SMAD1

Summary

SMAD1 (SMAD family member 1, HGNC:6767) is a protein-coding gene on chromosome 4q31.21, encoding SMAD family member 1 (Q15797). Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis.

The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene ‘mothers against decapentaplegic’ (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed.

Source: NCBI Gene 4086 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_005900

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6767
Approved symbol	SMAD1
Name	SMAD family member 1
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Aliases	MADR1, JV4-1
Ensembl gene	ENSG00000170365
Ensembl biotype	protein_coding
OMIM	601595
Entrez	4086

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 31 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000302085, ENST00000394092, ENST00000502342, ENST00000503324, ENST00000506626, ENST00000507367, ENST00000507594, ENST00000510948, ENST00000511125, ENST00000511255, ENST00000512019, ENST00000514168, ENST00000514778, ENST00000514831, ENST00000515385, ENST00000515527, ENST00000885680, ENST00000885681, ENST00000885682, ENST00000885683, ENST00000885684, ENST00000885685, ENST00000885686, ENST00000885687, ENST00000885688, ENST00000885689, ENST00000885690, ENST00000885691, ENST00000919686, ENST00000919687, ENST00000919688, ENST00000919689, ENST00000957198, ENST00000957199, ENST00000957200, ENST00000957201, ENST00000957202, ENST00000957203

RefSeq mRNA: 8 — MANE Select: NM_005900 NM_001003688, NM_001354811, NM_001354812, NM_001354813, NM_001354814, NM_001354816, NM_001354817, NM_005900

CCDS: CCDS3765

Canonical transcript exons

ENST00000302085 — 7 exons

Exon	Start	End
ENSE00001143042	145542582	145542698
ENSE00001143049	145539804	145540061
ENSE00001415759	145481853	145482038
ENSE00003488150	145546703	145546924
ENSE00003518528	145553784	145554040
ENSE00003801137	145514438	145515013
ENSE00003849039	145557791	145559176

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 97.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.8667 / max 137.0050, expressed in 1693 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49908	6.9748	1566
49907	2.9782	1416
49906	1.5306	979
49905	1.4558	869
49915	0.9014	582
49909	0.8208	435
49903	0.5704	343
49910	0.2053	89
49904	0.1875	66
49911	0.1344	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.00	gold quality
nipple	UBERON:0002030	96.69	gold quality
corpus epididymis	UBERON:0004359	96.27	gold quality
oocyte	CL:0000023	96.12	gold quality
visceral pleura	UBERON:0002401	94.98	gold quality
urethra	UBERON:0000057	94.50	gold quality
mammalian vulva	UBERON:0000997	94.42	gold quality
sperm	CL:0000019	94.17	gold quality
vena cava	UBERON:0004087	93.98	gold quality
palpebral conjunctiva	UBERON:0001812	93.88	gold quality
penis	UBERON:0000989	93.62	gold quality
skin of hip	UBERON:0001554	93.35	gold quality
pericardium	UBERON:0002407	93.33	gold quality
endothelial cell	CL:0000115	93.24	gold quality
colonic epithelium	UBERON:0000397	93.22	gold quality
adult organism	UBERON:0007023	93.20	gold quality
seminal vesicle	UBERON:0000998	92.99	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.91	gold quality
endometrium	UBERON:0001295	92.33	gold quality
upper leg skin	UBERON:0004262	92.22	gold quality
male germ cell	CL:0000015	92.10	gold quality
jejunal mucosa	UBERON:0000399	91.84	gold quality
jejunum	UBERON:0002115	91.72	gold quality
parietal pleura	UBERON:0002400	91.69	gold quality
trachea	UBERON:0003126	91.41	gold quality
pleura	UBERON:0000977	91.28	gold quality
caput epididymis	UBERON:0004358	91.21	gold quality
thoracic mammary gland	UBERON:0005200	91.21	gold quality
mammary gland	UBERON:0001911	91.15	gold quality
mammary duct	UBERON:0001765	91.06	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	64.09
E-MTAB-8142	yes	41.19
E-MTAB-6701	yes	30.55
E-HCAD-1	yes	20.38
E-MTAB-6678	yes	13.37
E-MTAB-9067	yes	12.56
E-ANND-3	yes	11.45
E-CURD-46	yes	10.80
E-MTAB-8410	yes	9.29
E-CURD-122	yes	4.43
E-GEOD-130148	yes	4.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

102 targeting SMAD1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877

Literature-anchored findings (GeneRIF, showing 40)

• Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation. (PMID:11811554)
• overexpression of adenoviral Smad1 and Smad2 proteins without exogenously added ligands induced inhibin B production (PMID:12354674)
• a novel nuclear export signal in Smad1 is essential for its signaling activity (PMID:12821673)
• CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins. (PMID:14701756)
• Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. (PMID:14732718)
• Antiproliferative and prodifferentiation effects of BMP4 were Smad1 dependent with JNK also contributing to differentiation. (PMID:15516492)
• MAB21L2 immunoprecipitates in vivo with the BMP4 effector SMAD1, whilst in vitro it binds SMAD1 and the SMAD1-SMAD4 complex (PMID:15613244)
• In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1. (PMID:15877825)
• Smad1 signaling pathway plays a role in cardioprotection against I/R injury. (PMID:15911698)
• activation by BMP-2 in lung cancer cells (PMID:16247476)
• Data show that phosphophoryn (PP) up-regulates bone morphogenetic protein 2 gene expression 12 h post-treatment with PP, much later than initial detection of Smad1 phosphorylation at 30 min. (PMID:16326713)
• the PI3-K pathway negatively regulates TGF-beta/Smad signaling in neuroblastoma cells (PMID:16412560)
• Human granulosa-like tumor cell line KGN expressed BMP type I (BMPR1A and BMPR1B) and type II receptors (BMPR2) and the BMP signaling molecules SMADs (SMAD1 and SMAD5). (PMID:16436528)
• BMP-2 antagonizes Wnt-3a signaling in osteoblast progenitors by promoting an interaction between Smad1 and Dvl-1 that restricts beta-catenin activation (PMID:16621789)
• PPM1A plays an important role in controlling BMP signaling through catalyzing Smad1 dephosphorylation (PMID:16931515)
• The Smad1 shows a distinctive expression profile as embryonic stem (ES) cells undergo differentiation in the embryoid body (EB) system, with peak levels in cell populations enriched for the hemangioblast. (PMID:16990609)
• SMAD1(SIP1)is involved in the progression of pancreatic cancer and plays a role in mediating signal transduction from collagen type I to downregulate E-cadherin expression. (PMID:17043655)
• These data suggest autocrine TGF-beta1 antagonizes BMP signaling through modulation of inducible Smad6 and the activity of BMP specific Smad1/5. (PMID:17359969)
• WNK1 is a dual modulator of TGFbeta-Smad signaling pathways (PMID:17392271)
• analysis of a novel functional link between Mps1 and Smads in a non-canonical Smad signaling pathway (PMID:17452325)
• DNA microarray and real-time RT-PCR revealed that Smad1 expression was upregulated in MT1-MMP-expressing cells and rapidly growing tumors (PMID:17455258)
• Knockdown of Smad1 increased motility and abrogated endoglin’s effects (PMID:17496924)
• The results illustrate, for the first time, a role for Smad1 in the integration of spatial information and in the niche-size-dependent control of hESC self-renewal and differentiation. (PMID:17948051)
• ubiquitination level of pseudo-phosphorylated Smad1 by CHIP is stronger than that of wild-type Smad1 and can be strongly inhibited by a phosphorylated tail of Smad1 (PMID:17963781)
• intron 1 of the follistatin gene has a critical role in mediating Smad-dependent effects of activin and regulating the expression level of this gene (PMID:18184649)
• The shear-induced G(2)/M arrest and corresponding changes in G(2)/M regulatory protein expression and activity were mediated by alpha(v)beta(3) and beta(1) integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. (PMID:18310319)
• Data show that the expression of key transcription factors, phosphorylated Smad1 protein, and the nuclear accumulation of Smad1 and Smad4 are inhibited by Ubc9 silencing. (PMID:18321803)
• SMAD 2/3 signaling directly supports NANOG expression, while SMAD 1/5/8 activation moderately represses SOX2. (PMID:18393632)
• activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. (PMID:18668566)
• ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. (PMID:18684712)
• TGFbeta activates PI3K to downregulate PTEN for enhancement of cell proliferation that is independent of SMAD proteins (PMID:18769113)
• Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC (PMID:18775991)
• BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease. (PMID:19056927)
• TGFbeta-mediated Smad1 phosphorylation appears to occur via different receptor complexes in a cell type-specific manner (PMID:19224917)
• 5-HT transactivates the serine kinase receptor, BMPR 1A, to activate Smads 1/5/8 via Rho and Rho kinase in in bovine and human pulmonary artery smooth muscle cells (PMID:19244313)
• increases of p16(INK4a) and p21(WAF1/cip1) expression in response to BMP4 were mediated by the Smad1/5/8 signaling pathway. (PMID:19269967)
• cGKI has a dual function in BMP signalling: (1) it modulates BMP receptor/Smad activity at the plasma membrane and (2) after redistribution to the nucleus, it further regulates transcription as a nuclear co-factor for Smads. (PMID:19424179)
• Decreased phosphorylation of Smad1, induced by decreased BMPR-1B expression, correlated with the malignant grade of human gliomas and a poor prognosis. (PMID:19513897)
• Data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans. (PMID:19819941)
• BMP9 acts as a proliferative factor for immortalized ovarian surface epithelial cells and ovarian cancer cell lines, signaling predominantly through an ALK2/Smad1/Smad4 pathway, the major BMP9 receptor in endothelial cells. (PMID:19996292)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	smad1	ENSDARG00000027199
mus_musculus	Smad1	ENSMUSG00000031681
rattus_norvegicus	Smad1	ENSRNOG00000018483

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD9 (ENSG00000120693), SMAD6 (ENSG00000137834), SMAD4 (ENSG00000141646), SMAD3 (ENSG00000166949), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 1 — Q15797 (reviewed: Q15797)

Alternative names: JV4-1, Mad-related protein 1, Mothers against decapentaplegic homolog 1, Transforming growth factor-beta-signaling protein 1

All UniProt accessions (7): Q15797, A0A1D5RMR4, D6RAY1, D6RBH9, D6RD62, D6RDN7, D6REQ3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis. Upon BMP ligand binding to their receptors at the cell surface, is phosphorylated by activated type I BMP receptors (BMPRIs) and associates with SMAD4 to form a heteromeric complex which translocates into the nucleus acting as transcription factor. In turn, the hetero-trimeric complex recognizes cis-regulatory elements containing Smad Binding Elements (SBEs) to modulate the outcome of the signaling network. SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Positively regulates BMP4-induced expression of odontogenic development regulator MSX1 following IPO7-mediated nuclear import.

Subunit / interactions. Found in a complex with SMAD4 and YY1. Interacts with HGS, NANOG and ZCCHC12. Upon C-terminus phosphorylation: forms trimers with another SMAD1 and the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit, CREB-binding protein (CBP), p300, SMURF1, SMURF2, USP15 and HOXC8. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with SKOR1. Interacts (via MH2 domain) with LEMD3. Binding to LEMD3 results in at least a partial reduction of receptor-mediated phosphorylation. Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts (via MH2 domain) with FAM83G (via MH2 domain); in a SMAD4-independent manner. Interacts with ZC3H3. Interacts with TMEM119. Interacts (via MH1 and MH2 domains) with ZNF8. Interacts with RANBP3L; the interaction increases when SMAD1 is not phosphorylated and mediates SMAD1 nuclear export. Interacts with EGR1; this interaction inhibits SMAD1 dephosphorylation. Interacts with SMAD6. Interacts with YAP1. Interacts with MTMR4; negatively regulates BMP signaling through SMAD1 dephosphorylation and retention in endosomes.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Highest expression seen in the heart and skeletal muscle.

Post-translational modifications. Phosphorylation of the C-terminal SVS motif by BMP type 1 receptor kinase activates SMAD1 by promoting dissociation from the receptor and trimerization with SMAD4. Phosphorylation by ERK2 MAP kinase in response to EGF or HGF prevents SMAD1 nuclear accumulation and transcriptional activity in response to BMP. Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm. Dephosphorylation is inhibited by association with EGR1. Phosphorylation by CDK8/9 creates binding sites for YAP1, and subsequent phosphorylation by GSK3 switches off YAP1 binding and adds binding sites for SMURF1. Ubiquitinated by SMAD-specific E3 ubiquitin ligase SMURF1, leading to its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm. Phospho-SMAD1 is ubiquitinated by CHIP leading to disruption of the SMAD1-SMAD4 complex.

Disease relevance. SMAD1 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.

Domain organisation. The MH2 domain mediates phosphorylation-dependent trimerization through L3 loop binding of phosphoserines in the adjacent subunit.

Similarity. Belongs to the dwarfin/SMAD family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15797-1	1	yes
Q15797-2	2

RefSeq proteins (8): NP_001003688, NP_001341740, NP_001341741, NP_001341742, NP_001341743, NP_001341745, NP_001341746, NP_005891* (*=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 (55 total): strand 14, mutagenesis site 12, helix 7, binding site 4, modified residue 4, splice variant 4, domain 2, region of interest 2, turn 2, compositionally biased region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3Q4A	X-RAY DIFFRACTION	1.54
3Q47	X-RAY DIFFRACTION	1.71
1KHU	X-RAY DIFFRACTION	2.5
5ZOK	X-RAY DIFFRACTION	2.85
2LAW	SOLUTION NMR
2LAX	SOLUTION NMR
2LAY	SOLUTION NMR
2LAZ	SOLUTION NMR
2LB0	SOLUTION NMR
2LB1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15797-F1	81.76	0.64

Functional residue map

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

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

Post-translational modifications (4): 1, 322, 463, 465

Mutagenesis-validated functional residues (12):

Position	Phenotype
297	reduced trimerization.
317	reduced trimerization.
373	reduced trimerization.
418	reduced trimerization.
419	loss of phosphorylation.
424	reduced trimerization.
426	reduced trimerization.
448	reduced trimerization.
461	abolishes the formation of the chip-smad1 complex.
463–465	increases interaction with ranbpl3.
463–465	decreases interaction with ranbpl3.
464	abolishes the formation of the chip-smad1 complex.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8941326	RUNX2 regulates bone development
R-HSA-9733709	Cardiogenesis
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9006936	Signaling by TGFB family members
R-HSA-9843743	Transcriptional regulation of brown and beige adipocyte differentiation
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 471 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_DENDRITE_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, PAX4_01, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (44): MAPK cascade (GO:0000165), ossification (GO:0001503), osteoblast differentiation (GO:0001649), ureteric bud development (GO:0001657), mesodermal cell fate commitment (GO:0001710), osteoblast fate commitment (GO:0002051), cardiac conduction system development (GO:0003161), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), intracellular iron ion homeostasis (GO:0006879), inflammatory response (GO:0006954), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), gamete generation (GO:0007276), negative regulation of cell population proliferation (GO:0008285), anatomical structure morphogenesis (GO:0009653), embryonic pattern specification (GO:0009880), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), BMP signaling pathway (GO:0030509), midbrain development (GO:0030901), hindbrain development (GO:0030902), primary miRNA processing (GO:0031053), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of transcription by RNA polymerase II (GO:0045944), stem cell differentiation (GO:0048863), negative regulation of muscle cell differentiation (GO:0051148), cartilage development (GO:0051216), cardiac muscle cell proliferation (GO:0060038), bone development (GO:0060348), SMAD protein signal transduction (GO:0060395), positive regulation of cartilage development (GO:0061036), positive regulation of dendrite development (GO:1900006), positive regulation of miRNA transcription (GO:1902895), positive regulation of sprouting angiogenesis (GO:1903672), anti-Mullerian hormone receptor signaling pathway (GO:1990262), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), regulation of gene expression (GO:0010468)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), DEAD/H-box RNA helicase binding (GO:0017151), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), metal ion binding (GO:0046872), co-SMAD binding (GO:0070410), I-SMAD binding (GO:0070411), primary miRNA binding (GO:0070878), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (13): chromatin (GO:0000785), nucleus (GO:0005634), nuclear inner membrane (GO:0005637), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991), SMAD protein complex (GO:0071141), homomeric SMAD protein complex (GO:0071142), heteromeric SMAD protein complex (GO:0071144), male germ cell nucleus (GO:0001673), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Developmental Biology	2
Signaling by TGFB family members	1
Deubiquitination	1
Transcriptional regulation by RUNX2	1
Transcriptional regulation of brown and beige adipocyte differentiation	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Signal Transduction	1
Adipogenesis	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
gene expression	2
regulation of DNA-templated transcription	2
SMAD binding	2
cytoplasm	2
protein-containing complex	2
SMAD protein complex	2
intracellular signaling cassette	1
multicellular organismal process	1
ossification	1
cell differentiation	1
mesonephric tubule development	1
mesodermal cell differentiation	1
cell fate commitment involved in formation of primary germ layer	1
osteoblast differentiation	1
cell fate commitment	1
cardiac muscle tissue development	1
RNA biosynthetic process	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
sexual reproduction	1
multicellular organismal reproductive process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
developmental process	1
anatomical structure development	1
pattern specification process	1
embryo development	1

Protein interactions and networks

STRING

889 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD1	SMURF1	Q9HCE7	724
SMAD1	ZFYVE9	O95405	700
SMAD1	SMAD4	Q13485	626
SMAD1	BMP7	P18075	619
SMAD1	SMN1	Q16637	565
SMAD1	NUP214	P35658	552
SMAD1	FOXH1	O75593	532
SMAD1	DSPP	Q9NZW4	528
SMAD1	SKIL	P12756	521
SMAD1	PDCD4	Q53EL6	497
SMAD1	ZNF423	Q2M1K9	495
SMAD1	TGFB1	P01137	492
SMAD1	DDX5	P17844	490
SMAD1	SMAD2	Q15796	490
SMAD1	BMPR1A	P36894	485

IntAct

183 interactions, top by confidence:

A	B	Type	Score
CCNT1	CDK9	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
CCNC	CDK8	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
SMAD4	SMAD1	psi-mi:“MI:0407”(direct interaction)	0.960
SMAD1	SMAD4	psi-mi:“MI:0407”(direct interaction)	0.960
SMAD1	SMAD4	psi-mi:“MI:0915”(physical association)	0.960
SMAD4	SMAD1	psi-mi:“MI:0915”(physical association)	0.960
SMAD4	SMAD1	psi-mi:“MI:2364”(proximity)	0.960
FAM83G	CSNK1A1	psi-mi:“MI:0914”(association)	0.900
SMURF2	SMAD1	psi-mi:“MI:0407”(direct interaction)	0.850
SMAD1	SMURF2	psi-mi:“MI:0915”(physical association)	0.850
DROSHA	DDX5	psi-mi:“MI:0914”(association)	0.740
SMAD1	LEMD3	psi-mi:“MI:0915”(physical association)	0.740
SMAD1	SMAD1	psi-mi:“MI:0407”(direct interaction)	0.710
SMAD1	SMAD1	psi-mi:“MI:0915”(physical association)	0.710
SMAD1	PSMB4	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (326): SMAD1 (Biochemical Activity), LEF1 (Affinity Capture-Western), SMURF1 (Reconstituted Complex), SMAD1 (Biochemical Activity), SMAD1 (Affinity Capture-Western), PARD3 (Reconstituted Complex), SMAD1 (Affinity Capture-MS), GSK3B (Co-localization), GLI3 (Co-localization), SMAD7 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD1 (Reconstituted Complex), SMAD1 (Affinity Capture-Western), SMAD1 (Affinity Capture-Western), SMAD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A3G1DJJ7, A4H824, A4HWF0, B0DX25, B0XPZ9, C1IWT1, G4NB33, O15198, O36367, O75603, P03209, P03234, P0C765, P10471, P11625, P15130, P17523, P17524, P21944, P23984, P24433, P27445, P70340, P79943, P97588, Q00111, Q02362, Q06428, Q06658, Q0ZME3, Q14EA6, Q15797, Q18LF8, Q1HVC7, Q1HVG0, Q1JQA2, Q2HRB6, Q32LJ5, Q3KSP9, Q3KSS7

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, O43541

SIGNOR signaling

103 interactions.

A	Effect	B	Mechanism
SMAD1	“form complex”	SMAD1/4	binding
SMAD6	down-regulates	SMAD1	binding
SMURF2	“down-regulates quantity by destabilization”	SMAD1	ubiquitination
STUB1	down-regulates	SMAD1	ubiquitination
PDP1	down-regulates	SMAD1	dephosphorylation
PDP2	down-regulates	SMAD1	dephosphorylation
SMAD1	up-regulates	DVL1	binding
CTDSP1	down-regulates	SMAD1	dephosphorylation
CTDSP2	down-regulates	SMAD1	dephosphorylation
PPM1A	down-regulates	SMAD1	dephosphorylation
SMURF2	down-regulates	SMAD1	ubiquitination
SMAD7	down-regulates	SMAD1
GSK3B	down-regulates	SMAD1	phosphorylation
CDK9	down-regulates	SMAD1	phosphorylation
CDK9	“down-regulates quantity by destabilization”	SMAD1	phosphorylation
MAPK1	down-regulates	SMAD1	phosphorylation
MAPK1	“down-regulates activity”	SMAD1	phosphorylation
CDK8	down-regulates	SMAD1	phosphorylation
SMAD1	up-regulates	SMAD4	phosphorylation
SMAD1	up-regulates	SMAD4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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	6	26.6×	1e-05
Signaling by BMP	6	25.8×	1e-05
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	5	18.6×	4e-04
Transcriptional regulation by RUNX2	6	18.4×	5e-05
Signaling by TGF-beta Receptor Complex	7	16.9×	2e-05
GLI3 is processed to GLI3R by the proteasome	6	16.2×	1e-04
Ubiquitin-dependent degradation of Cyclin D	5	16.0×	6e-04
Hedgehog ‘on’ state	8	15.3×	7e-06

GO biological processes:

GO term	Partners	Fold	FDR
mismatch repair	5	31.2×	1e-04
positive regulation of miRNA transcription	7	19.6×	3e-05
BMP signaling pathway	8	15.4×	3e-05
positive regulation of transcription elongation by RNA polymerase II	5	14.5×	2e-03
somatic stem cell population maintenance	6	14.3×	6e-04
epidermal growth factor receptor signaling pathway	5	11.9×	4e-03
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	5	10.1×	7e-03
negative regulation of transforming growth factor beta receptor signaling pathway	6	10.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	3
Benign	20

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000047752 (4:145554312 C>A), RS1000079756 (4:145528473 C>T), RS1000098599 (4:145551194 A>C,G), RS1000105832 (4:145506133 G>A), RS1000140370 (4:145486221 G>A,T), RS1000186915 (4:145488093 T>C,G), RS1000197463 (4:145519889 T>C), RS1000254125 (4:145537312 GTATGTTACC>G), RS1000340203 (4:145482229 C>A,G,T), RS1000359010 (4:145525981 G>A), RS1000370637 (4:145481954 GCGCCCGGC>G), RS1000384793 (4:145488340 A>G), RS1000401524 (4:145524393 G>C), RS1000459022 (4:145530812 C>A,T), RS1000523027 (4:145486384 T>C)

Disease associations

OMIM: gene MIM:601595 | disease phenotypes: MIM:178600

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant
pulmonary arterial hypertension	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD
pulmonary arterial hypertension	Disputed	AD

Mondo (3): pulmonary hypertension, primary, 1 (MONDO:0024533), congenital heart disease (MONDO:0005453), pulmonary arterial hypertension (MONDO:0015924)

Orphanet (1): Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003469_6	Response to cognitive-behavioural therapy in anxiety disorder	5.000000e-06
GCST006481_16	Lung function (FEV1)	2.000000e-08
GCST006481_40	Lung function (FEV1)	2.000000e-07
GCST006621_3	Midgestational cytokine/chemokine levels (maternal genetic effect)	2.000000e-08
GCST009525_1	Panic disorder	3.000000e-07
GCST010242_446	HDL cholesterol levels	4.000000e-11
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11
GCST90002384_145	Hemoglobin	3.000000e-09
GCST90002404_88	Red cell distribution width	5.000000e-10

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0004314	forced expiratory volume
EFO:0004747	protein measurement
EFO:0005939	parental genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:0009412	interleukin-1 alpha measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004509	hemoglobin measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	7
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	decreases reaction, increases phosphorylation, increases reaction, decreases expression, increases expression	3
aristolochic acid I	decreases expression, decreases reaction	2
dorsomorphin	decreases reaction, increases phosphorylation, affects cotreatment, decreases expression	2
LY2109761	increases expression, decreases expression, decreases reaction, increases phosphorylation	2
Arsenic Trioxide	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
aucubin	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression, decreases reaction	1
sodium bisulfide	decreases reaction, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
galangin	increases expression, increases phosphorylation, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
casticin	increases expression	1
vanadium pentoxide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
sirtinol	decreases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
bisphenol S	affects cotreatment, increases expression	1
LDN 193189	decreases reaction, increases phosphorylation	1
Resveratrol	increases phosphorylation	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6G0	SEES3-1V human SMAD1, clone1	Embryonic stem cell	Male
CVCL_A6G1	SEES3-1V human SMAD1, clone2	Embryonic stem cell	Male
CVCL_A6G2	SEES3-1V human SMAD1, clone3	Embryonic stem cell	Male
CVCL_B2GH	Abcam HeLa SMAD1 KO	Cancer cell line	Female
CVCL_B9RY	Abcam A-549 SMAD1 KO	Cancer cell line	Male
CVCL_D8AN	Ubigene A-549 SMAD1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE