SMAD3

Summary

SMAD3 (SMAD family member 3, HGNC:6769) is a protein-coding gene on chromosome 15q22.33, encoding SMAD family member 3 (P84022). Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. It is haploinsufficient (ClinGen: sufficient evidence).

The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene ‘mothers against decapentaplegic’ (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3.

Source: NCBI Gene 4088 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aneurysm-osteoarthritis syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 141
• Clinical variants (ClinVar): 1,250 total — 112 pathogenic, 69 likely-pathogenic
• Phenotypes (HPO): 118
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 204 downstream targets (CollecTRI)
• MANE Select transcript: NM_005902

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6769
Approved symbol	SMAD3
Name	SMAD family member 3
Location	15q22.33
Locus type	gene with protein product
Status	Approved
Aliases	JV15-2, HsT17436
Ensembl gene	ENSG00000166949
Ensembl biotype	protein_coding
OMIM	603109
Entrez	4088

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000327367, ENST00000439724, ENST00000537194, ENST00000540846, ENST00000558428, ENST00000558739, ENST00000558763, ENST00000558827, ENST00000558894, ENST00000559092, ENST00000559460, ENST00000559937, ENST00000560175, ENST00000560402, ENST00000560424, ENST00000679624, ENST00000680689, ENST00000681239, ENST00000714107, ENST00000714108, ENST00000714109, ENST00000714110, ENST00000714111

RefSeq mRNA: 11 — MANE Select: NM_005902 NM_001145102, NM_001145103, NM_001145104, NM_001407011, NM_001407012, NM_001407013, NM_001407014, NM_001407015, NM_001407016, NM_001407017, NM_005902

CCDS: CCDS10222, CCDS45288, CCDS53950, CCDS53951

Canonical transcript exons

ENST00000327367 — 9 exons

Exon	Start	End
ENSE00001346645	67065602	67066360
ENSE00002573361	67166779	67166853
ENSE00003553543	67164895	67165088
ENSE00003632793	67165253	67165384
ENSE00004013806	67187365	67187509
ENSE00004013808	67170554	67170604
ENSE00004013809	67181241	67181453
ENSE00004013810	67184727	67184864
ENSE00004013811	67190413	67195169

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 96.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.1606 / max 306.4835, expressed in 1767 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147300	21.8884	1718
147295	7.9110	1524
147316	1.9509	466
147296	1.9307	1054
147318	1.5325	444
147334	1.1683	614
147319	1.1000	355
147331	0.9504	573
147297	0.9358	640
147299	0.8083	538

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	96.43	gold quality
cartilage tissue	UBERON:0002418	95.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.88	gold quality
tongue squamous epithelium	UBERON:0006919	94.52	gold quality
esophagus mucosa	UBERON:0002469	93.53	gold quality
colonic epithelium	UBERON:0000397	93.26	gold quality
tendon	UBERON:0000043	93.25	gold quality
lower esophagus mucosa	UBERON:0035834	93.10	gold quality
muscle of leg	UBERON:0001383	93.03	gold quality
gastrocnemius	UBERON:0001388	92.76	gold quality
synovial joint	UBERON:0002217	92.53	gold quality
muscle organ	UBERON:0001630	92.42	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.28	gold quality
mucosa of urinary bladder	UBERON:0001259	92.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.99	gold quality
skeletal muscle tissue	UBERON:0001134	91.98	gold quality
vagina	UBERON:0000996	91.89	gold quality
right lobe of thyroid gland	UBERON:0001119	91.58	gold quality
thyroid gland	UBERON:0002046	91.52	gold quality
muscle tissue	UBERON:0002385	91.51	gold quality
epithelium of nasopharynx	UBERON:0001951	91.48	gold quality
urinary bladder	UBERON:0001255	91.47	gold quality
islet of Langerhans	UBERON:0000006	91.42	gold quality
left lobe of thyroid gland	UBERON:0001120	91.39	gold quality
tonsil	UBERON:0002372	91.30	gold quality
ectocervix	UBERON:0012249	91.29	gold quality
biceps brachii	UBERON:0001507	91.19	gold quality
calcaneal tendon	UBERON:0003701	91.06	gold quality
tibialis anterior	UBERON:0001385	91.05	gold quality
layer of synovial tissue	UBERON:0007616	90.88	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	21.65
E-ANND-3	yes	15.38
E-GEOD-83139	yes	12.36
E-ENAD-27	yes	6.35

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

204 targets.

Target	Regulation
ACHE	Activation
ACTA1	Unknown
ACTA2	Activation
ACTG2	Repression
ADAM2
AGTR1	Unknown
AHR	Unknown
ALPI	Activation
ANGPTL2	Unknown
ANGPTL4	Activation
ANKRD1	Activation
APOC3	Activation
APP	Repression
AR	Unknown
ASIC3	Repression
ASPN	Activation
BAMBI	Activation
BAX	Repression
BBC3	Activation
BCL2	Repression
BGLAP	Unknown
BIRC5	Unknown
BMPR2	Repression
CAT
CCL2	Activation
CCL20	Activation
CCL21	Activation
CCN1	Activation
CCN2	Unknown
CCND1	Unknown

JASPAR motifs

Motif	Name	Family
MA0795.1	SMAD3	SMAD factors

JASPAR matrix evidence (PMIDs): PMID:12582250

Upstream regulators (CollecTRI, top): AP1, AR, ARID1A, FLCN, KLF10, KLF11, MITF, NFKB, NR0B2, RARA, RUNX1, SMAD3, SMAD7, SP1, STAT1, TP53, TRIB3, WT1, WWTR1

miRNA regulators (miRDB)

176 targeting SMAD3, 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-3120-5P	100.00	65.56	965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-5193	100.00	67.26	1744
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4778-3P	99.93	70.40	1818

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• repression of transactivating activity by association with a novel splice variant of CCAAT-binding factor C subunit (PMID:12023901)
• HTLV-1 tax represses Smad-mediated TGF-beta signaling. (PMID:12097320)
• Smad3 trimerization, induced by phosphorylation, activates the TGF-beta signal by driving Smad3 dissociation from SARA & sets up the negative feedback mechanism by Ski. (PMID:12154125)
• Data suggest that SMAD3 interactions with the positive regulators NKX2.1 and HNF-3 underlie the molecular basis for TGF-beta-induced repression of surfactant protein B gene transcription. (PMID:12161428)
• Smad3 is unlikely to function as a classical tumor suppressor gene in the pathogenesis of sporadic parathyroid or enteropancreatic endocrine tumors. (PMID:12161532)
• Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. (PMID:12191474)
• interactions between AR, Smad3, and Smad4 may result in the differential regulation of the AR transactivation, which further strengthens their roles in the prostate cancer progression (PMID:12226080)
• adenovirally-expressed Smad3 augmented the TGF-beta-elicited induction of MMP-13 expression (PMID:12270924)
• Levels of phosphorylated Smad2/3 are sensors of the interplay between effects of retinoic acid and TGF-beta or vitamin D3 on monocytic and granulocytic differentiation of HL-60 cells. (PMID:12393416)
• HTLV1 Tax inhibits TGF-beta1 signaling by reducing the Smad3 DNA binding activity (PMID:12393612)
• autocrine regulation of TGF-beta2 production in endothelial cell hypoxia may involve cross-talk between Smad3 and hypoxia inducible factor-1alpha signaling pathways (PMID:12411310)
• Phenotypic and functional changes associated with TGF-beta1-induced fibroblast terminal differentiation are differentially regulated by Smad2, Smad3, and Smad4. (PMID:12531695)
• TGF-beta1 inhibited IFN-gamma and TNF-alpha-induced TARC production in HaCaT cells via Smad2/3. Modulation of TGF-beta/Smad signaling pathway may be beneficial for treatment of atopic dermatitis. (PMID:12615364)
• In SMAD4-negative cell lines, TGF-beta caused Smad3 to move to the nucleus in a Smad4-independent fashion. Nuclear translocation of Smad3 was not sufficient to activate reporters for TGF-beta-induced transcriptional responses. (PMID:12618756)
• Results suggest that the transcriptional cross talk between the TGFbeta-regulated Smads 3 and 4 and hepatocyte nuclear factor-4 is mediated by specific functional domains in the two types of transcription factors. (PMID:12631740)
• stimulates basal and Tat-mediated transcription of MCP-1 in human astrocytic cells (PMID:12758167)
• Mediation of tumor growth factor beta-1 induced collagen I expression in glomerular mesangial cells. (PMID:12759229)
• Down-regulation of Smad 3 expression by TGF-beta(1) at later stage is involved in negative modulation of TGF-beta(1) signaling. (PMID:12760775)
• SMAD3 has a role in regulating TGF-beta expression along with PIASy (PMID:12815042)
• Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts (PMID:12847691)
• A surface hydrophobic corridor within the MH2 domain of Smad3 is critical for association with CAN/Nup214 and nuclear import; Smad3 and Smad4 have different susceptibility to inhibition of import by cytoplasmic retention factor SARA (PMID:12917407)
• smad3 interacts directly with YB1 during TGFbeta signal inhibition by interferon gamma (PMID:12917425)
• Smad3 gene mutations could be associated with the pathogenesis of human osteoarthritis (PMID:12939660)
• a signal transduction cascade of the TGF-beta/Smad signaling pathway, which is activated in the GEC, appears to be involved in the development of focal segmental glomerulosclerosis (PMID:14531804)
• Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and exhibit distinct roles in different cell types (PMID:14555988)
• SMAD3 and SMAD4 activate gadd45beta through its third intron to facilitate G2 progression following TGFbeta treatment (PMID:14630914)
• TGF-beta and Smad3 mediate beta-hydroxybutyrate(HB)-induced cell cycle-dependent growth inhibition while Smad3 mediates beta-HB-induced collagen production and p21WAF1/p27kip1 protein expression in human proximal tubule (HK-2) cells. (PMID:14633126)
• Smad3 expression may have a critical role in tumor suppression in the early stages of gastric carcinogenesis. (PMID:14647420)
• PIAS3 and Smad3 interact with each other at the endogenous protein level in mammalian cells and also in vitro, and the association occurs through the C-terminal domain of Smad3. (PMID:14691252)
• a novel, functional binding element in the proximal region of the TN-C promoter mediating responsiveness to TGF-beta involving Smad3/4, Sp1, Ets1, and CBP/p300 (PMID:15001984)
• Analysis of the human SMAD3 promoter demonstrates that isoprenoid regulation of SMAD3 expression is dependent on Sp1/Sp3 activity (PMID:15044214)
• Tuberin (TSC2) interact with smad2/smad3 during TGF-beta1 growth regulation. (PMID:15066998)
• Smad3 has a role in Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs (PMID:15107418)
• menin and TGF-beta/Smad3 negatively regulate the BMP-2/Smad1/5- and Runx2-induced transcriptional activities leading to inhibition of cell differentiation (PMID:15150273)
• The most transcriptionally active splice variants of Smad3 are made in macrophages (but not SMCs) of fibrofatty lesions and are upregulated after cell differentiation from monocytes. Cyclin inhibitors are induced by Smads. Fibrous plaque SMCs make Smad3. (PMID:15166010)
• Gly-BSA increases DNA binding activity of Smad3 and that it stimulates PAI-1 transcription through Smad-binding CAGA sequences in the PAI-1 promoter in human mesangial cells (PMID:15198928)
• Our findings suggest that BAMBI transcription is regulated by TGF-beta signaling through direct binding of SMAD3 and SMAD4 to the BAMBI promoter. (PMID:15240101)
• sphingosine 1-phosphate receptors and the transforming growth factor beta-type I receptor serine/threonine kinase are essential for activation of Smad3 by lysophospholipids (PMID:15247277)
• Smad2/3 is activated in undifferentiated human embryonic stem cells and required for the expression of genes controlling Nodal signaling (PMID:15308665)
• HCV viral proteins interact with the TGF-beta signaling mediator Smad3 and differentially impair TGF-beta/Smad3-mediated transactivation and growth inhibition. (PMID:15334054)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smad3b	ENSDARG00000010207
danio_rerio	smad3a	ENSDARG00000036096
mus_musculus	Smad3	ENSMUSG00000032402
rattus_norvegicus	Smad2	ENSRNOG00000008620

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD9 (ENSG00000120693), SMAD6 (ENSG00000137834), SMAD4 (ENSG00000141646), SMAD1 (ENSG00000170365), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 3 — P84022 (reviewed: P84022)

Alternative names: JV15-2, Mothers against decapentaplegic homolog 3

All UniProt accessions (14): P84022, A0AAQ5BHE0, A0AAQ5BHF1, A0AAQ5BHI7, A0AAQ5BHJ5, A0AAQ5BHK2, H0YKE2, H0YL71, H0YMP2, H0YMY0, H0YNV1, H3BP09, H3BQ00, H3BVD1

UniProt curated annotations — full annotation on UniProt →

Function. Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.

Subunit / interactions. Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4; the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1. Interacts with NEDD9; the interaction promotes NEDD9 ubiquitination and proteasomal degradation. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex. Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with TGFBR1. Interacts with TGFB1I1. Interacts with PRDM16. Interacts with SNW1. Interacts (via MH2 domain) with ZFYVE9. Interacts with HDAC1. Interacts with TGIF2. Interacts with SKOR1. Interacts with SKOR2. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1. Interacts with ZNF451. Interacts with ZFHX3. Interacts weakly with ZNF8. Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1. Interacts with YAP1 (when phosphorylated at ‘Ser-127’). Interacts with MAGI2/ARIP1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts with HGS. Interacts with WWP1. Interacts with TTRAP. Interacts with FOXL2. Interacts with PML. Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts with ZC3H3. Interacts with TGIF. Interacts with CREBBP. Interacts with ATF2. Interacts with NEDD9; the interaction is inhibited by oxidation of NEDD9. Interacts with MTMR4; negatively regulates TGF-beta signaling through SMAD3 dephosphorylation and retention in endosomes. (Microbial infection) Interacts with SARS-CoV nucleoprotein.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1. Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta. Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling. Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are ‘in use’ are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover. Undergoes STUB1-mediated ubiquitination and degradation.

Disease relevance. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease may be caused by variants affecting the gene represented in this entry. Loeys-Dietz syndrome 3 (LDS3) [MIM:613795] An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and intellectual disability. The disease is caused by variants affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries, they have been classified as LDS3 by the OMIM resource.

Domain organisation. The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding. The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import. The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.

Similarity. Belongs to the dwarfin/SMAD family.

Isoforms (4)

UniProt ID	Names	Canonical?
P84022-1	1	yes
P84022-2	2
P84022-3	3
P84022-4	4

RefSeq proteins (11): NP_001138574, NP_001138575, NP_001138576, NP_001393940, NP_001393941, NP_001393942, NP_001393943, NP_001393944, NP_001393945, NP_001393946, NP_005893* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001132	SMAD_dom	Domain
IPR003619	MAD_homology1_Dwarfin-type	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR013019	MAD_homology_MH1	Domain
IPR013790	SMAD/Dwarfins	Family
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR036578	SMAD_MH1_sf	Homologous_superfamily

Pfam: PF03165, PF03166

UniProt features (101 total): mutagenesis site 23, strand 22, helix 16, modified residue 12, sequence variant 7, binding site 4, splice variant 3, region of interest 3, site 2, domain 2, cross-link 2, sequence conflict 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6YIB	X-RAY DIFFRACTION	1.7
1MJS	X-RAY DIFFRACTION	1.91
5OD6	X-RAY DIFFRACTION	2
5ODG	X-RAY DIFFRACTION	2.12
6ZMN	X-RAY DIFFRACTION	2.33
1OZJ	X-RAY DIFFRACTION	2.4
5XOC	X-RAY DIFFRACTION	2.4
1U7F	X-RAY DIFFRACTION	2.6
1MK2	X-RAY DIFFRACTION	2.74
1MHD	X-RAY DIFFRACTION	2.8
2LAJ	SOLUTION NMR
2LB2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P84022-F1	84.21	0.68

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 (2): 40 (required for trimerization); 41 (required for interaction with dna and jun and for functional cooperation with jun)

Ligand- & substrate-binding residues (4): 121; 126; 64; 109

Post-translational modifications (14): 2, 8, 179, 204, 208, 213, 378, 416, 418, 422, 423, 425, 33, 81

Mutagenesis-validated functional residues (23):

Position	Phenotype
8	reduced phosphorylation, increased transcriptional and antiproliferative activities. further increase in transcriptional
33	slightly decreased monoubiquitination.
40	little effect on interaction with dna or jun. abolishes interaction with dna and jun; when associated with a-41; a-43 an
41	greatly reduced interaction with dna and jun. abolishes interaction with dna and jun; when associated with a-40; a-44 an
43	little effect on interaction with dna or jun. abolishes interaction with dna and jun; when associated with a-40; a-41 an
44	little effect on interaction with dna or jun. abolishes interaction with jun; when associated with a-40; a-41 and a-43.
53	slightly decreased monoubiquitination.
74	reduced interaction with jun. loss of transcriptional activity and cooperation with jun.
81	decreased monoubiquitination.
179	reduced phosphorylation, increased transcriptional and increased antiproliferative activities. further increase in trans
204	increased transcriptional activity. further increased transcriptional activity; when associated with s-208.
208	increased transcriptional activity. further increased transcriptional activity; when associated with s-208.
213	reduced phosphorylation. increased transcriptional and antiproliferative activities. further increase in transcriptional
333	no effect on acetylation. completely abolishes acetylation and 97% reduction in transcriptional activity; when associate
341	no effect on acetylation. completely abolishes acetylation and 97% reduction in transcriptional activity; when associate
378	increased transcriptional activity. no further increase in transcriptional activity with ep300.
378	greatly reduced acetylation and 85% reduction in transcriptional activity. completely abolishes acetylation and 97% redu
409	no effect on acetylation. completely abolishes acetylation and 97% reduction in transcriptional activity; when associate
418	increased constitutive activity.
418	decreased activity.
422–425	does not abolish protein nuclear export. abolishes almost completely acetylation.
422–425	forms heterotrimers.
422–425	diminishes cargo protein export.

Function

Pathways and Gene Ontology

Reactome pathways

54 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1502540	Signaling by Activin
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3304356	SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3311021	SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487	SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-3656532	TGFBR1 KD Mutants in Cancer
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8941855	RUNX3 regulates CDKN1A transcription
R-HSA-8952158	RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9735871	SARS-CoV-1 targets host intracellular signalling and regulatory pathways
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9823730	Formation of definitive endoderm
R-HSA-9839394	TGFBR3 expression
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway

MSigDB gene sets: 1099 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, FXR_IR1_Q6, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, BROWNE_HCMV_INFECTION_6HR_DN

GO Biological Process (103): negative regulation of transcription by RNA polymerase II (GO:0000122), ureteric bud development (GO:0001657), response to hypoxia (GO:0001666), in utero embryonic development (GO:0001701), mesoderm formation (GO:0001707), somitogenesis (GO:0001756), release of cytochrome c from mitochondria (GO:0001836), liver development (GO:0001889), heart looping (GO:0001947), osteoblast development (GO:0002076), immune system development (GO:0002520), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), immune response (GO:0006955), transforming growth factor beta receptor signaling pathway (GO:0007179), JNK cascade (GO:0007254), endoderm development (GO:0007492), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), anatomical structure morphogenesis (GO:0009653), embryonic pattern specification (GO:0009880), response to gamma radiation (GO:0010332), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of epithelial to mesenchymal transition (GO:0010718), regulation of striated muscle tissue development (GO:0016202), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), signal transduction involved in regulation of gene expression (GO:0023019), cell differentiation (GO:0030154), negative regulation of ossification (GO:0030279), negative regulation of cell growth (GO:0030308), adrenal gland development (GO:0030325), positive regulation of cell migration (GO:0030335), positive regulation of bone mineralization (GO:0030501), thyroid gland development (GO:0030878), primary miRNA processing (GO:0031053), positive regulation of chondrocyte differentiation (GO:0032332), positive regulation of interleukin-1 beta production (GO:0032731), regulation of transforming growth factor beta2 production (GO:0032909), positive regulation of transforming growth factor beta3 production (GO:0032916)

GO Molecular Function (40): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription repressor activity (GO:0001217), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), transforming growth factor beta receptor binding (GO:0005160), collagen binding (GO:0005518), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), nuclear receptor binding (GO:0016922), DEAD/H-box RNA helicase binding (GO:0017151), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), nuclear mineralocorticoid receptor binding (GO:0031962), sterol response element binding (GO:0032810), nuclear glucocorticoid receptor binding (GO:0035259), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ubiquitin binding (GO:0043130), bHLH transcription factor binding (GO:0043425), sequence-specific DNA binding (GO:0043565), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), co-SMAD binding (GO:0070410), I-SMAD binding (GO:0070411), R-SMAD binding (GO:0070412), DNA-binding transcription factor binding (GO:0140297), promoter-specific chromatin binding (GO:1990841), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), chromatin binding (GO:0003682), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), enzyme binding (GO:0019899), metal ion binding (GO:0046872)

GO Cellular Component (13): chromatin (GO:0000785), nucleus (GO:0005634), nuclear inner membrane (GO:0005637), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), signaling receptor complex (GO:0043235), SMAD protein complex (GO:0071141), heteromeric SMAD protein complex (GO:0071144)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Loss of Function of SMAD2/3 in Cancer	2
Transcriptional regulation by RUNX3	2
FOXO-mediated transcription	2
Gastrulation	2
Developmental Biology	1
Signaling by TGFB family members	1
TGF-beta receptor signaling activates SMADs	1
Signaling by TGF-beta Receptor Complex	1
Loss of Function of SMAD4 in Cancer	1
Loss of Function of TGFBR1 in Cancer	1
Deubiquitination	1
Interleukin-1 family signaling	1
Signaling by NOTCH4	1
SARS-CoV-1-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription cis-regulatory region binding	3
protein-containing complex	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
chordate embryonic development	2
immune system process	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
transcription coregulator binding	2
enzyme binding	2
cilium	2
mesonephric tubule development	1
response to stress	1
response to decreased oxygen levels	1
formation of primary germ layer	1
mesoderm morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
gland development	1
hepaticobiliary system development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
osteoblast differentiation	1
cell development	1
system development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
MAPK cascade	1
tissue development	1

Protein interactions and networks

STRING

5036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD3	SNAI1	O95863	994
SMAD3	ZFYVE9	O95405	994
SMAD3	TGFBR1	P36897	994
SMAD3	E2F4	Q16254	993
SMAD3	EP300	Q09472	992
SMAD3	JUN	P05412	990
SMAD3	AKT1	P31749	990
SMAD3	SMAD4	Q13485	989
SMAD3	TGFBR2	P37173	986
SMAD3	MYC	P01106	983
SMAD3	SMAD2	Q15796	982
SMAD3	CTNNB1	P35222	980
SMAD3	SKIL	P12756	979
SMAD3	TGFB1	P01137	978
SMAD3	ATF3	P18847	977

IntAct

445 interactions, top by confidence:

A	B	Type	Score
SMAD3	SMAD4	psi-mi:“MI:0407”(direct interaction)	0.980
SMAD3	SMAD4	psi-mi:“MI:0915”(physical association)	0.980
SMAD3	SMAD4	psi-mi:“MI:2364”(proximity)	0.980
SMAD4	SMAD3	psi-mi:“MI:0915”(physical association)	0.980
CCNT1	CDK9	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
SKI	SMAD3	psi-mi:“MI:0914”(association)	0.840
SMAD3	ZFYVE9	psi-mi:“MI:0407”(direct interaction)	0.820
ZFYVE9	SMAD3	psi-mi:“MI:0915”(physical association)	0.820
SMAD3	ZFYVE9	psi-mi:“MI:0915”(physical association)	0.820
WWP1	SMAD3	psi-mi:“MI:0915”(physical association)	0.810
BLZF1	SMAD3	psi-mi:“MI:0915”(physical association)	0.810

BioGRID (959): SMAD3 (Two-hybrid), SMAD3 (Two-hybrid), MEOX2 (Two-hybrid), BLZF1 (Two-hybrid), WWP1 (Two-hybrid), CPSF7 (Two-hybrid), CCDC33 (Two-hybrid), TEKT4 (Two-hybrid), SMAD3 (Affinity Capture-Western), SMAD3 (Reconstituted Complex), EP300 (Reconstituted Complex), Sox9 (Reconstituted Complex), SMAD3 (Affinity Capture-Western), SMAD3 (Reconstituted Complex), SMAD3 (Affinity Capture-Western)

ESM2 similar proteins: A6YQT5, B2ZCQ1, B2ZCQ2, B2ZCQ3, C6EN00, O15198, O54835, O70436, P03209, P17926, P20403, P24433, P27445, P28937, P42003, P49408, P70340, P84022, P84023, P84024, P84025, P97454, P97588, Q02330, Q06658, Q09302, Q15796, Q15797, Q1HVG0, Q1JQA2, Q1W668, Q21733, Q3KSS7, Q56I99, Q5R6H7, Q5R7C0, Q62432, Q63073, Q6S6Q7, Q8B912

Diamond homologs: F5GUE5, O15198, O54835, P42003, P45896, P70340, P84022, P84024, P84025, P97454, P97588, Q02330, Q15797, Q1JQA2, Q56I99, Q5R6H7, Q8BUN5, Q99717, Q9I8V2, Q9I962, Q9JIW5, Q9R1V3, Q9W7E7, O35182, O70436, O70437, P45897, P84023, P97471, Q13485, Q15796, Q1HE26, Q1W668, Q21733, Q5R7C0, Q62432, Q95QI7, Q9GKQ9, Q9I9P9, O15105

SIGNOR signaling

147 interactions.

A	Effect	B	Mechanism
PIAS4	down-regulates	SMAD3	binding
BTRC	down-regulates	SMAD3	ubiquitination
FBXW11	up-regulates	SMAD3	ubiquitination
MYC	“down-regulates activity”	SMAD3	binding
NUP214	up-regulates	SMAD3	binding
EID2	down-regulates	SMAD3	binding
SMAD3	up-regulates	NOTCH1	binding
PIAS3	up-regulates	SMAD3	binding
SMAD3	“down-regulates quantity by repression”	MYC	“transcriptional regulation”
KAT2A	up-regulates	SMAD3	binding
AKT1	down-regulates	SMAD3	binding
CDK2	down-regulates	SMAD3	phosphorylation
CDK2	“down-regulates activity”	SMAD3	phosphorylation
MAPK1	unknown	SMAD3	phosphorylation
PML	up-regulates	SMAD3	binding
AXIN1	up-regulates	SMAD3
PPM1A	down-regulates	SMAD3	dephosphorylation
TRIM33	up-regulates	SMAD3	binding
TUBB	down-regulates	SMAD3	binding
GSK3B	“down-regulates quantity by destabilization”	SMAD3	phosphorylation
BCAR1	down-regulates	SMAD3	binding
CDK8	“down-regulates activity”	SMAD3	phosphorylation
CDK8	down-regulates	SMAD3	phosphorylation
CDK9	“down-regulates activity”	SMAD3	phosphorylation
CDK9	down-regulates	SMAD3	phosphorylation
MAPK1	“down-regulates activity”	SMAD3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	7	66.1×	5e-09
Downregulation of SMAD2/3:SMAD4 transcriptional activity	5	47.2×	8e-06
Signaling by TGF-beta Receptor Complex	7	36.0×	2e-07
Signaling by TGFB family members	8	23.7×	2e-07
Infectious disease	8	5.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
transforming growth factor beta receptor signaling pathway	5	16.6×	2e-03
transcription by RNA polymerase II	6	8.8×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — COADREAD, PAAD.

Clinical variants and AI predictions

ClinVar

1250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	112
Likely pathogenic	69
Uncertain significance	539
Likely benign	354
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066678	NM_005902.4(SMAD3):c.785A>T (p.Asp262Val)	Pathogenic
1073400	NM_005902.4(SMAD3):c.1274C>G (p.Ser425Cys)	Pathogenic
1329283	NM_005902.4(SMAD3):c.1154+1G>A	Pathogenic
1384214	NM_005902.4(SMAD3):c.745del (p.His249fs)	Pathogenic
1395868	NM_005902.4(SMAD3):c.281G>A (p.Trp94Ter)	Pathogenic
1401072	NM_005902.4(SMAD3):c.276G>A (p.Trp92Ter)	Pathogenic
1423096	NM_005902.4(SMAD3):c.964C>T (p.Gln322Ter)	Pathogenic
1429119	NM_005902.4(SMAD3):c.988del (p.Thr330fs)	Pathogenic
1447563	NM_005902.4(SMAD3):c.1217G>A (p.Trp406Ter)	Pathogenic
1453567	NM_005902.4(SMAD3):c.382C>T (p.Gln128Ter)	Pathogenic
1454233	NM_005902.4(SMAD3):c.65_71dup (p.Asn24fs)	Pathogenic
1456118	NC_000015.9:g.(?67358493)(67546969_?)del	Pathogenic
1456200	NM_005902.4(SMAD3):c.1262_1265dup (p.Ser423fs)	Pathogenic
1456991	NC_000015.9:g.(?67459097)(67482874_?)del	Pathogenic
1509360	NM_005902.4(SMAD3):c.1266del (p.Ser423fs)	Pathogenic
1735230	NM_005902.4(SMAD3):c.381C>A (p.Tyr127Ter)	Pathogenic
1791490	NM_005902.4(SMAD3):c.1008del (p.Gly337fs)	Pathogenic
1791777	NM_005902.4(SMAD3):c.109del (p.Ser37fs)	Pathogenic
1806663	NM_005902.4(SMAD3):c.696G>A (p.Trp232Ter)	Pathogenic
2006491	NM_005902.4(SMAD3):c.207-10_280delinsA	Pathogenic
2024941	NM_005902.4(SMAD3):c.695G>A (p.Trp232Ter)	Pathogenic
2027953	NM_005902.4(SMAD3):c.881dup (p.Arg295fs)	Pathogenic
2090592	NM_005902.4(SMAD3):c.714C>A (p.Tyr238Ter)	Pathogenic
2126622	NM_005902.4(SMAD3):c.276G>C (p.Trp92Cys)	Pathogenic
213764	NM_005902.4(SMAD3):c.787C>G (p.Pro263Ala)	Pathogenic
213779	NM_005902.4(SMAD3):c.82G>T (p.Glu28Ter)	Pathogenic
213787	NM_005902.4(SMAD3):c.990dup (p.Val331fs)	Pathogenic
213792	NM_005902.4(SMAD3):c.455del (p.Pro152fs)	Pathogenic
213797	NM_005902.4(SMAD3):c.154G>T (p.Glu52Ter)	Pathogenic
213807	NM_005902.4(SMAD3):c.263dup (p.Tyr88Ter)	Pathogenic

SpliceAI

2497 predictions. Top by Δscore:

Variant	Effect	Δscore
15:67164884:C:A	acceptor_gain	1.0000
15:67164889:T:TA	acceptor_gain	1.0000
15:67164890:GGCA:G	acceptor_loss	1.0000
15:67164891:GCAG:G	acceptor_loss	1.0000
15:67164892:CAG:C	acceptor_loss	1.0000
15:67165086:CAG:C	donor_loss	1.0000
15:67165087:AGGTA:A	donor_loss	1.0000
15:67165088:GG:G	donor_loss	1.0000
15:67165246:C:A	acceptor_gain	1.0000
15:67165247:G:A	acceptor_gain	1.0000
15:67165248:GACA:G	acceptor_loss	1.0000
15:67165251:A:AC	acceptor_loss	1.0000
15:67165251:A:AG	acceptor_gain	1.0000
15:67165252:G:GT	acceptor_gain	1.0000
15:67165252:GT:G	acceptor_gain	1.0000
15:67165252:GTT:G	acceptor_gain	1.0000
15:67165252:GTTC:G	acceptor_gain	1.0000
15:67165252:GTTCT:G	acceptor_gain	1.0000
15:67165381:CCAG:C	donor_loss	1.0000
15:67165382:CAGG:C	donor_loss	1.0000
15:67165383:AGGTA:A	donor_loss	1.0000
15:67165385:GTA:G	donor_loss	1.0000
15:67166769:T:TA	acceptor_gain	1.0000
15:67166851:CAGGT:C	donor_loss	1.0000
15:67166854:G:T	donor_loss	1.0000
15:67181240:GACCT:G	acceptor_gain	1.0000
15:67181419:G:GT	donor_gain	1.0000
15:67181420:A:T	donor_gain	1.0000
15:67181454:G:GG	donor_gain	1.0000
15:67181454:G:T	donor_loss	1.0000

AlphaMissense

2807 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:67066198:T:C	L15P	1.000
15:67066242:T:A	W30R	1.000
15:67066242:T:C	W30R	1.000
15:67066244:G:C	W30C	1.000
15:67066244:G:T	W30C	1.000
15:67066254:G:C	A34P	1.000
15:67066255:C:A	A34E	1.000
15:67066258:T:A	V35D	1.000
15:67066263:A:C	S37R	1.000
15:67066265:C:A	S37R	1.000
15:67066265:C:G	S37R	1.000
15:67066267:T:A	L38Q	1.000
15:67066267:T:C	L38P	1.000
15:67066270:T:A	V39D	1.000
15:67066272:A:G	K40E	1.000
15:67066275:A:G	K41E	1.000
15:67066277:A:C	K41N	1.000
15:67066277:A:T	K41N	1.000
15:67066279:T:C	L42P	1.000
15:67066306:T:A	L51Q	1.000
15:67066306:T:C	L51P	1.000
15:67066314:G:C	A54P	1.000
15:67066344:T:A	C64S	1.000
15:67066344:T:C	C64R	1.000
15:67066345:G:A	C64Y	1.000
15:67066345:G:C	C64S	1.000
15:67066345:G:T	C64F	1.000
15:67066346:C:G	C64W	1.000
15:67066354:T:A	I67N	1.000
15:67066360:G:T	R69M	1.000

dbSNP variants (sampled 300 via entrez): RS1000002123 (15:67165850 CTT>C), RS1000045859 (15:67118774 G>A), RS1000055513 (15:67106302 A>C), RS1000060274 (15:67135251 G>C), RS1000061439 (15:67080779 C>T), RS1000062773 (15:67160492 G>A,C,T), RS1000073077 (15:67087451 G>A), RS1000123692 (15:67075277 T>A,G), RS1000127686 (15:67142931 A>C), RS1000201808 (15:67183208 A>G), RS1000231117 (15:67189366 C>T), RS1000240942 (15:67188988 C>A,G,T), RS1000279746 (15:67109251 G>A), RS1000285121 (15:67069863 G>A,C), RS1000290053 (15:67098670 T>C)

Disease associations

OMIM: gene MIM:603109 | disease phenotypes: MIM:607086, MIM:130000, MIM:613795, MIM:609192, MIM:122455, MIM:611788, MIM:211980

GenCC curated gene-disease

Disease	Classification	Inheritance
aneurysm-osteoarthritis syndrome	Definitive	Unknown
familial thoracic aortic aneurysm and aortic dissection	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
aneurysm-osteoarthritis syndrome	Definitive	AD

Mondo (12): familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Ehlers-Danlos syndrome (MONDO:0020066), aneurysm-osteoarthritis syndrome (MONDO:0013426), Loeys-Dietz syndrome (MONDO:0018954), coronary artery disorder (MONDO:0005010), thoracic aortic aneurysm (MONDO:0005396), connective tissue disorder (MONDO:0003900), cutaneous polyarteritis nodosa (MONDO:0018592), aortic aneurysm, familial thoracic 1 (MONDO:0024559), idiopathic spontaneous coronary artery dissection (MONDO:0007385), aortic aneurysm, familial thoracic 6 (MONDO:0012730), lung cancer (MONDO:0008903)

Orphanet (7): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Ehlers-Danlos syndrome (Orphanet:98249), Aneurysm-osteoarthritis syndrome (Orphanet:284984), Loeys-Dietz syndrome (Orphanet:60030), Cutaneous polyarteritis nodosa (Orphanet:439729), Familial aortic dissection (Orphanet:229), Idiopathic spontaneous coronary artery dissection (Orphanet:458718)

HPO phenotypes

118 total (30 of 118 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000139	Uterine prolapse
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000525	Abnormality iris morphology
HP:0000545	Myopia
HP:0000577	Exotropia
HP:0000592	Blue sclerae
HP:0000689	Dental malocclusion
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000822	Hypertension
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis

GWAS associations

141 associations (top):

Study	Trait	p-value
GCST000057_2	Coronary heart disease	2.000000e-07
GCST000804_6	Asthma	4.000000e-09
GCST000879_39	Crohn’s disease	3.000000e-19
GCST001725_49	Inflammatory bowel disease	6.000000e-16
GCST001806_21	Corneal structure	5.000000e-10
GCST002083_29	Self-reported allergy	1.000000e-08
GCST002322_8	Asthma and hay fever	4.000000e-09
GCST002392_1	Lung cancer (smoking interaction)	4.000000e-06
GCST003097_26	Pediatric autoimmune diseases	8.000000e-11
GCST003116_3	Coronary artery disease	5.000000e-09
GCST003117_34	Myocardial infarction	1.000000e-07
GCST003987_6	Asthma	2.000000e-21
GCST003990_22	Allergy	4.000000e-08
GCST004063_24	Waist circumference adjusted for body mass index	1.000000e-08
GCST004063_35	Waist circumference adjusted for body mass index	2.000000e-09
GCST004131_39	Inflammatory bowel disease	3.000000e-21
GCST004132_25	Crohn’s disease	2.000000e-19
GCST004133_64	Ulcerative colitis	2.000000e-08
GCST004144_10	Thyroid cancer	3.000000e-09
GCST004144_11	Thyroid cancer	5.000000e-09
GCST004413_1	Spontaneous dizygotic twinning	6.000000e-11
GCST004500_104	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-10
GCST004500_17	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	1.000000e-09
GCST004501_134	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	8.000000e-10
GCST004501_135	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	8.000000e-09
GCST004504_100	Waist circumference adjusted for BMI in non-smokers	4.000000e-06
GCST004504_99	Waist circumference adjusted for BMI in non-smokers	3.000000e-07
GCST004600_24	Eosinophil percentage of white cells	1.000000e-10
GCST004606_83	Eosinophil count	5.000000e-11
GCST004617_156	Eosinophil percentage of granulocytes	4.000000e-10

EFO canonical traits (32, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0006527	smoking status measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0008433	pursuit maintenance gain measurement
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0007785	femoral neck bone mineral density
EFO:0007701	spine bone mineral density
EFO:0009270	heel bone mineral density
EFO:0009959	diverticular disease
EFO:0004312	vital capacity
EFO:0005763	pulse pressure measurement
EFO:1002040	Corneal astigmatism
EFO:0004341	body fat distribution
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0009774	serine measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D003240	Connective Tissue Diseases	C17.300
D003324	Coronary Artery Disease	C14.280.647.250.260; C14.907.137.126.339; C14.907.585.250.260
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D055947	Loeys-Dietz Syndrome	C05.660.207.532; C14.907.055.239.587; C14.907.109.139.587; C16.131.077.537; C16.320.510
C562834	Aortic Aneurysm, Familial Thoracic 1 (supp.)
C567085	Aortic Aneurysm, Familial Thoracic 6 (supp.)
C565153	Coronary Artery Dissection, Spontaneous (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1293258 (SINGLE PROTEIN), CHEMBL3885604 (PROTEIN FAMILY), CHEMBL4296077 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 353,088 (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
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL6246	ELLAGIC ACID	2	23,148

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12913535	SMAD3		0.00	0

Binding affinities (BindingDB)

39 measured of 60 human assays (65 total across all organisms); most potent 39 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-[(4-benzofuro[3,2-d]pyrimidinylthio)methyl]-2-furancarboxylic acid methyl ester	IC50	57.8 nM
1,3,6-Trimethyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1610 nM
5-hydroxy-1H-indole-2-carboxylic acid	IC50	1770 nM
3-phenyl-9,10-phenanthrenedione	IC50	2000 nM
5-(4,4-dimethyl-2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)-5-oxidanyl-1,3-diazinane-2,4,6-trione	IC50	2300 nM
2-[(Z)-(3,4-dihydroxyphenyl)-(3-hydroxy-4-keto-cyclohexa-2,5-dien-1-ylidene)methyl]besylic acid	IC50	3280 nM
6-[4-morpholinyl-(2,3,4-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol	IC50	3970 nM
2-(3-hydroxy-6-oxo-6H-xanthen-9-yl)benzoic acid	IC50	4890 nM
6-[(2,3-dimethoxyphenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	6430 nM
6-[(4-methoxyphenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	6510 nM
6-[(2-hydroxyphenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	6960 nM
2-(7-chloranyl-1-methyl-2-oxidanylidene-quinolin-4-yl)sulfanyl-N-[(1-ethylpyrrolidin-2-yl)methyl]ethanamide	IC50	8700 nM
2-[1,3-bis(oxidanylidene)isoindol-2-yl]-N-[[(4-oxidanylidene-6-propyl-1H-pyrimidin-2-yl)amino]-phenylazanyl-methylidene]propanamide	IC50	8780 nM
8-bromo-2-(methoxymethyl)-3-methyl-4,5-dioxo-1-benzo[e]indolecarboxylic acid ethyl ester	IC50	8870 nM
6-[4-morpholinyl-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol	IC50	9660 nM
6-[(3-methoxy-4-oxidanyl-phenyl)-morpholin-4-yl-methyl]-1,3-benzodioxol-5-ol	IC50	10100 nM
MLS000046465	IC50	10200 nM
6-[(4-chlorophenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	10300 nM
8-bromo-2,3-dimethyl-4,5-dioxo-1-benzo[e]indolecarboxylic acid ethyl ester	IC50	10400 nM
2-(1-benzotriazolyl)-3-(4-morpholinyl)naphthalene-1,4-dione	EC50	10500 nM
(4Z)-2-nitro-4-[(2-thiazolylhydrazo)methylidene]-1-cyclohexa-2,5-dienone	IC50	10800 nM
2-[(6-amino-3,5-dicyano-4-p-phenetyl-2-pyridyl)thio]acetic acid butyl ester	IC50	11000 nM
MLS000046472	IC50	11100 nM
6-[(3,4-dimethoxyphenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	12200 nM
4,5,6,7-tetrachloro-3’,4’,5’,6’-tetrahydroxy-1-spiro[isobenzofuran-3,9’-xanthene]one	IC50	12400 nM
6-[1-piperidinyl-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol	IC50	12500 nM
6-[1,3-benzodioxol-5-yl-[4-[1,3-benzodioxol-5-yl-(6-hydroxy-1,3-benzodioxol-5-yl)methyl]-1-piperazinyl]methyl]-1,3-benzodioxol-5-ol	IC50	14100 nM
MLS000564159	IC50	14100 nM
6-[(4-methoxyphenyl)-(1-pyrrolidinyl)methyl]-1,3-benzodioxol-5-ol	IC50	14600 nM
(6E)-6-(4-pyrrolidin-1-yl-1H-quinazolin-2-ylidene)cyclohexa-2,4-dien-1-one	IC50	14600 nM
2-[(3-methylbenzyl)sulfanyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile	IC50	18500 nM
5-[(3-aminooxycarbonyl-4-hydroxy-phenyl)-(3-aminooxycarbonyl-4-keto-cyclohexa-2,5-dien-1-ylidene)methyl]-2-hydroxy-benzoic acid amino ester	IC50	22500 nM
6-[(4-fluorophenyl)-(1-pyrrolidinyl)methyl]-1,3-benzodioxol-5-ol	IC50	23300 nM
C-(1-Propyl-1,2,3,4-tetrahydro-quinolin-6-yl)-methylamine	IC50	24600 nM
(2E)-3-(4-methylphenyl)-2-(2,3,3-trichloro-1-nitroprop-2-enylidene)-1,3-thiazolidin-4-one	IC50	27600 nM
MLS000046765	IC50	27700 nM
6-[(2-methoxyphenyl)-(4-morpholinyl)methyl]-1,3-benzodioxol-5-ol	IC50	35300 nM
6-[(4-methoxyphenyl)-[4-[(4-methoxyphenyl)-(6-oxidanyl-1,3-benzodioxol-5-yl)methyl]piperazin-1-yl]methyl]-1,3-benzodioxol-5-ol	IC50	36100 nM
MLS000526075	IC50	109000 nM

ChEMBL bioactivities

38 potent at pChembl≥5 of 64 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.67	IC50	21.6	nM	CHEMBL6172244
7.52	IC50	30	nM	CHEMBL5271361
7.42	IC50	38	nM	CHEMBL601757
7.41	IC50	39	nM	CHEMBL1334062
7.17	IC50	68	nM	CHEMBL5410106
7.17	IC50	68	nM	CHEMBL5439266
7.05	IC50	90	nM	CHEMBL5280678
7.00	IC50	100	nM	CHEMBL5405214
6.93	IC50	118.5	nM	CHEMBL6142750
6.86	IC50	137	nM	CHEMBL3400936
6.85	IC50	140	nM	CHEMBL3400936
6.85	IC50	140	nM	CHEMBL5434170
6.85	IC50	142	nM	ELLAGIC ACID
6.63	IC50	236	nM	CHEMBL5267203
6.62	IC50	240	nM	CHEMBL5267203
6.62	IC50	240	nM	CHEMBL5403707
6.54	IC50	286.2	nM	CHEMBL6146464
6.11	IC50	771	nM	CHEMBL1484547
5.75	IC50	1770	nM	CHEMBL1368373
5.70	IC50	2000	nM	CHEMBL1498509
5.64	IC50	2300	nM	CHEMBL1460342
5.56	IC50	2729	nM	CHEMBL1502394
5.55	IC50	2815	nM	CHEMBL1550490
5.49	IC50	3277	nM	PYROCATECHOL VIOLET
5.40	IC50	3968	nM	CHEMBL1609907
5.39	IC50	4098	nM	CHEMBL1498705
5.31	IC50	4890	nM	FLUORESCEIN
5.19	IC50	6511	nM	CHEMBL1319324
5.19	IC50	6427	nM	CHEMBL1436701
5.16	IC50	6959	nM	CHEMBL1360077
5.06	IC50	8777	nM	CHEMBL1461262
5.06	IC50	8699	nM	CHEMBL1563062
5.02	IC50	9462	nM	CHEMBL1449293
5.01	IC50	9658	nM	CHEMBL1316752
5.00	IC50	9894	nM	CHEMBL417727
5.00	IC50	1.007e+04	nM	CHEMBL1554780

PubChem BioAssay actives

13 with measured affinity, of 85 total; 9 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
(9E)-16-chloro-13,15-dihydroxy-5,6,6,10-tetramethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0300	uM
(5R,6S,7S,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0680	uM
(5R,6S,7S,9Z)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0680	uM
(5R,6S,9E)-16-chloro-13,15-dihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0900	uM
(5R,6S,7R,9Z)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.1000	uM
(9E)-16-chloro-6,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.1370	uM
(5S,6S,7S,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.1400	uM
(5R,6S,7R,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.2360	uM
(5S,6S,7R,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.2400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases expression, affects reaction, increases reaction, decreases response to substance, decreases reaction (+2 more)	9
Estradiol	decreases expression, decreases reaction, affects expression, affects cotreatment, decreases phosphorylation (+1 more)	8
bisphenol A	decreases reaction, decreases expression, affects methylation, decreases phosphorylation, increases methylation (+3 more)	7
Cadmium Chloride	increases abundance, increases phosphorylation, affects cotreatment, increases localization, affects binding (+3 more)	7
Cadmium	decreases expression, decreases reaction, increases abundance, increases phosphorylation, affects cotreatment	6
Tretinoin	increases phosphorylation, increases reaction, decreases phosphorylation, increases expression, decreases expression (+1 more)	6
Acetylcysteine	affects cotreatment, decreases expression, decreases reaction, increases abundance, increases phosphorylation (+1 more)	5
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases abundance, affects cotreatment, increases expression, decreases reaction, increases phosphorylation (+4 more)	4
Valproic Acid	decreases expression, increases methylation	4
Resveratrol	decreases reaction, increases phosphorylation, decreases expression	3
Fulvestrant	affects cotreatment, affects methylation, decreases phosphorylation, decreases reaction, increases methylation	3
Cisplatin	affects cotreatment, decreases expression, increases expression	3
Progesterone	decreases expression, affects cotreatment, decreases activity, increases chemical synthesis, increases reaction (+1 more)	3
Tobacco Smoke Pollution	affects expression, increases expression, affects reaction, increases secretion	3
trichostatin A	affects expression, increases expression, increases reaction	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance	2
ochratoxin A	decreases reaction, increases expression, increases phosphorylation, affects reaction, increases response to substance	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
S-(1,2-dichlorovinyl)cysteine	decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride	increases phosphorylation, decreases activity, increases chemical synthesis, decreases response to substance, increases response to substance (+1 more)	2
4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide	decreases reaction, increases expression	2
LY2109761	decreases reaction, increases phosphorylation	2
Zoledronic Acid	decreases reaction, increases phosphorylation, increases expression	2
Acetaminophen	increases expression, decreases expression	2
Arsenic	increases reaction, increases expression, decreases reaction, affects cotreatment, decreases expression (+1 more)	2
Benzo(a)pyrene	affects methylation	2
Copper	affects binding, increases expression	2
Doxorubicin	decreases reaction, increases localization, decreases expression	2
Endosulfan	increases phosphorylation, decreases reaction, increases expression	2

ChEMBL screening assays

24 unique, capped per target: 18 binding, 6 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614060	Functional	PUBCHEM_BIOASSAY: SMAD Transcription Factor Inhibitors Secondary Dose Response Confirmation. (Class of assay: confirmatory) [Related pubchem assays: 715 (Primary dose response assay preceding this secondary confirmation assay.), 630 (Primar	PubChem BioAssay data set
CHEMBL2401266	Binding	Inhibition of TGF-beta-induced Smad3 phosphorylation in human MDA-MB-231 cells treated 12 hrs before TGF-beta challenge measured after 1 hr by Western blotting	Curcuminoids block TGF-β signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. — J Nat Prod

Cellosaurus cell lines

20 cell lines: 15 cancer cell line, 3 embryonic stem cell, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1266	HCC2998	Cancer cell line	Sex unspecified
CVCL_1G06	HROC69	Cancer cell line	Male
CVCL_1G07	HROC69 T0 M2	Cancer cell line	Male
CVCL_2478	HCT 8	Cancer cell line	Male
CVCL_4443	LIM2551	Cancer cell line	Male
CVCL_A6G6	SEES3-1V human SMAD3, clone1	Embryonic stem cell	Male
CVCL_A6G7	SEES3-1V human SMAD3, clone2	Embryonic stem cell	Male
CVCL_A6G8	SEES3-1V human SMAD3, clone3	Embryonic stem cell	Male
CVCL_A8CZ	HEK-Blue TGF-beta	Transformed cell line	Female
CVCL_B1HM	Abcam A-549 SMAD3 KO 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT00025766	PHASE4	COMPLETED	Angioplasty and Heart Stents to Treat Individuals With an Occluded Artery Following a Heart Attack
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00111566	PHASE4	COMPLETED	BRIEF-PCI: Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention
NCT00129038	PHASE4	COMPLETED	Modified-release Dipyridamole/Aspirin (200mg/25mg bd) Versus Aspirin (75mg) in Aspirin-resistant Patients
NCT00133003	PHASE4	COMPLETED	Abciximab, Clopidogrel and Percutaneous Coronary Intervention in Acute Coronary Syndrome (ISAR-REACT-2)
NCT00133237	PHASE4	COMPLETED	Drug-eluting-stents for Unprotected Left Main Stem Disease (ISAR-LEFT-MAIN)
NCT00133692	PHASE4	COMPLETED	INVEST: INternational VErapamil SR Trandolapril STudy
NCT00139386	PHASE4	COMPLETED	Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial
NCT00140465	PHASE4	COMPLETED	75 or 150 mg Clopidogrel Maintenance Doses Following PCI (ISAR-CHOICE-2)
NCT00140530	PHASE4	COMPLETED	Nonpolymer- and Polymer-Based Drug-Eluting Stents for Restenosis (ISAR-TEST-1)
NCT00146575	PHASE4	COMPLETED	Sirolimus- and Paclitaxel-Eluting Stents for Small Vessels (ISAR-SMART-3)
NCT00152308	PHASE4	TERMINATED	Non-Polymer-Based, Rapamycin-Eluting Stents to Prevent Restenosis
NCT00155350	PHASE4	UNKNOWN	Treatment of Coronary Atherosclerosis by Insulin Sensitizers in Insulin-Resistant Patients
NCT00162370	PHASE4	COMPLETED	A Study of Stress Echocardiography in Post-Menopausal Women at Risk for Coronary Disease
NCT00163202	PHASE4	COMPLETED	Comparative Atorvastatin Pleiotropic Effects
NCT00169819	PHASE4	COMPLETED	EArly Discharge After Transradial Stenting of CoronarY Arteries: The EASY Study
NCT00171275	PHASE4	COMPLETED	Fluvastatin in the Therapy of Acute Coronary Syndrome
NCT00175240	PHASE4	COMPLETED	Enhancing the Secondary Prevention of Coronary Artery Disease
NCT00180388	PHASE4	TERMINATED	VENEK: Healing in Different Vein Harvesting Methods During Aortocoronary Coronary Artery Bypass Graft Surgery (CABG)
NCT00180583	PHASE4	COMPLETED	Vision II: Evaluation of GALILEO Intravascular Radiotherapy System
NCT00189215	PHASE4	COMPLETED	Long-Term Cognitive Decline After Coronary Artery Bypass Grafting: is Off-Pump Surgery Beneficial?
NCT00200629	PHASE4	TERMINATED	Both Exercise and Adenosine Stress Testing
NCT00202904	PHASE4	COMPLETED	Effectiveness and Safety of Ezetimibe Added to Atorvastatin in Patients With High Cholesterol and Coronary Heart Disease (Study P03740)
NCT00209404	PHASE4	COMPLETED	Iodixanol in Multidetector-Row Computed Tomography-Coronary Angiography (MDCT-CA)
NCT00209430	PHASE4	COMPLETED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Coronary Angiography
NCT00220558	PHASE4	UNKNOWN	GISSOC II: Sirolimus Eluting Stent Versus Bare Metal Stent in Chronic Total Coronary Occlusions
NCT00222261	PHASE4	COMPLETED	Aspirin Non-responsiveness and Clopidogrel Endpoint Trial.
NCT00229528	PHASE4	COMPLETED	Effect of Paroxetine on COAT-Platelet Production in Normal Volunteers and Patients With Cardiovascular Disease
NCT00232804	PHASE4	COMPLETED	The BRIDGE Registry: Safety and Efficacy Registry of Bx Cypher Stent
NCT00232856	PHASE4	COMPLETED	A Study of the Cypher SES to Treat Restenotic Native Coronary Artery Lesions.
NCT00235066	PHASE4	COMPLETED	The CYPHER™ Stent Study in Patients With Small de Novo Coronary Artery Lesions.
NCT00235092	PHASE4	COMPLETED	The REALITY Study - Head-to-Head Comparison Between Cypher and Taxus
NCT00235950	PHASE4	COMPLETED	Assessment of the Lipid Lowering Effect of Rosuvastatin Compared to Atorvastatin in Subjects With Coronary Heart Disease
NCT00238004	PHASE4	UNKNOWN	The Low HDL On Six Weeks Statin Therapy (LOW) Study
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00242944	PHASE4	COMPLETED	Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS)
NCT00243477	PHASE4	COMPLETED	MOTIV Study- Effect of Antidepressive Treatment by Escitalopram in Patients Undergoing Coronary Artery Bypass Grafting