SMAD5

Summary

SMAD5 (SMAD family member 5, HGNC:6771) is a protein-coding gene on chromosome 5q31.1, encoding SMAD family member 5 (Q99717). Transcriptional regulator that plays a role in various cellular processes including embryonic development, cell differentiation, angiogenesis and tissue homeostasis.

The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4090 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 31 total
• Transcription factor: yes — 39 downstream targets (CollecTRI)
• MANE Select transcript: NM_005903

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6771
Approved symbol	SMAD5
Name	SMAD family member 5
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	Dwfc, JV5-1
Ensembl gene	ENSG00000113658
Ensembl biotype	protein_coding
OMIM	603110
Entrez	4090

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000506223, ENST00000507118, ENST00000507245, ENST00000507637, ENST00000509297, ENST00000509962, ENST00000511116, ENST00000513418, ENST00000514777, ENST00000515005, ENST00000545279, ENST00000545620, ENST00000865393, ENST00000865394, ENST00000865395, ENST00000865396, ENST00000865397, ENST00000865398, ENST00000925663, ENST00000925664, ENST00000925665, ENST00000925666, ENST00000925667, ENST00000953243, ENST00000953244

RefSeq mRNA: 3 — MANE Select: NM_005903 NM_001001419, NM_001001420, NM_005903

CCDS: CCDS75308

Canonical transcript exons

ENST00000545279 — 8 exons

Exon	Start	End
ENSE00001375348	136147832	136147906
ENSE00002232122	136177337	136182733
ENSE00003542635	136172434	136172655
ENSE00003558908	136174376	136174632
ENSE00003585794	136163272	136163391
ENSE00003658167	136160856	136161107
ENSE00003746319	136132845	136132962
ENSE00003791350	136153592	136154163

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.6161 / max 530.2786, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58710	35.7826	1806
58711	0.5160	228
58712	0.3175	135

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of paranasal sinus	UBERON:0005030	97.13	gold quality
caput epididymis	UBERON:0004358	97.00	gold quality
cauda epididymis	UBERON:0004360	96.92	gold quality
mammary duct	UBERON:0001765	96.65	gold quality
corpus epididymis	UBERON:0004359	96.15	gold quality
nipple	UBERON:0002030	96.14	gold quality
germinal epithelium of ovary	UBERON:0001304	95.92	gold quality
superficial temporal artery	UBERON:0001614	95.88	gold quality
calcaneal tendon	UBERON:0003701	95.75	gold quality
skin of hip	UBERON:0001554	95.58	gold quality
endothelial cell	CL:0000115	95.48	gold quality
urethra	UBERON:0000057	95.45	gold quality
secondary oocyte	CL:0000655	95.12	gold quality
colonic epithelium	UBERON:0000397	95.10	gold quality
tibia	UBERON:0000979	95.07	gold quality
upper leg skin	UBERON:0004262	95.03	gold quality
pericardium	UBERON:0002407	94.92	gold quality
parietal pleura	UBERON:0002400	94.83	gold quality
seminal vesicle	UBERON:0000998	94.77	gold quality
trigeminal ganglion	UBERON:0001675	94.74	gold quality
cardia of stomach	UBERON:0001162	94.62	gold quality
visceral pleura	UBERON:0002401	94.30	gold quality
oral cavity	UBERON:0000167	94.15	gold quality
penis	UBERON:0000989	93.97	gold quality
gingival epithelium	UBERON:0001949	93.95	gold quality
lower lobe of lung	UBERON:0008949	93.93	gold quality
saphenous vein	UBERON:0007318	93.90	gold quality
mammalian vulva	UBERON:0000997	93.87	gold quality
pylorus	UBERON:0001166	93.74	gold quality
superior surface of tongue	UBERON:0007371	93.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	7.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

39 targets.

Target	Regulation
AKT2	Unknown
ALPL	Activation
BGLAP	Activation
BIRC5	Repression
BMP2	Activation
BMP4
CASP3	Repression
CASP8	Repression
CDKN1A	Unknown
CDKN1B	Unknown
CSF1
DLX3	Unknown
DSG4	Unknown
DSPP	Activation
FAS	Repression
FASLG	Repression
GADD45G	Activation
GATA2	Unknown
GATA3	Activation
GTF2F2
HAND1	Activation
HEY1	Activation
HMOX1	Activation
ID1	Activation
ID2	Activation
ID3	Activation
KLF1
PDGFA
PPARG
PPP4C

JASPAR motifs

Motif	Name	Family
MA1557.1	SMAD5	SMAD factors

JASPAR matrix evidence (PMIDs): PMID:11527422

miRNA regulators (miRDB)

238 targeting SMAD5, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 40)

• regulatory signals are active at transcriptionally subnuclear sites (PMID:12060751)
• Smad5 activation by BMP4 in human hematopoietic cells results in significantly increased proliferation of erythroid progenitors and formation of glycophorin-A+ cells. (PMID:12064918)
• up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection (PMID:12473652)
• Results demonstrate a mitochondrial distribution of Smad5 in non-stimulated chondroprogenitor cells. (PMID:12849988)
• SMAD5 undergoes copy number gain and increased expression, rather than loss of expression, and therefore does not act as a tumor-suppressor gene in hepatocellular carcinoma (PMID:14670176)
• In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad5. (PMID:15877825)
• We used homology-modeling techniques to generate a reliable molecular model of the Smad5 MH1 domain based on the crystal structure of Smad3 MH1 domain (PMID:16243555)
• activation by BMP-2 in lung cancer cells (PMID:16247476)
• 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)
• These data suggest autocrine TGF-beta1 antagonizes BMP signaling through modulation of inducible Smad6 and the activity of BMP specific Smad1/5. (PMID:17359969)
• SMAD5 gene was found to be associated with schizophrenia. (PMID:18298822)
• 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)
• SMAD 2/3 signaling directly supports NANOG expression, while SMAD 1/5/8 activation moderately represses SOX2. (PMID:18393632)
• ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. (PMID:18684712)
• Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC (PMID:18775991)
• 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)
• 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)
• Studies indicate SMAD5beta isoform plays role in hematopoietic stem cell homeostasis. (PMID:20148926)
• Prostacyclin analogues inhibited smooth muscle cell proliferation and prevented progression of pulmonary hypertension while enhancing Smad1/5 phosphorylation and Id1 gene expression. (PMID:20522807)
• CHIP inhibits the signaling activities of Smad1/5 by recruiting Smad1/5 from the functional R-/Co-Smad complex and further promoting the ubiquitination/degradation of Smad1/5 in a chaperone-independent manner. (PMID:21454478)
• Results show that BMP4-induced changes in OvCa cell morphology and motility are Smad-dependent with shRNA targeting Smads 1, 4, and 5. (PMID:21945631)
• found that restoration of SMAD5, in addition to the TGF-beta type II receptor, which was epigenetically silenced by the latent viral protein latency-associated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-beta signaling (PMID:22013049)
• Data suggest that Smads 1, 5 and 8 as potential prognostic markers and therapeutic targets for mTOR inhibition therapy of prostate cancer. (PMID:22452883)
• TNF activated NF-kappaB pathway and inhibited the phosphorylation of Smad 1/5/8 and BMP-2-induced osteoblastic differentiation in BMMSCs (PMID:22897816)
• our studies establish that loss of SMAD1/5 leads to upregulation of PDGFA in ovarian granulosa cells (PMID:22964636)
• CD44 signaling regulates phosphorylation of RUNX2. Localization of RUNX2 in the nucleus requires phosphorylation of Smad-5 by integrin alphavbeta3 signaling. (PMID:22966907)
• ATP production by NaF promotes hypertrophy-like changes via activation of phospho-Smad5 (PMID:23384547)
• Oscillatory shear stress induces synergistic interactions between specific BMPRs and integrin to activate Smad1/5 through the Shc/FAK/ERK pathway (PMID:23387849)
• a detailed computational model for TGF-beta signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. (PMID:23804438)
• Results indicate that BMP/Smad signaling pathway was altered during the period of osteogenesis, and that the activities of p-Smad1/5 were required for Saos-2 cells viability and differentiation induced by fluoride. (PMID:23918166)
• the shear-induced apoptosis and autophagy are mediated by bone morphogenetic protein receptor type (BMPR)-IB, BMPR-specific Smad1 and Smad5, and p38 mitogen-activated protein kinase. (PMID:24021264)
• among the 15 SNPs, rs3206634 was significantly associated with KD in a recessive model (odds ratio = 2.31, p = 0.019), whereas there was no association between any of the 15 SNPs and CALs. (PMID:24163009)
• Specific gene siRNAs knock-down further confirmed the osteogenic effects of Genistein on BMP2, SMAD5 and RUNX2 protein expression (PMID:24339730)
• Inhibiting Smurf1 mediated ubiquitination of Smad1/5. (PMID:24828823)
• Our results indicated that KGN promoted the type-I collagen synthesis of dermal fibroblasts in vitro and in the dermis of mice through activation of the smad4/smad5 pathway. (PMID:24928394)
• balance between Smad1/5- and Smad2/3-dependent signaling defines the outcome of the effect of TGF-beta on atherosclerosis where Smad1/5 is responsible for proatherogenic effects (PMID:25505291)
• The polycomb group protein L3MBTL1 represses a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells. (PMID:25754204)
• adult human Sertoli cells assumed similar morphological features, stable global gene expression profiles and numerous proteins, and activation of AKT and SMAD1/5 during long-period culture. (PMID:25880873)
• Overexpression of the BMP4/SMAD4/SMAD5 signaling pathway could predict poor clinical outcome in skull base chordomas, suggesting activation of this pathway is involved in chordoma pathogenesis. (PMID:26339396)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smad5	ENSDARG00000037238
mus_musculus	Smad5	ENSMUSG00000021540
rattus_norvegicus	Smad5	ENSRNOG00000022870
caenorhabditis_elegans		WBGENE00000910

Paralogs (7): SMAD7 (ENSG00000101665), SMAD9 (ENSG00000120693), SMAD6 (ENSG00000137834), SMAD4 (ENSG00000141646), SMAD3 (ENSG00000166949), SMAD1 (ENSG00000170365), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 5 — Q99717 (reviewed: Q99717)

Alternative names: JV5-1, Mothers against decapentaplegic homolog 5

All UniProt accessions (7): D6R9D4, D6RBB4, D6RIZ9, Q99717, H0YAK7, H0YAM3, Q68DB7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that plays a role in various cellular processes including embryonic development, cell differentiation, angiogenesis 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. Non-phosphorylated SMAD5 has a cytoplasmic role in energy metabolism regulation by promoting mitochondrial respiration and glycolysis in response to cytoplasmic pH changes. Mechanistically, interacts with hexokinase 1/HK1 and thereby accelerates glycolysis.

Subunit / interactions. Homodimer. Forms trimers with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit and SMURF1. Interacts with SUV39H1 and SUV39H2. Interacts (via MH2 domain) with LEMD3. Interacts with WWP1. Interacts with TMEM119. Interacts with ZNF8. Interacts with RANBP3L. Interacts with HK1. Interacts with HGS; this interaction attenuates BMP signaling.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase. Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.

Similarity. Belongs to the dwarfin/SMAD family.

RefSeq proteins (3): NP_001001419, NP_001001420, NP_005894* (*=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 (34 total): helix 7, strand 7, binding site 4, compositionally biased region 4, modified residue 3, sequence conflict 3, domain 2, initiator methionine 1, chain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6FZS	X-RAY DIFFRACTION	2.31
6TCE	X-RAY DIFFRACTION	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99717-F1	81.55	0.65

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): 110; 122; 127; 65

Post-translational modifications (3): 2, 463, 465

Mutagenesis-validated functional residues (1):

Position	Phenotype
419	loss of phosphorylation and interaction with smad4.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-162582	Signal Transduction
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 368 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, RRAGTTGT_UNKNOWN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A

GO Biological Process (34): osteoblast differentiation (GO:0001649), ureteric bud development (GO:0001657), Mullerian duct regression (GO:0001880), osteoblast fate commitment (GO:0002051), cardiac conduction system development (GO:0003161), regulation of transcription by RNA polymerase II (GO:0006357), intracellular iron ion homeostasis (GO:0006879), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), germ cell development (GO:0007281), anatomical structure morphogenesis (GO:0009653), embryonic pattern specification (GO:0009880), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), erythrocyte differentiation (GO:0030218), BMP signaling pathway (GO:0030509), negative regulation of apoptotic process (GO:0043066), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), stem cell differentiation (GO:0048863), cartilage development (GO:0051216), cardiac muscle contraction (GO:0060048), bone development (GO:0060348), SMAD protein signal transduction (GO:0060395), negative regulation of Fas signaling pathway (GO:1902045), anti-Mullerian hormone receptor signaling pathway (GO:1990262), negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), developmental process (GO:0032502), cellular response to growth factor stimulus (GO:0071363), transforming growth factor beta receptor superfamily signaling pathway (GO:0141091)

GO Molecular Function (12): 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), DEAD/H-box RNA helicase binding (GO:0017151), ubiquitin protein ligase binding (GO:0031625), metal ion binding (GO:0046872), I-SMAD binding (GO:0070411), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (11): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), protein-containing complex (GO:0032991), SMAD protein complex (GO:0071141), heteromeric SMAD protein complex (GO:0071144), male germ cell nucleus (GO:0001673), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
developmental process involved in reproduction	2
osteoblast differentiation	2
transcription by RNA polymerase II	2
transforming growth factor beta receptor superfamily signaling pathway	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
protein-containing complex	2
ossification	1
cell differentiation	1
mesonephric tubule development	1
male sex differentiation	1
anatomical structure regression	1
cell fate commitment	1
cardiac muscle tissue development	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	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
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
developmental process	1
anatomical structure development	1
pattern specification process	1
embryo development	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
cellular developmental process	1
myeloid cell differentiation	1
erythrocyte homeostasis	1

Protein interactions and networks

STRING

1896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD5	SMAD4	Q13485	988
SMAD5	SMAD9	O15198	958
SMAD5	SMURF1	Q9HCE7	923
SMAD5	SMAD3	P84022	904
SMAD5	ACVR1	Q04771	876
SMAD5	BMPR1A	P36894	872
SMAD5	SMAD2	Q15796	871
SMAD5	ACVRL1	P37023	859
SMAD5	DDX5	P17844	836
SMAD5	BMPR2	Q13873	831
SMAD5	BMP7	P18075	826
SMAD5	BMP2	P12643	820
SMAD5	TGFB1	P01137	815
SMAD5	BMP4	P12644	814
SMAD5	BMPR1B	P78366	806

IntAct

66 interactions, top by confidence:

A	B	Type	Score
DROSHA	DDX5	psi-mi:“MI:0914”(association)	0.740
SMAD5	SMURF2	psi-mi:“MI:0915”(physical association)	0.660
DDX5	SMAD1	psi-mi:“MI:0914”(association)	0.610
SMURF2	NEDD4	psi-mi:“MI:0914”(association)	0.590
DDX5	SMAD5	psi-mi:“MI:0915”(physical association)	0.560
SMAD5	DDX5	psi-mi:“MI:0914”(association)	0.560
POU6F2	SMAD5	psi-mi:“MI:0915”(physical association)	0.560
WBP2	SMAD5	psi-mi:“MI:0915”(physical association)	0.560
SMAD5	KLK6	psi-mi:“MI:0915”(physical association)	0.560
SMAD5	LITAF	psi-mi:“MI:0915”(physical association)	0.560
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
SSMEM1	NDUFA7	psi-mi:“MI:0914”(association)	0.530
TMEM192	STXBP3	psi-mi:“MI:0914”(association)	0.530
SMAD5	RUNX2	psi-mi:“MI:0915”(physical association)	0.400
SMAD5	SMURF1	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	CXXC5	psi-mi:“MI:0915”(physical association)	0.370
SOX7	SMAD5	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	PTPN12	psi-mi:“MI:0915”(physical association)	0.370
SF3B1	SMAD5	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	MTMR10	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	PNKP	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	SFPQ	psi-mi:“MI:0915”(physical association)	0.370
SNRPA	SMAD5	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	PSMD11	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (125): SMAD5 (Biochemical Activity), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-MS), SMAD5 (Two-hybrid), WBP2 (Two-hybrid), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-MS), SMAD5 (Affinity Capture-Western), TAF12 (Affinity Capture-MS), MED24 (Affinity Capture-MS), MED29 (Affinity Capture-MS), SMAD5 (Affinity Capture-RNA)

ESM2 similar proteins: A2AVJ0, F4IXJ7, F5H9W9, O00712, O41804, O75603, P09265, P0CK37, P0CK38, P0CO74, P0CO75, P13622, P13623, P17924, P17926, P21740, P36714, P53963, P70255, P70257, P97454, P97863, Q00041, Q01769, Q02362, Q02780, Q04360, Q0VCL6, Q14938, Q1HVH2, Q1PDC6, Q2HR75, Q3KSU1, Q4JQW5, Q56I99, Q56XX3, Q5K2K5, Q5K2K6, Q5R6H7, Q6AYM7

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

27 interactions.

A	Effect	B	Mechanism
SMURF2	“down-regulates quantity by destabilization”	SMAD5	ubiquitination
SMAD5	up-regulates	SMAD4	phosphorylation
STUB1	down-regulates	SMAD5	ubiquitination
BMPR1A	up-regulates	SMAD5	phosphorylation
BMPR1B	up-regulates	SMAD5	phosphorylation
SMURF2	down-regulates	SMAD5	ubiquitination
BMP2	up-regulates	SMAD5
SMURF1	down-regulates	SMAD5	ubiquitination
BMPR1B	“up-regulates activity”	SMAD5	phosphorylation
BMPR1A	“up-regulates activity”	SMAD5	phosphorylation
SMAD5	“form complex”	SMAD5/SMAD4	binding
SMURF	down-regulates	SMAD5	ubiquitination
ROCK1	“up-regulates activity”	SMAD5	phosphorylation
ACVR1	up-regulates	SMAD5	phosphorylation
SKI	down-regulates	SMAD5	binding
SKIL	down-regulates	SMAD5	binding
BMPR1A	up-regulates	SMAD5
BMPR1B	up-regulates	SMAD5
ACVR1	up-regulates	SMAD5
SMAD5	up-regulates	Differentiation
SMAD5	“up-regulates quantity”	SATB2	“transcriptional regulation”
SMAD5	“up-regulates quantity”	SMAD6	“transcriptional regulation”
SMAD5	“up-regulates quantity”	HAND1	“transcriptional regulation”
SMAD5	“up-regulates quantity”	GADD45G	“transcriptional regulation”
SMAD5	“up-regulates quantity”	GATA3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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
mRNA Polyadenylation	6	11.2×	2e-03
mRNA Splicing - Major Pathway	7	8.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
BMP signaling pathway	6	21.1×	2e-04
mRNA splicing, via spliceosome	6	9.6×	4e-03
ubiquitin-dependent protein catabolic process	6	7.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1817 predictions. Top by Δscore:

Variant	Effect	Δscore
5:136132959:GCGA:G	donor_gain	1.0000
5:136132960:CGAGT:C	donor_loss	1.0000
5:136132961:GA:G	donor_gain	1.0000
5:136132961:GAGT:G	donor_loss	1.0000
5:136132962:AG:A	donor_loss	1.0000
5:136132963:G:GG	donor_gain	1.0000
5:136132963:GT:G	donor_loss	1.0000
5:136132965:GAGT:G	donor_loss	1.0000
5:136132967:G:GG	donor_gain	1.0000
5:136163267:CTTA:C	acceptor_loss	1.0000
5:136163268:TTAG:T	acceptor_loss	1.0000
5:136163270:A:AG	acceptor_gain	1.0000
5:136163270:AGC:A	acceptor_loss	1.0000
5:136163270:AGCT:A	acceptor_gain	1.0000
5:136163271:G:GC	acceptor_gain	1.0000
5:136163271:GC:G	acceptor_gain	1.0000
5:136163271:GCT:G	acceptor_gain	1.0000
5:136163271:GCTG:G	acceptor_gain	1.0000
5:136163271:GCTGA:G	acceptor_gain	1.0000
5:136163389:GGG:G	donor_gain	1.0000
5:136163390:GG:G	donor_gain	1.0000
5:136163390:GGG:G	donor_gain	1.0000
5:136163391:GG:G	donor_gain	1.0000
5:136163391:GGTAA:G	donor_loss	1.0000
5:136163392:G:GG	donor_gain	1.0000
5:136163393:T:A	donor_loss	1.0000
5:136163398:G:GT	donor_gain	1.0000
5:136172420:T:TA	acceptor_gain	1.0000
5:136172429:CACA:C	acceptor_loss	1.0000
5:136172430:ACAG:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000141699 (5:136147020 T>C), RS1000155697 (5:136177953 G>A), RS1000191522 (5:136162788 A>G), RS1000205842 (5:136131772 T>G), RS1000215877 (5:136173670 T>A,C), RS1000381988 (5:136169822 G>A), RS1000382397 (5:136152939 C>T), RS1000383038 (5:136176619 G>A), RS1000454838 (5:136136445 A>G), RS1000516236 (5:136149744 A>T), RS1000541697 (5:136179326 GAAA>G,GAA,GAAAA), RS1000570528 (5:136135175 A>G), RS1000838100 (5:136166138 A>G), RS1000842028 (5:136174858 A>T), RS1000927457 (5:136182032 A>G,T)

Disease associations

OMIM: gene MIM:603110 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007387_46	Insomnia symptoms (never/rarely vs. sometimes/usually)	1.000000e-07
GCST007388_34	Insomnia symptoms (never/rarely vs. usually)	3.000000e-12
GCST007559_10	Sleep duration (short sleep)	8.000000e-10
GCST90002395_462	Mean platelet volume	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007876	insomnia measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	3
Aflatoxin B1	decreases methylation, increases expression, increases methylation	3
Cadmium Chloride	decreases expression, decreases methylation, increases abundance, increases expression	3
sodium arsenite	decreases expression, decreases reaction, increases phosphorylation, increases reaction	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression, decreases reaction	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
aucubin	increases expression	1
bisphenol A	decreases expression	1
dimethylselenide	increases expression, increases oxidation	1
beta-lapachone	decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
1-UFT protocol	decreases response to substance	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
sirtinol	decreases phosphorylation	1
pyrachlostrobin	increases expression	1
dorsomorphin	decreases reaction, increases phosphorylation	1
LDN 193189	increases phosphorylation, decreases reaction	1
picoxystrobin	increases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	increases phosphorylation	1
Leflunomide	increases expression	1
Bexarotene	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Allergens	affects cotreatment, decreases expression	1
Arsenic	affects expression	1

Cellosaurus cell lines

9 cell lines: 4 cancer cell line, 3 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6H2	SEES3-1V human SMAD5, clone1	Embryonic stem cell	Male
CVCL_A6H3	SEES3-1V human SMAD5, clone2	Embryonic stem cell	Male
CVCL_A6H4	SEES3-1V human SMAD5, clone3	Embryonic stem cell	Male
CVCL_B1BI	Abcam HEK293 SMAD5 KO	Transformed cell line	Female
CVCL_B9S1	Abcam A-549 SMAD5 KO	Cancer cell line	Male
CVCL_D8AS	Ubigene A-549 SMAD5 KO	Cancer cell line	Male
CVCL_D8VJ	Ubigene HCT 116 SMAD5 KO	Cancer cell line	Male
CVCL_D9S9	Ubigene HEK293 SMAD5 KO	Transformed cell line	Female
CVCL_E0PB	Ubigene HeLa SMAD5 KO	Cancer cell line	Female

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