	25.65	gold quality
ectocervix	UBERON:0012249	25.48	gold quality
pancreas	UBERON:0001264	25.28	gold quality
lung	UBERON:0002048	25.24	gold quality
popliteal artery	UBERON:0002250	25.20	gold quality
tibial artery	UBERON:0007610	25.15	gold quality
kidney	UBERON:0002113	25.14	gold quality
descending thoracic aorta	UBERON:0002345	25.03	gold quality
gastrocnemius	UBERON:0001388	24.69	gold quality
myometrium	UBERON:0001296	24.55	gold quality
uterine cervix	UBERON:0000002	24.12	gold quality
cortex of kidney	UBERON:0001225	23.93	gold quality
stomach	UBERON:0000945	23.58	gold quality
fallopian tube	UBERON:0003889	23.19	gold quality
body of pancreas	UBERON:0001150	23.08	gold quality
heart left ventricle	UBERON:0002084	22.96	gold quality
rectum	UBERON:0001052	22.80	gold quality
adult mammalian kidney	UBERON:0000082	22.74	gold quality
upper lobe of left lung	UBERON:0008952	22.32	gold quality
smooth muscle tissue	UBERON:0001135	22.15	gold quality
lower esophagus mucosa	UBERON:0035834	22.15	gold quality
body of stomach	UBERON:0001161	22.14	gold quality
right ovary	UBERON:0002118	21.95	gold quality
anterior cingulate cortex	UBERON:0009835	21.93	gold quality
thoracic mammary gland	UBERON:0005200	21.76	gold quality
adrenal gland	UBERON:0002369	21.71	gold quality
fundus of stomach	UBERON:0001160	21.64	gold quality
cerebellum	UBERON:0002037	21.57	gold quality
sigmoid colon	UBERON:0001159	21.42	gold quality
ovary	UBERON:0000992	21.41	gold quality
prostate gland	UBERON:0002367	21.38	gold quality
small intestine	UBERON:0002108	21.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	21.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	21.19	gold quality
saliva-secreting gland	UBERON:0001044	21.05	gold quality
spleen	UBERON:0002106	20.94	gold quality
skin of leg	UBERON:0001511	20.86	gold quality
Ammon’s horn	UBERON:0001954	20.83	gold quality
cerebellar cortex	UBERON:0002129	20.72	gold quality
esophagus mucosa	UBERON:0002469	20.65	gold quality
omental fat pad	UBERON:0010414	20.65	gold quality
cerebellar hemisphere	UBERON:0002245	20.41	gold quality
vagina	UBERON:0000996	20.36	gold quality
transverse colon	UBERON:0001157	20.31	gold quality
apex of heart	UBERON:0002098	20.28	gold quality
tibial nerve	UBERON:0001323	20.27	gold quality
minor salivary gland	UBERON:0001830	20.25	gold quality
temporal lobe	UBERON:0001871	20.22	gold quality
left ovary	UBERON:0002119	20.16	gold quality
right adrenal gland	UBERON:0001233	20.14	gold quality
left adrenal gland	UBERON:0001234	20.03	gold quality
body of uterus	UBERON:0009853	19.97	gold quality
left adrenal gland cortex	UBERON:0035825	19.97	gold quality
mucosa of transverse colon	UBERON:0004991	19.91	gold quality
right frontal lobe	UBERON:0002810	19.86	gold quality
nucleus accumbens	UBERON:0001882	19.68	gold quality
substantia nigra	UBERON:0002038	19.51	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	38270.02
E-ANND-3	no	1.81

HPA expression

RNA tissue specificity: Not detected

14 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Medulla oblongata	tissue	1.0
Putamen	tissue	0.8
Nucleus accumbens	tissue	0.8
Hippocampus	tissue	0.8
Postcentral gyrus	tissue	0.8
Substantia nigra	tissue	0.7
Spinal cord	tissue	0.7
Retrosplenial cortex	tissue	0.7
Locus coeruleus	tissue	0.6
Choroid plexus	tissue	0.5
Bone marrow	tissue	0.2
Testis	tissue	0.1
Retina	tissue	0.1
Epididymis	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 183; highest nTPM — Orbitofrontal gyrus, anterior (1.2), Paracentral lobule, posterior (1.2), Corpus callosum, splenium (white matter) (1.1), Paraventricular nucleus (1.1), Postcentral gyrus, ventral (1.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPB, CEBPZ, CTCF, DNMT1, EGR1, EGR2, ELF1, ETS1, ETV6, FOS, FOXC2, GATA3, HR, JUN, JUNB, JUND, KCNIP3, MYC, NFATC1, NFATC2, NFIL3, NFKB, PITX2, POU1F1, POU2F1, POU2F2, REL, RUNX1, RUNX1T1, SMARCA5, SP1, STAT5A, TFAP2A, TXK, VEZF1, YY1, ZNF91

miRNA regulators (miRDB)

Targeting IL3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

22 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-759	96.16	66.77	873
HSA-MIR-3914	94.91	65.77	643
HSA-MIR-4474-5P	94.23	67.95	568
HSA-MIR-6886-5P	91.08	63.10	105

Functional genomics

gnomAD constraint: pLI 1.12e-05, LOEUF 1.43, missense Z 1.04 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000296870 — one region, missense o/e 0.84.

Literature-anchored findings (GeneRIF, showing 40)

• binding kinetics of native IL-3 and several variants to IL-3 receptor (PMID:11700046)
• IL-3 induces MHC class II and B7.2 expression on eosinophils and renders them capable of supporting T cell proliferation to superantigen and antigen-derived peptides. (PMID:11714768)
• inhibition of signaling by antisense oligodeoxynucleotides targeting the common beta chain of receptors (PMID:11763346)
• ectopically expressed in myeloid leukemic cells with t(5;12)(q31;p13), suggesting that expression of IL3 was deregulated by the translocation, indicating a variant leukemogenic mechanism for translocations involving the 5’ end of ETV6 (PMID:11861295)
• Antiapoptotic cytokine IL-3 + SCF + FLT3L influence on proliferation of gamma-irradiated AC133+/CD34+ progenitor cells. (PMID:12002675)
• Monocytes cultured in the presence of IL-3 (plus IL-4) differentiate into dendritic cells that produce less IL-12 and shift T helper (Th) cell responses toward a Th2 cytokine pattern. (PMID:12055233)
• Data suggest that increased activity of mutated interleukin 3 is due to a change from a rare ligand to a common one, allowing the increase in IL-3-dependent signaling. (PMID:12093816)
• role in potentiating hematopoietic cell migration (PMID:12135758)
• The IL-3 gene is regulated by two enhancers that have distinct but overlapping tissue specificities. (PMID:12165512)
• WEHI-3B-derived IL-3 stimulation of mcl-1 gene transcription through the SIE motif involves phosphorylation of PU.1 at serine 142 by a p38(MAPK)-dependent pathway. (PMID:12612065)
• Incubation of eosinophils with IL-3 leads to reduced expression of IL-5R alpha which is sustained for up to 5 days; in contrast, expression of IL-3R alpha is increased by IL-3, whereas GM-CSF receptor alpha expression in eosinophils is unaffected by IL-3. (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)
• expression of alleles of the genes encoding IL-2, IL-3, IL-4, and IL-13 in CD4(+) T cell clones (PMID:12884288)
• IL-3 plays important roles in local eosinophil activation (PMID:12943658)
• 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)
• increased IL-3 levels in the bone marrow microenvironment of MM patients with imbalanced AML-1A and AML-1B expression can increase bone destruction and tumor cell growth. (PMID:14615378)
• 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)
• ability of TGF-beta1 to polarize the differentiation of HPCs induced by IL-3 towards LC development, although IL-3 DCs were unable to form BGs partly because of their poor ability to induce Langerin. (PMID:14675189)
• positive immunostaining for IL-3 by TILs in ‘in situ’ breast cancers sustains the possibility that early in tumor development, IL-3 can contribute to the chronic immaturity of these vessels (PMID:14755254)
• Interleukin-3 binding to the human betac receptor involves functional epitopes formed by domains 1 and 4 of different protein chains (PMID:15060062)
• The IL3 regulates the growth and differentiation of hematopoietic progenitor cells and functionally activates mature neutrophils or macrophages. (PMID:15576295)
• Endogenous IL-3 is required to maintain the lymphatic endothelial cell (LEC) phenotype in culture, and the addition of IL-3 to dermal blood endothelial cells (BEC) appears to induce transdifferentiation of BEC into LEC. (PMID:15585837)
• CD45+ cells were required for the capacity of IL-3 to inhibit osteoblast differentiation. IL-3 plays a dual role in the bone destructive process in myeloma by both stimulating osteoclasts and indirectly inhibiting osteoblast formation (PMID:15878977)
• Multiple logistic regression revealed a significant association between the appearance of nucleated RBCs in the blood and erythropoietin, IL-3, IL-6, and age. (PMID:15988318)
• Expression of CD48 on human peripheral blood eosinophils is regulated by interleukin (IL)-3. (PMID:16785501)
• In this paper provide the evidence that multiple single nucleotide polymorphisms in and around interleukin 3 (IL3) are associated with the disease in the Irish. (PMID:17179997)
• IL-3 can not replace GM-CSF to induce the differentiation of human monocytes into Langerhans cells in culture (PMID:17273755)
• About 18% of Indian subjects studied showed non histamine-releaser phenotype & also had reduced Lyn & Syk kinase expression. Non-releasers have also shown less potent isoform of IL-3/P8, which is suspected to be responsible for non-releaser phenotype (PMID:17507237)
• IL-3 is a central inducer of CD69 expression, while antigen is an enhancing factor acting on basophils cooperatively with IL-3. (PMID:17541278)
• IL-3-induced upregulation of CD203c is a late event and is not accompanied by upregulation of CD63. (PMID:17624239)
• IL-3 up-regulates the expression of the antiapoptotic proteins cIAP2, Mcl-1, and Bcl-X(L) and induces a rapid and sustained de novo expression of the serine/threonine kinase Pim1 that closely correlates with cytokine-enhanced survival. (PMID:18768389)
• We found evidence of a joint effect between IL3 (rs31400) and DTNBP1 (PMID:18804346)
• IL-1beta and IL-3 stimulated endothelium induces proliferation and differentiation of myeloid precursors, while IL-6 treatment induced a benefit of HPC survival. (PMID:18826654)
• SNP rs40401 in the interleukin-3 gene was associated with risk of asthma (PMID:18829683)
• These data argue that the regulation of the IL-3 and the GM-CSF promoters depends on the positions of their enhancers relative to the conserved CTCF/cohesin-binding sites. (PMID:19158269)
• autocrine IL-3 activity resulting from low-level IgE/FcepsilonRI cross-linking by specific allergen represents an important mechanism behind the hyperreactive nature of basophils that has long been observed in allergic disease. (PMID:19201898)
• This study provides convincing evidence that the IL3 gene is a susceptibility locus for GD in the Chinese population. (PMID:19262575)
• Synergistic protecting effect of cord blood CD34+ cells over-expressing both interleukin-3 and Flt3 ligand on lethally irradiated mice. (PMID:19529981)
• IL-3 and oncogenic Abl regulate the myeloblast transcriptome by altering mRNA stability (PMID:19829692)
• The IL-3/GM-CSF locus undergoes progressive stages of activation, with stepwise increases in active modifications and the proportion of cytokine-expressing cells, throughout the course of T cell differentiation. (PMID:20147630)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il3	ENSMUSG00000018914
rattus_norvegicus	Il3	ENSRNOG00000026786

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96552) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
enlarged spleen	1
enlarged lymph nodes	1
hindlimb paralysis	1
ataxia	1
circling	1
male infertility	1
female infertility	1
premature death	1
abnormal B cell differentiation	1
increased pre-B cell number	1
increased susceptibility to parasitic infection	1
cachexia	1
abnormal pancreatic islet morphology	1
abnormal mast cell differentiation	1
decreased susceptibility to type IV hypersensitivity reaction	1
decreased interleukin-3 secretion	1
decreased bone mineral content	1

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
Pan troglodytes	Q28809	98.7%	Diamond
Hylobates lar	P06740	94.0%	Diamond
Saguinus oedipus	P51445	91.5%	Diamond
Callithrix jacchus	Q28334	91.5%	Diamond
Macaca mulatta	P25140	87.4%	Diamond
Bos taurus	P49875	85.4%	Diamond
Canis lupus familiaris	Q9BDX4	46.5%	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
CSF2	protein-coding	1437
PDLIM4	protein-coding	8572
P4HA2	protein-coding	8974
ACSL6-AS2	ncRNA	124901062
ACSL6	protein-coding	23305
MEIKIN	protein-coding	728637
FNIP1	protein-coding	96459
P4HA2-AS1	ncRNA	100861518
ACSL6-AS1	ncRNA	101927693

Protein

Protein identifiers

Interleukin-3 — P08700 (reviewed: P08700)

Alternative names: Hematopoietic growth factor, Mast cell growth factor, Multipotential colony-stimulating factor, P-cell-stimulating factor

All UniProt accessions (1): P08700

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine secreted predominantly by activated T-lymphocytes as well as mast cells and osteoblastic cells that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells. Also stimulates mature basophils, eosinophils, and monocytes to become functionally activated. In addition, plays an important role in neural cell proliferation and survival. Participates as well in bone homeostasis and inhibits osteoclast differentiation by preventing NF-kappa-B nuclear translocation and activation. Mechanistically, exerts its biological effects through a receptor composed of IL3RA subunit and a signal transducing subunit IL3RB. Receptor stimulation results in the rapid activation of JAK2 kinase activity leading to STAT5-mediated transcriptional program. Alternatively, contributes to cell survival under oxidative stress in non-hematopoietic systems by activating pathways mediated by PI3K/AKT and ERK.

Subunit / interactions. Interacts with IL3RA.

Subcellular location. Secreted.

Tissue specificity. Activated T-cells, mast cells, natural killer cells.

Induction. Upon activation of the T-cell receptor/CD3 pathway and can be augmented by coactivation of the CD3 and CD28 pathways.

Similarity. Belongs to the IL-3 family.

RefSeq proteins (1): NP_000579* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002183	IL-3	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF02059

UniProt features (20 total): helix 10, sequence variant 4, glycosylation site 2, signal peptide 1, chain 1, strand 1, disulfide bond 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
5UWC	Cytokine-receptor complex	X-RAY DIFFRACTION	2.4
5UV8	Interleukin-3 Receptor Complex	X-RAY DIFFRACTION	2.7
6NMY	A Cytokine-receptor complex	X-RAY DIFFRACTION	3.3
1JLI	HUMAN INTERLEUKIN 3 (IL-3) MUTANT WITH TRUNCATION AT BOTH N-AND C-TERMINI AND 14 RESIDUE …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08700-F1	83.59	0.60

Human Protein Atlas

Protein class: Predicted secreted proteins

Protein evidence: Evidence at protein level

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 (1)

Type	Positions
Disulfide bond	35–103

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	34, 89

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 15; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-912526	Interleukin receptor SHC signaling	curated
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-8939247	RUNX1 regulates transcription of genes involved in interleukin signaling	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: 129 (showing top): REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, MODULE_92, GOBP_EMBRYONIC_HEMOPOIESIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, HOFMANN_CELL_LYMPHOMA_UP, MODULE_45, GOMF_GROWTH_FACTOR_ACTIVITY, RACCACAR_AML_Q6, KEGG_FC_EPSILON_RI_SIGNALING_PATHWAY, GOBP_CELL_CELL_SIGNALING, RAY_ALZHEIMERS_DISEASE, AML_Q6, MORF_IL4, KEGG_ASTHMA

GO Biological Process (7): immune response (GO:0006955), cell-cell signaling (GO:0007267), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), embryonic hemopoiesis (GO:0035162), interleukin-3-mediated signaling pathway (GO:0038156), cell surface receptor signaling pathway via STAT (GO:0097696)

GO Molecular Function (4): cytokine activity (GO:0005125), interleukin-3 receptor binding (GO:0005135), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Signaling by Interleukins	2
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

18 GO namespaces:

Category	Terms
receptor ligand activity	2
immune system process	1
response to stimulus	1
cell communication	1
signaling	1
system development	1
animal gross anatomical part developmental process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
hemopoiesis	1
embryonic organ development	1
cytokine-mediated signaling pathway	1
cell surface receptor signaling pathway	1
cytokine receptor binding	1
growth factor receptor binding	1
binding	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via STAT	BP	direct assay
embryonic hemopoiesis	BP	direct assay
interleukin-3-mediated signaling pathway	BP	direct assay
positive regulation of cell population proliferation	BP	direct assay
cytokine activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 2,392 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL3	CSF2	P04141	966
IL3	IL5	P05113	952
IL3	KITLG	P21583	930
IL3	CSF3	P09919	924
IL3	IL4	P05112	923
IL3	THPO	P40225	911
IL3	FLT3LG	P49771	910
IL3	IL6	P05231	909
IL3	EPO	P01588	894
IL3	IL2	P01585	881
IL3	CD34	P28906	878
IL3	KIT	P10721	863
IL3	CSF1	P09603	856
IL3	IFNG	P01579	854
IL3	IL3RA	P26951	849
IL3	IL13	P35225	849

IntAct

Human interaction partners of IL3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
IL3RA	direct interaction	0.610	5
CSF2RB	physical association	0.590	1

BioGRID (8 interactions; top human partners by supporting records): IL3RA (Reconstituted Complex; 2 records), BCR (Affinity Capture-Western), CSF2RB (Reconstituted Complex), S100A6 (Reconstituted Complex), S100P (Reconstituted Complex), UBE2G2 (Affinity Capture-MS), VHL (Negative Genetic)

SIGNOR signaling

showing 3 of 4 signaling interactions:

A	Effect	B	Mechanism
IL3	up-regulates	IL3RA	binding
IL3	up-regulates	NFIL3
NFIL3	“up-regulates quantity by expression”	IL3	“transcriptional regulation”

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
★ IL-3 receptor-IL-3 complex	3	CSF2RB, IL3, IL3RA

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;IL3RA	ligand	Signaling by Interleukin

Disease & clinical

Genetic variants

Variant evidence for IL3: 22 ClinVar records (0 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 15 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	7
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 125):

Position(s)	Effect	Δscore	Sites
5:132060869–132060870	donor_loss	1.0000	2
5:132060958	acceptor_gain	1.0000
5:132061009–132061010	donor_loss	1.0000	4
5:132062523	acceptor_gain	1.0000
5:132062524–132062525	acceptor_loss	1.0000	3
5:132062568–132062569	donor_loss	1.0000	5
5:132060799	donor_gain	0.9900
5:132060869–132060870	donor_loss	0.9900	3
5:132060965–132060966	acceptor_loss	0.9900	5
5:132061009	donor_loss	0.9900

AlphaMissense

131 missense substitutions predicted likely pathogenic (of 996 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
F80	8	0.928	0.987
F126	7	0.944	0.987
C103	7	0.882	0.930
N76	7	0.852	0.956
C35	7	0.824	0.893
K129	6	0.896	0.945
Y133	5	0.905	0.951
F132	5	0.809	0.934
L67	5	0.798	0.945
I42	4	0.817	0.901
D63	4	0.685	0.745
L130	3	0.907	0.977
I118	3	0.877	0.907
L97	3	0.876	0.945
I116	3	0.868	0.884
L134	3	0.865	0.972
L46	3	0.793	0.928
L100	3	0.752	0.898
A83	3	0.740	0.937
L77	3	0.730	0.949

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:147740 | disease phenotypes:

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	amber

GWAS associations

15 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
GCST000879_18	Crohn’s disease	1e-20
GCST010701_3	Cortical surface area (MOSTest)	1e-20
GCST004864_32	Perceived unattractiveness to mosquitoes	1e-9
GCST010703_310	Brain morphology (MOSTest)	3e-9
GCST010702_71	Subcortical volume (MOSTest)	2e-8
GCST001438_16	Crohn’s disease	4e-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
GCST008158_90	Body mass index	9e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs181781	Metabolism/PK	3	tacrolimus	Kidney Transplantation

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs181781	IL3	3	2.25	1	tacrolimus

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs181781	tacrolimus	Metabolism/PK	Genotype AA is associated with increased exposure to tacrolimus in people with Kidney Transplantation as compared to genotypes AG + GG.	PMID:28112181

Binding affinities (BindingDB)

7 measured of 12 human assays (12 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1R,4R)-5-[2-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1-methylimidazo[4,5-c]pyridin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane	IC50	1.1 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
(1R,4R)-5-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1-methylimidazo[4,5-c]pyridin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane	IC50	2.6 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
(1R,4R)-5-[6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1-methyl-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]imidazo[4,5-c]pyridin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane	IC50	3 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1-methyl-2-(4-methylpiperazin-1-yl)-4-piperidin-1-ylimidazo[4,5-c]pyridine	IC50	3.5 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
(1R,4R)-5-[2-[4-(2-methoxyethyl)piperazin-1-yl]-6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1-methylimidazo[4,5-c]pyridin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane	IC50	5 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
[6-[6-(4-methoxy-3-pyridinyl)-4-methylpyrazolo[4,3-c]pyridin-1-yl]-1,3-dimethyl-4-propylpyrrolo[3,2-c]pyridin-2-yl]-(4-methylpiperazin-1-yl)methanone	IC50	7.07 nM	WO-2022090481: SUBSTITUTED 1H-PYRAZOLO[4,3-C]PYRIDINES AND DERIVATIVES AS EGFR INHIBITORS
AZD-9291	IC50	71 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
Wortmannin	decreases reaction, increases expression, increases phosphorylation, decreases expression, affects cotreatment	2
Mustard Gas	affects expression, affects reaction, increases secretion	2
Zinc	affects cotreatment, affects expression, affects binding	2
fluorene-9-bisphenol	decreases expression	1
TL8-506	affects cotreatment, increases secretion	1
alclometasone dipropionate	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
oxophenylarsine	decreases expression, decreases reaction	1
emamectin benzoate	increases expression	1
10-(octyloxy)decyl-2-(trimethylammonium)ethyl phosphate	affects cotreatment, decreases reaction, increases expression, increases phosphorylation	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Adrenal Cortex Hormones	decreases reaction, increases expression	1
Ethanol	increases expression	1
Aspartame	decreases expression	1
Beclomethasone	decreases reaction, increases expression, increases secretion	1
Benzo(a)pyrene	increases methylation	1
Betamethasone Valerate	decreases expression	1
Dexamethasone	decreases expression	1
Dust	increases expression	1
Hydralazine	affects cotreatment, decreases expression	1
Menthol	decreases expression	1
Methotrexate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Poly I-C	affects cotreatment, increases secretion	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Dronabinol	increases expression	1
Theophylline	decreases expression	1

Clinical trials (associated diseases)

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