TGFB1

Summary

TGFB1 (transforming growth factor beta 1, HGNC:11766) is a protein-coding gene on chromosome 19q13.2, encoding Transforming growth factor beta-1 proprotein (P01137). Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease.

Source: NCBI Gene 7040 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Camurati-Engelmann disease (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 462 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 149
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Transcription factor: yes — 51 downstream targets (CollecTRI)
• MANE Select transcript: NM_000660

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11766
Approved symbol	TGFB1
Name	transforming growth factor beta 1
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	CED, TGFbeta
Ensembl gene	ENSG00000105329
Ensembl biotype	protein_coding
OMIM	190180
Entrez	7040

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000221930, ENST00000597453, ENST00000598758, ENST00000600196, ENST00000677934, ENST00000890114, ENST00000966383, ENST00000966384

RefSeq mRNA: 1 — MANE Select: NM_000660 NM_000660

CCDS: CCDS33031

Canonical transcript exons

ENST00000221930 — 7 exons

Exon	Start	End
ENSE00000708412	41332128	41332281
ENSE00000708416	41348295	41348455
ENSE00000842441	41341883	41342030
ENSE00001136703	41352690	41353922
ENSE00001196164	41330323	41331210
ENSE00003463661	41344747	41344864
ENSE00003650791	41342170	41342247

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 120.2311 / max 2379.9696, expressed in 1820 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181053	80.8984	1790
181050	16.2256	1709
181047	6.2447	1507
181052	5.6877	1504
181051	3.8746	1347
181039	2.0887	767
181045	1.3205	774
181046	1.2351	723
208825	1.1512	616
181049	0.9525	538

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.08	gold quality
monocyte	CL:0000576	98.51	gold quality
leukocyte	CL:0000738	98.47	gold quality
mononuclear cell	CL:0000842	98.43	gold quality
stromal cell of endometrium	CL:0002255	98.27	gold quality
ascending aorta	UBERON:0001496	96.77	gold quality
thoracic aorta	UBERON:0001515	96.75	gold quality
descending thoracic aorta	UBERON:0002345	96.68	gold quality
right coronary artery	UBERON:0001625	96.46	gold quality
spleen	UBERON:0002106	96.43	gold quality
lower esophagus mucosa	UBERON:0035834	96.32	gold quality
right lung	UBERON:0002167	95.95	gold quality
endocervix	UBERON:0000458	95.60	gold quality
blood	UBERON:0000178	95.46	gold quality
aorta	UBERON:0000947	95.39	gold quality
upper lobe of left lung	UBERON:0008952	95.20	gold quality
left coronary artery	UBERON:0001626	95.04	gold quality
bone marrow cell	CL:0002092	94.85	gold quality
ectocervix	UBERON:0012249	94.61	gold quality
coronary artery	UBERON:0001621	94.59	gold quality
upper lobe of lung	UBERON:0008948	94.55	gold quality
popliteal artery	UBERON:0002250	94.50	gold quality
tibial artery	UBERON:0007610	94.50	gold quality
mucosa of stomach	UBERON:0001199	93.90	gold quality
body of uterus	UBERON:0009853	93.65	gold quality
lymph node	UBERON:0000029	93.14	gold quality
omental fat pad	UBERON:0010414	92.73	gold quality
peritoneum	UBERON:0002358	92.67	gold quality
metanephros cortex	UBERON:0010533	92.50	gold quality
left uterine tube	UBERON:0001303	92.39	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	4451.79
E-CURD-112	yes	36.73
E-MTAB-10287	yes	33.37
E-GEOD-135922	yes	29.58
E-MTAB-9221	yes	21.37
E-CURD-122	yes	20.29
E-HCAD-6	yes	18.93
E-HCAD-10	yes	17.19
E-MTAB-9067	yes	11.18
E-ANND-3	yes	6.71

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

51 targets.

Target	Regulation
ACTA2	Activation
ADAMTS4	Activation
ANKH	Activation
BGLAP	Repression
CCN2	Activation
CCNA2	Repression
CDH1	Repression
CDK4	Repression
CDKN2B	Activation
CILP	Activation
COL1A1	Activation
COL1A2	Activation
COL2A1	Activation
COL3A1	Activation
COL4A1	Activation
DNAH10	Repression
ELN	Activation
ENG	Activation
ENPP1	Activation
FGFR1	Activation
HBA1	Activation
HBB	Activation
IDE	Activation
ITGA2	Activation
ITGA3	Repression
KRT1	Repression
LPL	Activation
LPP	Activation
MMP2	Repression
MMP9	Repression

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ASCL1, ASH1L, ATF2, BCL11B, CEBPB, CREB1, DLX2, E2F1, EGR1, ELF3, ETV4, FGF2, FGF9, FOS, FOSB, FOSL2, FOXC1, FOXC2, FOXO1, FOXP3, GATA6, GGCX, GLI1, GLI2, GLI3, GTF2I, HAND1, HIF1A, HR, HTATIP2, ID1, IRF6, JUN, JUND, KLF10, KLF2, KLF4

miRNA regulators (miRDB)

45 targeting TGFB1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-609	99.82	64.26	505
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-606	98.72	67.34	960
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364

Literature-anchored findings (GeneRIF, showing 40)

• downregulates expression of integrin alpha6 in lens epithelial cells; gene expression regulation (PMID:11374867)
• Association of polymorphisms with genetic susceptibility to osteoporosis (PMID:11740340)
• Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis. (PMID:11750277)
• Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system (PMID:11769974)
• Ectopic expression of eIF-4E in human colon cancer cells promotes the stimulation of adhesion molecules by transforming growth factorbeta (PMID:11771728)
• PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter. (PMID:11776328)
• decrease in p21cip1 levels was mediated by a TGFbeta-initiated Ras-dependent, but smad-independent post-transcriptional mechanism (PMID:11784716)
• effect on renal function of polymorphism in heart transplant recipients (PMID:11803605)
• Human TGF-beta1 induces an accumulation of connexin43 in a lysosomal compartment in bovine endothelial cells. (PMID:11824477)
• TGF-beta1 is the predominant isoform in lymphoid organs and regulates autoimmunity and inflammation. Smad proteins 2,3,4,6,& 7 are involved in its signal transduction pathways. (PMID:11826761)
• The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-beta1 in NCI-H929 multiple myeloma cells. (PMID:11836565)
• induction in keratinocytes after gamma irradiation (PMID:11839086)
• TGFbeta can promote DNA instability through down-regulation of Rad51 and inhibition of DNA repair. (PMID:11867550)
• Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis.TGF-beta1 promotes dendritic cell differentiation and maturation. (PMID:11876742)
• S. stercoralis patients with HTLV-I showed a high frequency of expression of TGF-beta-1, but those without HTLV-I did not. (PMID:11876761)
• decreased levels of active TGFb in HIV, and immunosuppresed patients, and in patients with Pneumocystis carinii pneumonia (PMID:11906036)
• REVIEW: role of TGFB1 as an anti-differentiating factor and modulator of gene expression and differentiation potential of hematopoietic elements. (PMID:11908736)
• TGFbeta1-induced parathyroid hormone-related protein(PTHrP)mRNA stability might be, in part, the result of cis-acting sequences within the coding region of the PTHrP mRNA. (PMID:11911944)
• Molecular mechanism of transforming growth factor (TGF)-beta1-induced glutathione depletion in alveolar epithelial cells. Involvement of AP-1/ARE and Fra-1. (PMID:11912197)
• common TGF-beta1 polymorphisms are not associated with a risk of developing Dupuytren’s disease. (PMID:11924651)
• TGF-beta 1 expression level can be a risk factor for alcoholic liver disease and might be related to the inflammatory activity and fibrosis of the liver in patients. (PMID:11925630)
• down-regulated UPA in normal and dystrophic myoblasts; was the only growth factor tested able to exceptionally up-regulate PAI-1, mainly in dystrophic satellite cells; and induced a dose-dependent increase of Matrigel invasion only in dystrophic myoblasts (PMID:11928807)
• results suggest the importance of alphaEbeta7 expression by TGF-beta in selective localization of intestinal intraepithelial T lymphocytes (PMID:11934870)
• no correlation between the concentration of either isoform of TGFbeta in milk and the corresponding TGFbeta in plasma (PMID:11991670)
• production by different populations of erythroid cells derived from human embryonal liver (PMID:11991675)
• Transforming growth factor-beta1 enhanced smooth muscle actin expression in TR-PCT1 cells, but this expression was reduced by subsequent treatment with basic fibroblast growth factor. (PMID:11998866)
• TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with cystic fibrosis liver disease. (PMID:12000722)
• TGF beta 1 was able to suppress the expression of Id-1, a helix-loop-helix (HLH) protein, which plays important roles in the inhibition of cell differentiation and growth arrest. (PMID:12020803)
• TGF-beta1, TGF-beta2 and TGF-beta3 isoforms are produced by chondrosarcomas and could have a potential role as autocrine growth stimulators in these neoplasms (PMID:12021923)
• results suggest that the TGF-beta1 gene at chromosome 19q13.1 may be a candidate susceptibility locus for hypertension in Japanese women (PMID:12032592)
• Signaling transduction induced by PF4 in erythroleukemia cells was compared with that induced by TGFB1, which is also a potent inhibitor of HEL growth. (PMID:12041672)
• TGF beta1 expression and angiogenesis in colorectal cancer tissue. (PMID:12046078)
• TGF-beta 1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. (PMID:12055267)
• Direct stimulation of tubular epithelial cells with TGF-beta(1)/epithelial growth factor results in an increased migratory capacity across bovine tubular basement membranes preparations. (PMID:12057905)
• present in diabetic foot ulcers (PMID:12060054)
• induced in cicatricial pemphigoid: possible role(s) in dermal fibrosis (PMID:12061838)
• TGF-beta polymorphisms do not have a strong influence on disease onset or clinical progression in sarcoidosis and tuberculosis, although this polymorphism might have an effect on the immune response in a tuberculosis host (PMID:12068984)
• p38 MAP kinase regulation of AP-2 binding in TGF-beta1-stimulated chondrogenesis of human trabecular bone-derived cells (PMID:12081893)
• TGF-beta1-stimulated osteoblasts require intracellular calcium signaling for enhanced alpha5 integrin expression (PMID:12081894)
• No significant variations in the distribution of the genotypes and haplotypes were observed between Alzheimer patients and controls. (PMID:12082048)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgfb1b	ENSDARG00000034895
danio_rerio	tgfb1a	ENSDARG00000041502
mus_musculus	Tgfb1	ENSMUSG00000002603
rattus_norvegicus	Tgfb1	ENSRNOG00000020652

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Transforming growth factor beta-1 proprotein — P01137 (reviewed: P01137)

All UniProt accessions (4): P01137, A0A499FJK2, A0A7I2V5Z9, A0A7I2YQL8

UniProt curated annotations — full annotation on UniProt →

Function. Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively. Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix. Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with ‘milieu molecules’, such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1. Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia. Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1. Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration. Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix. At the same time, LAP chain interacts with ‘milieu molecules’, such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus. TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1. Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal. While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and ‘milieu molecules’. Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner. At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development. At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells. Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus. Positively regulates odontoblastic differentiation in dental papilla cells, via promotion of IPO7-mediated translocation of phosphorylated SMAD2 to the nucleus and subsequent transcription of target genes. Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling and the HTRA protease activity is required for this inhibition. May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling. Interacts with CD109, DPT and ASPN. Interacts with EFEMP2. Interacts with TSKU; the interaction contributes to regulation of the hair cycle. Homodimer; disulfide-linked. Interacts with transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains TGF-beta-1 in a latent state; each latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer. Interacts with LTBP1; leading to regulation of TGF-beta-1 activation. Interacts with LRRC32/GARP; leading to regulation of TGF-beta-1 activation on the surface of activated regulatory T-cells (Tregs). Interacts with LRRC33/NRROS; leading to regulation of TGF-beta-1 in macrophages and microglia. Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1. Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction. Interacts with HSP90AB1; inhibits latent TGFB1 activation. Interact with PSG9; leading to TGFB1 activation. Interacts with TGFBR3. Homodimer; disulfide-linked. Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction.

Subcellular location. Secreted. Extracellular space. Extracellular matrix Secreted.

Tissue specificity. Highly expressed in bone. Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage.

Post-translational modifications. Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive. N-glycosylated. Deglycosylation leads to activation of Transforming growth factor beta-1 (TGF-beta-1); mechanisms triggering deglycosylation-driven activation of TGF-beta-1 are however unclear.

Disease relevance. Camurati-Engelmann disease (CAEND) [MIM:131300] An autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision. The disease is caused by variants affecting the gene represented in this entry. Inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE) [MIM:618213] An autosomal recessive disorder characterized by severe infantile inflammatory bowel disease manifesting as bloody diarrhea and failure to thrive, global developmental delay, epilepsy, brain atrophy and encephalopathy. Affected individuals suffer from recurrent infections associated with impaired T-cell response to stimulation and decreased T-cell subsets, including regulatory and helper T cells. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ‘straitjacket’ and ‘arm’ domains encircle the Transforming growth factor beta-1 (TGF-beta-1) monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104. The cell attachment site motif mediates binding to integrins (ITGAV:ITGB6 or ITGAV:ITGB8). The motif locates to a long loop in the arm domain called the bowtie tail. Integrin-binding stabilizes an alternative conformation of the bowtie tail. Activation by integrin requires force application by the actin cytoskeleton, which is resisted by the ‘milieu molecules’ (such as LTBP1, LRRC32/GARP and/or LRRC33/NRROS), resulting in distortion of the prodomain and release of the active TGF-beta-1.

Polymorphism. In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.

Miscellaneous. TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_000651* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001111	TGF-b_propeptide	Domain
IPR001839	TGF-b_C	Domain
IPR003939	TGFb1	Family
IPR015615	TGF-beta-like	Family
IPR016319	TGF-beta	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF00688

UniProt features (85 total): strand 27, sequence variant 13, mutagenesis site 11, helix 9, disulfide bond 8, turn 5, glycosylation site 3, region of interest 3, chain 2, signal peptide 1, sequence conflict 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
8UDZ	X-RAY DIFFRACTION	2.21
9VJJ	X-RAY DIFFRACTION	2.48
8C7H	ELECTRON MICROSCOPY	2.7
6OM2	X-RAY DIFFRACTION	2.77
5VQP	X-RAY DIFFRACTION	2.9
8REW	ELECTRON MICROSCOPY	2.98
3KFD	X-RAY DIFFRACTION	3
4KV5	X-RAY DIFFRACTION	3
8VSC	ELECTRON MICROSCOPY	3
6GFF	X-RAY DIFFRACTION	3.1
8VSD	ELECTRON MICROSCOPY	3.2
7Y1T	ELECTRON MICROSCOPY	3.24
9FDY	ELECTRON MICROSCOPY	3.4
5FFO	X-RAY DIFFRACTION	3.49
6P7J	X-RAY DIFFRACTION	3.5
9FKP	ELECTRON MICROSCOPY	3.72
7Y1R	ELECTRON MICROSCOPY	4.01
1KLA	SOLUTION NMR
1KLC	SOLUTION NMR
1KLD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01137-F1	80.11	0.41

Antibody-complex structures (SAbDab): 5 — 4KV5, 6GFF, 8C7H, 8REW, 8UDZ

Functional residue map

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

Catalytic / active sites (1): 278–279 (cleavage; by furin)

Disulfide bonds (8): 33, 223, 225, 285–294, 293–356, 322–387, 326–389, 355

Glycosylation sites (3): 176, 82, 136

Mutagenesis-validated functional residues (11):

Position	Phenotype
33	abolishes interchain disulfide bond with ltbp1 and/or lrrc32, and subsequent regulation of activation of tgf-beta-1.
75	does not affect integrin-binding or activation of tgf-beta-1.
158	does not affect integrin-binding or activation of tgf-beta-1.
160	does not affect integrin-binding or activation of tgf-beta-1.
193	does not affect integrin-binding or activation of tgf-beta-1.
232–236	strongly inhibits integrin-binding and activation of tgf-beta-1.
234–236	strongly inhibits integrin-binding and activation of tgf-beta-1.
237	does not affect integrin-binding or activation of tgf-beta-1.
254	does not affect integrin-binding or activation of tgf-beta-1.
257–260	strongly inhibits integrin-binding and activation of tgf-beta-1.
278	prevents cleavage and subsequent maturation of the protein. generated in order to mimic the structure of the transformin

Function

Pathways and Gene Ontology

Reactome pathways

52 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-168277	Influenza Virus Induced Apoptosis
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173791	TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
R-HSA-3000170	Syndecan interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-3304356	SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3642279	TGFBR2 MSI Frameshift Mutants in Cancer
R-HSA-3645790	TGFBR2 Kinase Domain Mutants in Cancer
R-HSA-3656532	TGFBR1 KD Mutants in Cancer
R-HSA-3656535	TGFBR1 LBD Mutants in Cancer
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-5689603	UCH proteinases
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8941855	RUNX3 regulates CDKN1A transcription
R-HSA-8941858	Regulation of RUNX3 expression and activity
R-HSA-8951936	RUNX3 regulates p14-ARF
R-HSA-9839389	TGFBR3 regulates TGF-beta signaling
R-HSA-109582	Hemostasis
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1474244	Extracellular matrix organization
R-HSA-1566948	Elastic fibre formation
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168255	Influenza Infection
R-HSA-168256	Immune System

MSigDB gene sets: 1541 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, AHRARNT_01, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_DNA_RECOMBINATION

GO Biological Process (200): negative regulation of transcription by RNA polymerase II (GO:0000122), cell morphogenesis (GO:0000902), vasculogenesis (GO:0001570), ureteric bud development (GO:0001657), epithelial to mesenchymal transition (GO:0001837), neural tube closure (GO:0001843), regulation of sodium ion transport (GO:0002028), sprouting angiogenesis (GO:0002040), chondrocyte differentiation (GO:0002062), columnar/cuboidal epithelial cell maturation (GO:0002069), hematopoietic progenitor cell differentiation (GO:0002244), connective tissue replacement involved in inflammatory response wound healing (GO:0002248), adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains (GO:0002460), tolerance induction to self antigen (GO:0002513), negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002859), heart valve morphogenesis (GO:0003179), aortic valve morphogenesis (GO:0003180), protein export from nucleus (GO:0006611), ATP biosynthetic process (GO:0006754), phosphate-containing compound metabolic process (GO:0006796), intracellular calcium ion homeostasis (GO:0006874), transforming growth factor beta receptor signaling pathway (GO:0007179), Notch signaling pathway (GO:0007219), negative regulation of neuroblast proliferation (GO:0007406), salivary gland morphogenesis (GO:0007435), endoderm development (GO:0007492), heart development (GO:0007507), female pregnancy (GO:0007565), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), primordial germ cell migration (GO:0008354), response to xenobiotic stimulus (GO:0009410), response to wounding (GO:0009611), response to gamma radiation (GO:0010332), gene expression (GO:0010467), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of extracellular matrix disassembly (GO:0010716), positive regulation of epithelial to mesenchymal transition (GO:0010718)

GO Molecular Function (12): type II transforming growth factor beta receptor binding (GO:0005114), cytokine activity (GO:0005125), growth factor activity (GO:0008083), enzyme binding (GO:0019899), type I transforming growth factor beta receptor binding (GO:0034713), type III transforming growth factor beta receptor binding (GO:0034714), identical protein binding (GO:0042802), protein serine/threonine kinase activator activity (GO:0043539), protein-containing complex binding (GO:0044877), transforming growth factor beta receptor binding (GO:0005160), protein binding (GO:0005515), deubiquitinase activator activity (GO:0035800)

GO Cellular Component (14): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), neuronal cell body (GO:0043025), blood microparticle (GO:0072562), microvillus (GO:0005902), secretory granule (GO:0030141)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Transcriptional regulation by RUNX3	3
Signaling by TGF-beta Receptor Complex	2
Loss of Function of TGFBR2 in Cancer	2
Loss of Function of TGFBR1 in Cancer	2
Response to elevated platelet cytosolic Ca2+	1
Influenza Infection	1
Hemostasis	1
Elastic fibre formation	1
TGF-beta receptor signaling activates SMADs	1
Non-integrin membrane-ECM interactions	1
Extracellular matrix organization	1
Loss of Function of SMAD2/3 in Cancer	1
Adipogenesis	1
Deubiquitination	1
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell differentiation	3
transforming growth factor beta receptor binding	3
anatomical structure morphogenesis	2
receptor ligand activity	2
protein binding	2
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
mesonephric tubule development	1
mesenchymal cell differentiation	1
primary neural tube formation	1
tube closure	1
sodium ion transport	1
regulation of metal ion transport	1
angiogenesis	1
cartilage development	1
columnar/cuboidal epithelial cell development	1
epithelial cell maturation	1
hemopoiesis	1
wound healing involved in inflammatory response	1
connective tissue replacement	1
adaptive immune response	1
tolerance induction	1
natural killer cell mediated cytotoxicity directed against tumor cell target	1
negative regulation of natural killer cell mediated immune response to tumor cell	1
regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1
negative regulation of natural killer cell mediated cytotoxicity	1
heart valve development	1
aortic valve development	1
heart valve morphogenesis	1
intracellular protein transport	1
nuclear export	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
metabolic process	1
protein serine/threonine kinase activity	1

Protein interactions and networks

STRING

7020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGFB1	TGFBR1	P36897	999
TGFB1	TGFBR2	P37173	999
TGFB1	ENG	P17813	997
TGFB1	LTBP1	P22064	996
TGFB1	DCN	P07585	993
TGFB1	TGFBR3	Q03167	992
TGFB1	LTBP4	Q8N2S1	990
TGFB1	SMAD7	O15105	978
TGFB1	SMAD3	P84022	978
TGFB1	IGF1	P01343	976
TGFB1	LTBP3	Q9NS15	975
TGFB1	EGFR	P00533	973
TGFB1	THBS1	P07996	973
TGFB1	FGF2	P09038	971
TGFB1	FN1	P02751	969

IntAct

232 interactions, top by confidence:

A	B	Type	Score
TGFB1	TGFBR2	psi-mi:“MI:0407”(direct interaction)	0.890
TGFBR2	TGFB1	psi-mi:“MI:0407”(direct interaction)	0.890
TGFBR2	TGFB1	psi-mi:“MI:0914”(association)	0.890
TGFBR2	TGFB1	psi-mi:“MI:0915”(physical association)	0.890
TGFB1	TGFBR2	psi-mi:“MI:0915”(physical association)	0.890
TGFB1	LRRC32	psi-mi:“MI:0915”(physical association)	0.850
TGFB1	LRRC32	psi-mi:“MI:0407”(direct interaction)	0.850
TGFB1	LTBP1	psi-mi:“MI:0407”(direct interaction)	0.640
TGFB1	LTBP1	psi-mi:“MI:0915”(physical association)	0.640
LRRC32	SMPD2	psi-mi:“MI:0914”(association)	0.640
ERP44	TGFB1	psi-mi:“MI:0914”(association)	0.640
APP	TGFB1	psi-mi:“MI:2364”(proximity)	0.600
TGFB1	APP	psi-mi:“MI:0915”(physical association)	0.600
APP	TGFB1	psi-mi:“MI:0914”(association)	0.600
TGFB1	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
TGFB1		psi-mi:“MI:0915”(physical association)	0.560
MEOX2	TGFB1	psi-mi:“MI:0915”(physical association)	0.560
	TGFB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (344): TGFB1 (Two-hybrid), CCDC33 (Two-hybrid), TGFB1 (Two-hybrid), NMT1 (Affinity Capture-MS), NMT2 (Affinity Capture-MS), FEM1B (Affinity Capture-MS), LAMC1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), RMND5A (Affinity Capture-MS), C4orf48 (Affinity Capture-MS), EIF1AX (Affinity Capture-MS), TGFB1 (Affinity Capture-MS), AGR3 (Two-hybrid), ANGPTL4 (Two-hybrid), BCAS3 (Two-hybrid)

ESM2 similar proteins: A1Z623, A2SXS5, A8YXY3, F1LQY6, O02718, O19011, O60613, P01137, P04202, P07200, P09533, P11456, P18341, P50747, P54831, Q08BI9, Q0P5I0, Q1LZ96, Q2KIJ6, Q2TBX5, Q38HS2, Q3UHE1, Q3UX43, Q58CS8, Q5C9Z4, Q5R812, Q5RB75, Q6IEE6, Q6PCX7, Q6X4M2, Q802F3, Q802G7, Q8BJQ9, Q8IVD9, Q8NC56, Q8R1N4, Q8R1T1, Q8TDX6, Q8VHC3, Q8WUX9

Diamond homologs: O19006, O19011, O93449, P01137, P03970, P04088, P04202, P07200, P09531, P09533, P09858, P10600, P15203, P16047, P16176, P17125, P17246, P17247, P18341, P20863, P21214, P27090, P27539, P30371, P42917, P50414, P54831, P55103, P61811, P61812, Q07257, Q07258, Q38HS2, Q38L25, Q66KL4, Q6X2S4, Q804S2, Q9NR23, Q9PTQ2, Q9WUK5

SIGNOR signaling

71 interactions.

A	Effect	B	Mechanism
TGFB1	“down-regulates quantity by repression”	BGLAP	“transcriptional regulation”
ITGB8	up-regulates	TGFB1
TGFB1	“down-regulates quantity by repression”	RNF111	“transcriptional regulation”
FGF2	“up-regulates quantity by expression”	TGFB1	“transcriptional regulation”
FGF9	“up-regulates quantity by expression”	TGFB1	“transcriptional regulation”
TGFB1	“up-regulates activity”	TGFB1	binding
TGFB1	“down-regulates quantity by repression”	OMD	“transcriptional regulation”
TDGF1	“down-regulates activity”	TGFB1	binding
TGFB1	“up-regulates quantity by expression”	CDKN1B
TGFB1	down-regulates	SKP2
TGFB1	“up-regulates quantity by expression”	MYOCD	“transcriptional regulation”
TGFB1	up-regulates	NfKb-p65/p50
TGFB1	“up-regulates quantity by expression”	LPP	“transcriptional regulation”
TGFB1	“up-regulates activity”	TGFBR1	binding
PRKAA1	down-regulates	TGFB1
TGFB1	“down-regulates activity”	CyclinE/CDK2
TGFB1	“up-regulates activity”	PIK3CG
TGFB1	“up-regulates activity”	PPP2R2A	binding
TGFB1	“up-regulates activity”	PIK3R1	binding
LTBP1	“up-regulates activity”	TGFB1	binding
TGFB1	“down-regulates quantity by repression”	RUNX2	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	HBA1	“transcriptional regulation”
TGFB1	“down-regulates quantity by repression”	PAX6	“transcriptional regulation”
TGFB1	“down-regulates quantity by repression”	KRT1	“transcriptional regulation”
FBN1	“up-regulates quantity”	TGFB1	binding
TGFB1	“up-regulates quantity by expression”	COL4A1	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	ACTA2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TGF-beta receptor signaling activates SMADs	6	20.4×	6e-05
Molecules associated with elastic fibres	5	16.1×	7e-04
Signaling by TGF-beta Receptor Complex	6	12.5×	5e-04
Developmental Lineage of Pancreatic Ductal Cells	5	11.9×	2e-03
ECM proteoglycans	7	11.0×	3e-04
Non-integrin membrane-ECM interactions	6	9.7×	1e-03
Signaling by TGFB family members	7	8.4×	9e-04
Post-translational protein phosphorylation	8	8.3×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of SMAD protein signal transduction	6	19.6×	1e-04
negative regulation of cell adhesion	5	16.4×	1e-03
transforming growth factor beta receptor signaling pathway	12	16.3×	1e-08
keratinization	8	16.0×	2e-05
extracellular matrix disassembly	5	15.7×	1e-03
roof of mouth development	7	14.8×	1e-04
regulation of cell adhesion	5	13.1×	3e-03
negative regulation of transforming growth factor beta receptor signaling pathway	7	10.4×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	256
Likely benign	149
Benign	25

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
12528	NM_000660.7(TGFB1):c.673T>C (p.Cys225Arg)	Pathogenic
12531	NM_000660.7(TGFB1):c.652C>T (p.Arg218Cys)	Pathogenic
12533	NM_000660.7(TGFB1):c.667T>C (p.Cys223Arg)	Pathogenic
3234856	NM_000660.7(TGFB1):c.571_577del (p.Asp191fs)	Likely pathogenic
383807	NM_000660.7(TGFB1):c.897C>G (p.Tyr299Ter)	Likely pathogenic
488346	NM_000660.7(TGFB1):c.1159T>C (p.Cys387Arg)	Likely pathogenic
803561	NM_000660.7(TGFB1):c.512A>G (p.Tyr171Cys)	Likely pathogenic

SpliceAI

2395 predictions. Top by Δscore:

Variant	Effect	Δscore
19:41301667:G:T	donor_gain	1.0000
19:41301705:G:T	donor_loss	1.0000
19:41301706:T:A	donor_loss	1.0000
19:41302643:T:A	acceptor_gain	1.0000
19:41302644:G:A	acceptor_gain	1.0000
19:41302649:A:AG	acceptor_gain	1.0000
19:41302946:GGAG:G	donor_gain	1.0000
19:41302947:G:GT	donor_gain	1.0000
19:41302950:G:GC	donor_loss	1.0000
19:41303965:A:AG	acceptor_gain	1.0000
19:41303966:A:G	acceptor_gain	1.0000
19:41303968:A:AG	acceptor_gain	1.0000
19:41303968:ACAG:A	acceptor_gain	1.0000
19:41303969:C:G	acceptor_gain	1.0000
19:41303969:CA:C	acceptor_loss	1.0000
19:41303970:A:AG	acceptor_gain	1.0000
19:41303970:AGGT:A	acceptor_loss	1.0000
19:41303971:G:GG	acceptor_gain	1.0000
19:41303971:G:GT	acceptor_loss	1.0000
19:41304262:G:GG	donor_gain	1.0000
19:41304262:GT:G	donor_loss	1.0000
19:41306445:CCAGT:C	acceptor_loss	1.0000
19:41306446:CAGTA:C	acceptor_loss	1.0000
19:41306447:A:AG	acceptor_gain	1.0000
19:41306448:G:GA	acceptor_gain	1.0000
19:41306448:GT:G	acceptor_gain	1.0000
19:41306448:GTA:G	acceptor_gain	1.0000
19:41306448:GTAT:G	acceptor_gain	1.0000
19:41310351:A:G	donor_gain	1.0000
19:41310355:GG:G	donor_gain	1.0000

AlphaMissense

2513 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:41331059:C:G	C389S	1.000
19:41331060:A:G	C389R	1.000
19:41331060:A:T	C389S	1.000
19:41331064:G:C	C387W	1.000
19:41331065:C:A	C387F	1.000
19:41331065:C:G	C387S	1.000
19:41331065:C:T	C387Y	1.000
19:41331066:A:T	C387S	1.000
19:41331089:A:G	L379P	1.000
19:41331128:A:T	I366N	1.000
19:41331134:A:G	L364P	1.000
19:41331157:G:C	C356W	1.000
19:41331158:C:A	C356F	1.000
19:41331158:C:G	C356S	1.000
19:41331158:C:T	C356Y	1.000
19:41331159:A:G	C356R	1.000
19:41331159:A:T	C356S	1.000
19:41331161:C:T	C355Y	1.000
19:41332164:G:C	C326W	1.000
19:41332165:C:G	C326S	1.000
19:41332165:C:T	C326Y	1.000
19:41332166:A:G	C326R	1.000
19:41332166:A:T	C326S	1.000
19:41332171:C:T	G324E	1.000
19:41332172:C:A	G324W	1.000
19:41332172:C:G	G324R	1.000
19:41332172:C:T	G324R	1.000
19:41332176:G:C	C322W	1.000
19:41332177:C:A	C322F	1.000
19:41332177:C:G	C322S	1.000

dbSNP variants (sampled 300 via entrez): RS1000046464 (19:41336629 A>G), RS1000070456 (19:41336488 C>T), RS1000171648 (19:41351561 T>C), RS1000336219 (19:41348056 C>A), RS1000410355 (19:41336839 A>C), RS1000438828 (19:41354191 G>A), RS1000610360 (19:41353491 A>AG), RS1000964516 (19:41343113 T>G), RS1001098955 (19:41347759 C>T), RS1001307646 (19:41330214 C>G), RS1001473424 (19:41355221 A>G), RS1001576461 (19:41332815 A>G,T), RS1001856350 (19:41331651 C>T), RS1001959836 (19:41348113 A>G), RS1002004691 (19:41346684 A>G)

Disease associations

OMIM: gene MIM:190180 | disease phenotypes: MIM:618213, MIM:131300, MIM:219700, MIM:614175

GenCC curated gene-disease

Disease	Classification	Inheritance
Camurati-Engelmann disease	Definitive	Autosomal dominant
inflammatory bowel disease, immunodeficiency, and encephalopathy	Strong	Autosomal recessive
Camurati-Engelmann disease type 1	Strong	Autosomal dominant
cystic fibrosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
inflammatory bowel disease, immunodeficiency, and encephalopathy	Limited	AR

Mondo (6): inflammatory bowel disease, immunodeficiency, and encephalopathy (MONDO:0032601), Camurati-Engelmann disease (MONDO:0007542), Camurati-Engelmann disease type 1 (MONDO:0700385), cystic fibrosis (MONDO:0009061), Meckel syndrome, type 10 (MONDO:0013609), IL10-related early-onset inflammatory bowel disease (MONDO:0016542)

Orphanet (5): Infantile inflammatory bowel disease with neurological involvement (Orphanet:565788), Camurati-Engelmann disease (Orphanet:1328), Meckel syndrome (Orphanet:564), Cystic fibrosis (Orphanet:586), Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome (Orphanet:238569)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000016	Urinary retention
HP:0000135	Hypogonadism
HP:0000246	Sinusitis
HP:0000303	Mandibular prognathia
HP:0000365	Hearing impairment
HP:0000501	Glaucoma
HP:0000520	Proptosis
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000763	Sensory neuropathy
HP:0000787	Nephrolithiasis
HP:0000823	Delayed puberty
HP:0000925	Abnormality of the vertebral column
HP:0000929	Abnormal skull morphology
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000940	Abnormal diaphysis morphology
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001293	Cranial nerve compression
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002454_12	Colorectal cancer	1.000000e-08
GCST003494_2	Colorectal cancer	4.000000e-07
GCST004787_13	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	4.000000e-08
GCST004898_3	Preterm birth (maternal effect)	5.000000e-07
GCST005194_185	Coronary artery disease	4.000000e-17
GCST005195_126	Coronary artery disease	2.000000e-17
GCST005196_237	Coronary artery disease	7.000000e-15
GCST005196_238	Coronary artery disease	4.000000e-16
GCST007269_138	Pulse pressure	8.000000e-11
GCST007856_49	Colorectal cancer or advanced adenoma	1.000000e-06
GCST007990_15	Coronary artery disease	2.000000e-08
GCST008114_4	Type 2 diabetes	1.000000e-06
GCST008613_2	Hematuria	1.000000e-11
GCST008617_4	Hematuria (moderate to severe)	2.000000e-09
GCST008618_1	Hematuria (mild)	9.000000e-08
GCST010866_163	Coronary artery disease	1.000000e-26
GCST90002402_563	Platelet count	2.000000e-11
GCST90013663_63	Alanine aminotransferase levels	4.000000e-09
GCST90013664_93	Aspartate aminotransferase levels	2.000000e-25

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003917	premature birth
EFO:0005939	parental genotype effect measurement
EFO:0005763	pulse pressure measurement
EFO:0004309	platelet count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1795178 (SINGLE PROTEIN), CHEMBL3988637 (PROTEIN FAMILY), CHEMBL4296077 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 898 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3260567	VACTOSERTIB	2	898

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1800469	Toxicity	3	aspirin
rs1800469	Toxicity	3	irinotecan	Colorectal Neoplasms
rs1800470	Efficacy	3	rituximab	Rheumatoid arthritis
rs1800471	Efficacy	3	rituximab	Rheumatoid arthritis

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1800469	B9D2, TGFB1, TMEM91	3	2.50	2	aspirin;irinotecan
rs1800470	TGFB1, TMEM91	3	2.75	1	rituximab
rs1800471	TGFB1, TMEM91	3	3.25	1	rituximab
rs2241716	TGFB1		0.00	0

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.89	IC50	12.9	nM	VACTOSERTIB
7.42	IC50	38.2	nM	CHEMBL5280211
7.25	IC50	56	nM	CHEMBL5272606
5.80	IC50	1600	nM	CHEMBL5078185
5.17	IC50	6700	nM	CHEMBL4448117

PubChem BioAssay actives

5 with measured affinity, of 40 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-fluoro-N-[[5-(6-methyl-2-pyridinyl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-imidazol-2-yl]methyl]aniline	1937994: Inhibition of TGF-beta receptor (unknown origin)	ic50	0.0129	uM
2-tert-butyl-N-[4-[1-cyclopropyl-3-(oxan-4-yl)pyrazol-4-yl]oxy-2-pyridinyl]pyridin-4-amine	1937994: Inhibition of TGF-beta receptor (unknown origin)	ic50	0.0382	uM
4-[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-6-methyl-4-pyridinyl]quinoline-6-carboxamide	1937994: Inhibition of TGF-beta receptor (unknown origin)	ic50	0.0560	uM
(2R)-6-amino-N-[(2R)-1-[[(2R)-1-[[(2R,3R)-1-[[(2R)-1-[[(1R)-2-[[(2R)-6-amino-1-[[(2R,3R)-1-[[(2R)-1-[[(2R)-1-[[(2R,3R)-1-[[(2R)-1-[[(2R)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-2-cyclohexylacetyl]amino]hexanamide	1823380: Inhibition of TGF beta 1 (unknown origin) expressed in HEK293 cells transfected with Smad2/3 responsive reporter plasmid incubated for 4 hrs by dual luciferase reporter gene assay	ic50	1.6000	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-2-cyclohexylacetyl]amino]-N-[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(1S)-2-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]pentanediamide	1823380: Inhibition of TGF beta 1 (unknown origin) expressed in HEK293 cells transfected with Smad2/3 responsive reporter plasmid incubated for 4 hrs by dual luciferase reporter gene assay	ic50	6.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	decreases reaction, increases secretion, increases expression, decreases expression, decreases secretion (+2 more)	13
sodium arsenite	increases expression, increases secretion, decreases expression, affects acetylation, affects expression (+6 more)	12
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases phosphorylation, decreases reaction, increases expression, affects reaction, decreases response to substance (+2 more)	12
Resveratrol	affects reaction, decreases reaction, increases expression, increases phosphorylation, decreases activity (+3 more)	12
Arsenic Trioxide	increases reaction, increases secretion, affects reaction, decreases reaction, increases expression (+2 more)	12
Particulate Matter	increases secretion, affects cotreatment, decreases expression, increases abundance, increases expression (+1 more)	11
Acetylcysteine	increases phosphorylation, decreases reaction, increases expression, increases secretion, increases abundance (+1 more)	9
Dexamethasone	decreases expression, decreases reaction, increases expression, increases phosphorylation, increases reaction (+1 more)	9
Glucose	increases secretion, increases expression, affects cotreatment, decreases expression, increases cleavage (+4 more)	9
Quercetin	affects cotreatment, increases expression, decreases reaction, decreases expression, increases secretion	9
Cadmium Chloride	affects cotreatment, increases phosphorylation, decreases expression, decreases reaction, increases abundance (+2 more)	9
bisphenol A	affects expression, affects cotreatment, decreases expression, affects binding, increases reaction (+2 more)	7
SB 203580	increases secretion, affects localization, decreases expression, increases phosphorylation, decreases reaction (+1 more)	7
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases activity, increases phosphorylation, decreases reaction, increases expression, increases secretion	7
Estradiol	increases expression, affects expression, decreases expression, increases secretion, decreases metabolic processing (+4 more)	7
Paraquat	affects reaction, increases expression, increases reaction, decreases reaction, affects cotreatment	7
Tetrachlorodibenzodioxin	affects reaction, increases activity, increases reaction, decreases reaction, increases expression (+3 more)	7
Tobacco Smoke Pollution	decreases expression, increases expression, affects cotreatment, decreases reaction, increases secretion	7
Tretinoin	increases cleavage, increases expression, increases reaction, affects cotreatment, increases secretion (+7 more)	7
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases reaction, increases phosphorylation, increases secretion, decreases response to substance, decreases reaction (+2 more)	6
(+)-JQ1 compound	affects cotreatment, decreases expression, decreases reaction, increases expression, increases secretion	6
Arsenic	increases reaction, affects methylation, affects cotreatment, increases expression, decreases expression (+1 more)	6
Hydrogen Peroxide	decreases reaction, increases expression, affects expression, affects reaction, increases phosphorylation (+4 more)	6
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, increases reaction, affects expression, affects cotreatment (+1 more)	6
Troglitazone	decreases reaction, increases expression, increases secretion, decreases expression	5
Cadmium	decreases reaction, increases abundance, increases expression, decreases expression	5
Progesterone	increases expression, increases secretion, decreases secretion, decreases reaction, increases abundance (+3 more)	5
1-Methyl-3-isobutylxanthine	increases phosphorylation, increases reaction, affects cotreatment, decreases expression, decreases reaction (+1 more)	5
Cyclosporine	increases expression, decreases reaction	5
Reactive Oxygen Species	decreases reaction, increases abundance, affects cotreatment	5

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3117118	Binding	Inhibition of TGFbetaR1-mediated smad phosphorylation in human HaCaT cells at 1 uM measured within 24 hrs by dual-luciferase reporter gene assay	Synthesis and biological evaluation of novel tetrahydro-β-carboline derivatives as antitumor growth and metastasis agents through inhibiting the transforming growth factor-β signaling pathway. — J Med Chem

Cellosaurus cell lines

9 cell lines: 5 cancer cell line, 3 embryonic stem cell, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7J0	SEES3-1V human TGFB1, clone1	Embryonic stem cell	Male
CVCL_A7J1	SEES3-1V human TGFB1, clone2	Embryonic stem cell	Male
CVCL_A7J2	SEES3-1V human TGFB1, clone3	Embryonic stem cell	Male
CVCL_B2IF	Abcam HeLa TGFB1 KO	Cancer cell line	Female
CVCL_B2QH	Abcam A-549 TGFB1 KO	Cancer cell line	Male
CVCL_B8QR	Abcam HCT 116 TGFB1 KO	Cancer cell line	Male
CVCL_B9C8	Abcam MCF-7 TGFB1 KO	Cancer cell line	Female
CVCL_E7G3	RMF/EG	Telomerase immortalized cell line	Female
CVCL_XU18	HAP1 TGFB1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
NCT01712334	PHASE4	COMPLETED	A Study of the Comparable Efficacy and Safety of Pulmozyme (Dornase Alfa) Delivered by the eRapid Nebulizer System in Patients With Cystic Fibrosis
NCT01737983	PHASE4	COMPLETED	Effect of Lactobacillus Reuteri in Cystic Fibrosis
NCT01844778	PHASE4	COMPLETED	Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
NCT01880346	PHASE4	COMPLETED	Comparison of Absorption of Vitamin D in Cystic Fibrosis
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01937325	PHASE4	UNKNOWN	CPET in CF Patients With One G551D Mutation Taking VX770
NCT02015663	PHASE4	TERMINATED	Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on / 28 Day Off Cycles
NCT02048592	PHASE4	UNKNOWN	Impact of Immunonutrition on the Patients With Cystic Fibrosis