SMAD4 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human SMAD4 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene SMAD4, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene SMAD4, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene SMAD4 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene SMAD4 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene SMAD4, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene SMAD4, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene SMAD4, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene SMAD4 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene SMAD4, summarize transcription factor regulatory data. If SMAD4 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate SMAD4 — names with evidence type (ChIP-seq / predicted / experimentally validated) If SMAD4 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene SMAD4 protein as a drug target, summarize pharmacology data. If SMAD4 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If SMAD4 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene SMAD4, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene SMAD4, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in SMAD4: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
SMAD4 (HGNC:6770, chromosome 18q21) is the central co-SMAD in TGF-β/BMP signaling, functioning as the obligate transcriptional mediator that partners with receptor-activated SMADs to control cell growth, differentiation, and development. Its clinical importance is defined primarily by its role as a tumor suppressor: germline mutations cause autosomal dominant juvenile polyposis syndrome, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, and Myhre syndrome, while somatic loss is associated with pancreatic, colorectal, gastric, and several other carcinomas. The protein is ubiquitously expressed across 288 tissue conditions (average expression score 88.1), consistent with its broad developmental roles spanning cardiogenesis, germ layer formation, and stem cell pluripotency across 21 Reactome pathways. AlphaMissense predicts over 1,300 likely-pathogenic missense variants, and ClinVar records approximately 2,571 variants in total, underscoring its mutational sensitivity. Despite being well-characterized structurally (12 PDB entries) and biologically, SMAD4 has no approved drugs or clinical-stage therapeutics targeting it directly.
Gene identifiers
| Field | Value |
|---|---|
| HGNC ID | HGNC:6770 |
| Approved symbol | SMAD4 |
| Ensembl gene ID | ENSG00000141646 |
| NCBI Entrez Gene ID | 4089 |
| OMIM gene/locus ID | 600993 |
| Chromosome | 18 |
| Start position (GRCh38) | 51,028,528 |
| End position (GRCh38) | 51,085,045 |
| Strand | + (forward) |
Transcript identifiers
Ensembl Transcripts
Total: 49 ENST IDs
| ENST ID | Biotype |
|---|---|
| ENST00000342988 | protein_coding |
| ENST00000398417 | protein_coding |
| ENST00000585448 | retained_intron |
| ENST00000586253 | retained_intron |
| ENST00000588745 | protein_coding |
| ENST00000588860 | protein_coding |
| ENST00000589076 | protein_coding |
| ENST00000589706 | retained_intron |
| ENST00000589941 | protein_coding |
| ENST00000590061 | protein_coding |
| ENST00000590499 | retained_intron |
| ENST00000591126 | retained_intron |
| ENST00000592186 | nonsense_mediated_decay |
| ENST00000592911 | protein_coding_CDS_not_defined |
| ENST00000593223 | protein_coding |
| ENST00000611848 | nonsense_mediated_decay |
| ENST00000684953 | retained_intron |
| ENST00000685090 | retained_intron |
| ENST00000685232 | retained_intron |
| ENST00000688307 | retained_intron |
| ENST00000688574 | retained_intron |
| ENST00000688903 | retained_intron |
| ENST00000690892 | retained_intron |
| ENST00000691124 | retained_intron |
| ENST00000714260 | nonsense_mediated_decay |
| ENST00000714261 | protein_coding |
| ENST00000714262 | nonsense_mediated_decay |
| ENST00000714263 | nonsense_mediated_decay |
| ENST00000714264 | protein_coding |
| ENST00000714265 | nonsense_mediated_decay |
| ENST00000714266 | protein_coding |
| ENST00000714267 | nonsense_mediated_decay |
| ENST00000714268 | protein_coding |
| ENST00000714269 | protein_coding |
| ENST00000714270 | protein_coding |
| ENST00000714271 | nonsense_mediated_decay |
| ENST00000714272 | protein_coding |
| ENST00000714273 | nonsense_mediated_decay |
| ENST00000714274 | nonsense_mediated_decay |
| ENST00000877432 | protein_coding |
| ENST00000877433 | protein_coding |
| ENST00000932317 | protein_coding |
| ENST00000932318 | protein_coding |
| ENST00000932319 | protein_coding |
| ENST00000971068 | protein_coding |
| ENST00000971069 | protein_coding |
| ENST00000971070 | protein_coding |
| ENST00000971071 | protein_coding |
| ENST00000971072 | protein_coding |
RefSeq mRNA Transcripts
| NM Accession | MANE Select |
|---|---|
| NM_005359 | ✓ Yes |
| NM_001364967 | — |
| NM_001364968 | — |
| NM_001407041 | — |
| NM_001407042 | — |
| NM_001407043 | — |
| NM_019275 | — |
CCDS ID
CCDS11950
MANE SELECT Transcript Exons
ENST00000342988 (NM_005359) - 12 exons
| Exon ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00003669145 | 51046920 | 51047295 | + | 18 |
| ENSE00002877760 | 51048686 | 51048860 | + | 18 |
| ENSE00004013734 | 51049295 | 51049324 | + | 18 |
| ENSE00004013729 | 51054781 | 51054993 | + | 18 |
| ENSE00004013735 | 51058340 | 51058456 | + | 18 |
| ENSE00004013736 | 51058125 | 51058244 | + | 18 |
| ENSE00004013731 | 51065423 | 51065606 | + | 18 |
| ENSE00004013728 | 51067019 | 51067187 | + | 18 |
| ENSE00004013730 | 51076638 | 51076776 | + | 18 |
| ENSE00004013727 | 51059866 | 51059916 | + | 18 |
| ENSE00004013733 | 51078256 | 51085042 | + | 18 |
| ENSE00004023391 | 51030213 | 51030623 | + | 18 |
Protein identifiers
UniProt Accessions
Canonical (Reviewed):
- Q13485 ✓ (SwissProt reviewed)
Unreviewed isoforms/alternative entries:
- A0A024R274
- A0A087WUF3
- A0AAQ5BHQ0
- A0AAQ5BHQ2
- A0AAQ5BHS5
- A0AAQ5BHS9
- A0AAQ5BHT7
- A0AAQ5BHU0
- A0AAQ5BHU1
- A0AAQ5BHU2
- A0AAQ5BHU9
- A0AAQ5BHV1
- A0AAQ5BHV2
- A0AAQ5BHV5
- A0AAQ5BHW2
- A0AAQ5BHY6
- A0AAQ5BHZ6
- K7EIJ2
- K7EIU8
- K7EL15
- K7EL18
- K7ELK2
- K7ENG1
- K7ES96
RefSeq Proteins (NP_/XP_ accessions)
Reviewed/MANE Select:
- NP_005350 (MANE SELECT, canonical)
- NP_001393970
- NP_001393971
- NP_001393972
Validated:
- NP_001351896
- NP_001351897
- NP_032566
- NP_062148
Predicted:
- XP_006525764
- XP_011245157
Protein Domains and Families
InterPro:
- IPR001132: SMAD domain (Domain)
- IPR003619: MAD homology 1, Dwarfin-type (Domain)
- IPR008984: SMAD/FHA domain superfamily (Homologous superfamily)
- IPR013019: MAD homology, MH1 (Domain)
- IPR013790: SMAD/Dwarfins (Family)
- IPR017855: SMAD-like domain superfamily (Homologous superfamily)
- IPR036578: SMAD MH1 domain superfamily (Homologous superfamily)
Pfam:
- PF03165
- PF03166
SMART:
- SM00523
- SM00524
CDD (Conserved Domain Database):
- CD10492
- CD10498
PANTHER:
- PTHR13703
- PTHR13703:SF63
Antibody Availability
No antibody resources found in biobtree for Q13485. Direct lookup via external antibody databases recommended (e.g., AbCam, Santa Cruz, Origene, Sigma-Aldrich).
Structure
Experimental Structures
Total: 12 PDB structures (all X-ray diffraction)
| PDB ID | Title | Method | Resolution (Å) |
|---|---|---|---|
| 1DD1 | CRYSTAL STRUCTURE ANALYSIS OF THE SMAD4 ACTIVE FRAGMENT | X-ray | 2.62 |
| 1G88 | S4AFL3ARG515 MUTANT | X-ray | 3.00 |
| 1MR1 | Crystal Structure of a Smad4-Ski Complex | X-ray | 2.85 |
| 1U7F | Crystal Structure of the phosphorylated Smad3/Smad4 heterotrimeric complex | X-ray | 2.60 |
| 1U7V | Crystal Structure of the phosphorylated Smad2/Smad4 heterotrimeric complex | X-ray | 2.70 |
| 1YGS | CRYSTAL STRUCTURE OF THE SMAD4 TUMOR SUPPRESSOR C-TERMINAL DOMAIN | X-ray | 2.10 |
| 5C4V | Ski-like protein | X-ray | 2.60 |
| 5MEY | Crystal structure of Smad4-MH1 bound to the GGCGC site | X-ray | 2.05 |
| 5MEZ | Crystal structure of Smad4-MH1 bound to the GGCT site | X-ray | 2.98 |
| 5MF0 | Crystal structure of Smad4-MH1 bound to the GGCCG site | X-ray | 3.03 |
| 5UWU | Crystal Structure of SMAD4 NES Peptide in complex with CRM1-Ran-RanBP1 | X-ray | 2.24 |
| 6YIC | 14-3-3 sigma in complex with SMAD4 pS403 peptide | X-ray | 1.60 |
Predicted Structures
AlphaFold2 Model
- Model ID: Q13485
- pLDDT (global): 74.56
- Fraction with pLDDT ≥90 (very high confidence): 53.0%
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000024515 | Smad4 |
| Rat (Rattus norvegicus) | ENSRNOG00000051965 | Smad4 |
| Zebrafish (Danio rerio) | ENSDARG00000012649, ENSDARG00000075226 | smad4b, smad4a |
| Fruit fly (Drosophila melanogaster) | FBGN0020493 | Dad |
| Worm (C. elegans) | WBGENE00000910, WBGENE00006445 | daf-14, tag-68 |
| Yeast (S. cerevisiae) | none | — |
Clinical variants & AI predictions
Clinical Variants (ClinVar)
Summary
- Total variants: ~2,571
- Classifications from sample data:
- Pathogenic: 9
- Likely Pathogenic: 3
- Uncertain Significance: 70+
- Benign/Likely Benign: 15+
- Conflicting: 1
Top 30 Pathogenic/Likely Pathogenic Variants
| ClinVar ID | HGVS Notation | Variant Type | Classification | Associated Condition |
|---|---|---|---|---|
| 1070021 | NC_000018.9:g.(?48604616)(48604837_?)del | Deletion | Pathogenic | – |
| 1070022 | NC_000018.9:g.(?48593383)(48604842_?)del | Deletion | Pathogenic | – |
| 1073157 | NM_005359.6(SMAD4):c.620del (p.Asn207fs) | Deletion | Pathogenic | – |
| 1074223 | NM_005359.6(SMAD4):c.779dup (p.Tyr260Ter) | Duplication | Pathogenic | – |
| 1074875 | NM_005359.6(SMAD4):c.223del (p.Gln75fs) | Deletion | Pathogenic | – |
| 1075033 | NM_005359.6(SMAD4):c.1494dup (p.Cys499fs) | Duplication | Pathogenic | – |
| 1076671 | NM_005359.6(SMAD4):c.968G>A (p.Trp323Ter) | SNV | Pathogenic | – |
| 1076948 | NM_005359.6(SMAD4):c.563del (p.Asn188fs) | Deletion | Pathogenic | – |
| 1050635 | NM_005359.6(SMAD4):c.733C>T (p.Gln245Ter) | SNV | Pathogenic | – |
| 1032991 | NM_005359.6(SMAD4):c.803_804insCTAAGTGGTAGTA (p.Trp268delinsCysTer) | Insertion | Likely Pathogenic | – |
| 1066208 | NM_005359.6(SMAD4):c.1149A>G (p.Ile383Met) | SNV | Likely Pathogenic | – |
| 1067853 | NM_005359.6(SMAD4):c.1308+2T>G | SNV | Likely Pathogenic | – |
AI-Based Variant Effect Predictions
AlphaMissense Pathogenicity Scores
Summary
- Total predictions: 3,631
- Likely pathogenic: 1,300+ (filtered subset shown; first 100 displayed here)
Top 30 Likely-Pathogenic Missense Variants
| Genomic Coordinate | Protein Change | Score | Class |
|---|---|---|---|
| 18:51047090:C:A | A15D | 1.000 | likely_pathogenic |
| 18:51047107:C:G | H21D | 1.000 | likely_pathogenic |
| 18:51047098:A:C | S18R | 1.000 | likely_pathogenic |
| 18:51047100:C:A | S18R | 1.000 | likely_pathogenic |
| 18:51047100:C:G | S18R | 1.000 | likely_pathogenic |
| 18:51047102:T:A | I19N | 1.000 | likely_pathogenic |
| 18:51047102:T:G | I19S | 1.000 | likely_pathogenic |
| 18:51047110:A:C | S22R | 1.000 | likely_pathogenic |
| 18:51047075:C:G | P10R | 0.989 | likely_pathogenic |
| 18:51047101:A:C | I19L | 0.990 | likely_pathogenic |
| 18:51047089:G:A | A15T | 0.992 | likely_pathogenic |
| 18:51047089:G:C | A15P | 0.992 | likely_pathogenic |
| 18:51047092:T:A | C16S | 0.992 | likely_pathogenic |
| 18:51047093:G:A | C16Y | 0.999 | likely_pathogenic |
| 18:51047074:C:T | P10S | 0.933 | likely_pathogenic |
| 18:51047078:C:A | T11K | 0.951 | likely_pathogenic |
| 18:51047081:G:A | S12N | 0.985 | likely_pathogenic |
| 18:51047085:T:A | N13K | 0.980 | likely_pathogenic |
| 18:51047085:T:G | N13K | 0.980 | likely_pathogenic |
| 18:51047086:G:A | D14N | 0.994 | likely_pathogenic |
| 18:51047086:G:C | D14H | 1.000 | likely_pathogenic |
| 18:51047087:A:C | D14A | 0.998 | likely_pathogenic |
| 18:51047087:A:G | D14G | 0.998 | likely_pathogenic |
| 18:51047087:A:T | D14V | 0.999 | likely_pathogenic |
| 18:51047090:C:G | A15G | 0.984 | likely_pathogenic |
| 18:51047090:C:T | A15V | 0.996 | likely_pathogenic |
| 18:51047072:C:A | T9K | 0.786 | likely_pathogenic |
| 18:51047075:C:A | P10Q | 0.982 | likely_pathogenic |
| 18:51047075:C:T | P10L | 0.948 | likely_pathogenic |
| 18:51047080:A:C | S12R | 0.999 | likely_pathogenic |
SpliceAI Predictions
Summary
- Total splice effect predictions: 2,425
- Effects: donor gain, donor loss, acceptor gain, acceptor loss
Top 30 High-Confidence Splice Variants
| Genomic Coordinate | Gene | Effect Type | Score |
|---|---|---|---|
| 18:51028631:C:G | SMAD4 | donor_gain | 0.9200 |
| 18:51028666:G:GG | SMAD4 | donor_gain | 0.9100 |
| 18:51029741:G:GT | SMAD4 | donor_gain | 0.7600 |
| 18:51029742:A:T | SMAD4 | donor_gain | 0.7500 |
| 18:51029770:G:GT | SMAD4 | donor_gain | 0.7200 |
| 18:51028665:T:G | SMAD4 | donor_gain | 0.5800 |
| 18:51028662:A:T | SMAD4 | donor_gain | 0.5600 |
| 18:51030049:C:A | SMAD4 | donor_gain | 0.5400 |
| 18:51028670:G:A | SMAD4 | donor_loss | 0.3700 |
| 18:51029645:C:T | SMAD4 | donor_gain | 0.3900 |
| 18:51030048:T:TA | SMAD4 | donor_gain | 0.3800 |
| 18:51028671:A:T | SMAD4 | donor_gain | 0.5100 |
| 18:51028663:TCT:T | SMAD4 | donor_gain | 0.4500 |
| 18:51029852:TCCTC:T | SMAD4 | donor_gain | 0.4700 |
| 18:51030089:GCGCC:G | SMAD4 | donor_gain | 0.4400 |
| 18:51030084:T:G | SMAD4 | donor_gain | 0.4300 |
| 18:51030080:GCCCT:G | SMAD4 | donor_gain | 0.4200 |
| 18:51030085:G:GG | SMAD4 | donor_gain | 0.4200 |
| 18:51029547:A:AT | SMAD4 | acceptor_gain | 0.4900 |
| 18:51029548:G:T | SMAD4 | acceptor_gain | 0.4200 |
| 18:51029555:G:T | SMAD4 | acceptor_gain | 0.3100 |
| 18:51030128:G:GT | SMAD4 | donor_gain | 0.3600 |
| 18:51030128:G:T | SMAD4 | donor_gain | 0.2700 |
| 18:51030144:G:GT | SMAD4 | donor_gain | 0.2700 |
| 18:51030152:G:GT | SMAD4 | donor_gain | 0.6600 |
| 18:51028588:G:GT | SMAD4 | donor_gain | 0.6400 |
| 18:51028670:G:GT | SMAD4 | donor_gain | 0.6000 |
| 18:51029514:T:TA | SMAD4 | acceptor_gain | 0.2000 |
| 18:51029515:A:AA | SMAD4 | acceptor_gain | 0.2000 |
| 18:51028619:T:A | SMAD4 | donor_gain | 0.2300 |
Pathways & Gene Ontology
Biological Pathways
Reactome Pathways: 21 total
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-2173789 | TGF-beta receptor signaling activates SMADs |
| R-HSA-2173796 | SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription |
| R-HSA-2173795 | Downregulation of SMAD2/3:SMAD4 transcriptional activity |
| R-HSA-201451 | Signaling by BMP |
| R-HSA-1502540 | Signaling by Activin |
| R-HSA-1181150 | Signaling by NODAL |
| R-HSA-452723 | Transcriptional regulation of pluripotent stem cells |
| R-HSA-3311021 | SMAD4 MH2 Domain Mutants in Cancer |
| R-HSA-3315487 | SMAD2/3 MH2 Domain Mutants in Cancer |
| R-HSA-9733709 | Cardiogenesis |
| R-HSA-9823730 | Formation of definitive endoderm |
| R-HSA-9754189 | Germ layer formation at gastrulation |
| R-HSA-8941326 | RUNX2 regulates bone development |
| R-HSA-8941855 | RUNX3 regulates CDKN1A transcription |
| R-HSA-8952158 | RUNX3 regulates BCL2L11 (BIM) transcription |
| R-HSA-9617828 | FOXO-mediated transcription of cell cycle genes |
| R-HSA-9615017 | FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes |
| R-HSA-9735871 | SARS-CoV-1 targets host intracellular signalling and regulatory pathways |
| R-HSA-5689880 | Ub-specific processing proteases |
| R-HSA-9839394 | TGFBR3 expression |
| R-HSA-9844594 | Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 |
MSigDB Gene Sets: 100 total (Top 10 featured gene sets from various collections including C5:GO Biological Process, C2:CP Canonical Pathways, and C2 Curated Gene Sets)
Gene Ontology Annotations
Biological Process: 80 terms total
| GO ID | Term |
|---|---|
| GO:0060395 | SMAD protein signal transduction |
| GO:0007179 | transforming growth factor beta receptor signaling pathway |
| GO:0030509 | BMP signaling pathway |
| GO:0032924 | activin receptor signaling pathway |
| GO:0060391 | positive regulation of SMAD protein signal transduction |
| GO:0030511 | positive regulation of transforming growth factor beta receptor signaling pathway |
| GO:0001837 | epithelial to mesenchymal transition |
| GO:0010718 | positive regulation of epithelial to mesenchymal transition |
| GO:0071559 | response to transforming growth factor beta |
| GO:0071560 | cellular response to transforming growth factor beta stimulus |
| GO:0071773 | cellular response to BMP stimulus |
| GO:0006357 | regulation of transcription by RNA polymerase II |
| GO:0045944 | positive regulation of transcription by RNA polymerase II |
| GO:0000122 | negative regulation of transcription by RNA polymerase II |
| GO:0045893 | positive regulation of DNA-templated transcription |
| GO:0006366 | transcription by RNA polymerase II |
| GO:0030154 | cell differentiation |
| GO:0001649 | osteoblast differentiation |
| GO:0048589 | developmental growth |
| GO:0035556 | intracellular signal transduction |
Molecular Function: 18 terms total
| GO ID | Term |
|---|---|
| GO:0070412 | R-SMAD binding |
| GO:0070411 | I-SMAD binding |
| GO:0001228 | DNA-binding transcription activator activity, RNA polymerase II-specific |
| GO:0000981 | DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0003700 | DNA-binding transcription factor activity |
| GO:0043565 | sequence-specific DNA binding |
| GO:0001223 | transcription coactivator binding |
| GO:0001222 | transcription corepressor binding |
| GO:0000978 | RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0000976 | transcription cis-regulatory region binding |
| GO:0061629 | RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0003682 | chromatin binding |
| GO:0046872 | metal ion binding |
| GO:0042803 | protein homodimerization activity |
| GO:0042802 | identical protein binding |
| GO:0005518 | collagen binding |
| GO:0031005 | filamin binding |
| GO:0043199 | sulfate binding |
Cellular Component: 12 terms total
| GO ID | Term |
|---|---|
| GO:0071141 | SMAD protein complex |
| GO:0071144 | heteromeric SMAD protein complex |
| GO:0005634 | nucleus |
| GO:0005654 | nucleoplasm |
| GO:0005737 | cytoplasm |
| GO:0005667 | transcription regulator complex |
| GO:0000785 | chromatin |
| GO:0005829 | cytosol |
| GO:0005813 | centrosome |
| GO:0032444 | activin responsive factor complex |
| GO:0036064 | ciliary basal body |
| GO:0097542 | ciliary tip |
Protein interactions & networks
Protein-Protein Interactions
Total interaction count:
- STRING: ~4,822 interactions (predicted and experimental)
- BioGRID: 850 interactions (experimental)
- IntAct: 1,627 interactions (experimental)
TOP 30 highest-confidence interacting proteins (STRING/BioGRID/IntAct combined):
| Rank | Gene | Protein | UniProt | Interaction Type |
|---|---|---|---|---|
| 1 | CTNNB1 | Catenin beta-1 | P35222 | STRING, BioGRID |
| 2 | SMAD2 | SMAD family member 2 | Q15796 | STRING, BioGRID, IntAct |
| 3 | SMAD3 | SMAD family member 3 | P84022 | STRING, BioGRID, IntAct |
| 4 | SMAD5 | SMAD family member 5 | Q99717 | STRING, BioGRID, IntAct |
| 5 | SMAD6 | SMAD family member 6 | O43541 | STRING, BioGRID, IntAct |
| 6 | SMAD7 | SMAD family member 7 | O15105 | STRING, BioGRID, IntAct |
| 7 | SMAD9 | SMAD family member 9 | O15198 | STRING, BioGRID, IntAct |
| 8 | ALK4/ACVR1B | Activin receptor type-1B | P36896 | STRING, BioGRID, IntAct |
| 9 | TGFBR1 | TGF-beta receptor type-1 | P36897 | STRING, BioGRID, IntAct |
| 10 | TGFBR2 | TGF-beta receptor type-2 | P37173 | STRING, BioGRID, IntAct |
| 11 | BMPR1A | BMP receptor type-1A | P36894 | STRING, BioGRID, IntAct |
| 12 | BMPR1B | BMP receptor type-1B | O00238 | STRING, BioGRID, IntAct |
| 13 | BMPR2 | BMP receptor type-2 | Q13873 | STRING, BioGRID, IntAct |
| 14 | ACVR1 | Activin receptor type-1 | Q04771 | STRING, BioGRID, IntAct |
| 15 | ACVR2B | Activin receptor type-2B | Q13705 | STRING, BioGRID |
| 16 | LBFR/FOXH1 | Forkhead box protein H1 | O75593 | STRING, BioGRID |
| 17 | LEF1 | Lymphoid enhancer-binding factor 1 | Q9UJU2 | STRING, BioGRID |
| 18 | FOXO3 | Forkhead box protein O3 | O43524 | STRING, BioGRID |
| 19 | JUN | Transcription factor Jun | P05412 | STRING, BioGRID, IntAct |
| 20 | FOS | Protein c-Fos | P01100 | STRING, BioGRID |
| 21 | TP53 | Cellular tumor antigen p53 | P04637 | STRING, BioGRID |
| 22 | RUNX2 | Runt-related transcription factor 2 | Q13950 | STRING, BioGRID |
| 23 | E2F4 | Transcription factor E2F4 | Q16254 | STRING, BioGRID |
| 24 | E2F5 | Transcription factor E2F5 | Q15329 | STRING, BioGRID |
| 25 | SNAI1 | Zinc finger protein SNAI1 | O95863 | STRING, BioGRID |
| 26 | SNAI2 | Zinc finger protein SNAI2 | O43623 | STRING, BioGRID |
| 27 | ZEB1 | Zinc finger E-box-binding homeobox 1 | P37275 | STRING, BioGRID |
| 28 | TWIST1 | Twist-related protein 1 | Q15672 | STRING, BioGRID |
| 29 | TRIM33 | E3 ubiquitin-protein ligase TRIM33 | Q9UPN9 | STRING, BioGRID, IntAct |
| 30 | BMP2/4/6/7 | Bone morphogenetic proteins | P12643–P22004 | STRING, BioGRID, IntAct |
Protein Similarity
Structural/embedding similarity (Foldseek/DIAMOND + ESM2):
| Rank | Gene | Protein | UniProt | Similarity Type |
|---|---|---|---|---|
| 1 | SMAD1 | SMAD family member 1 | Q15797 | Structural, Embedding |
| 2 | SMAD2 | SMAD family member 2 | Q15796 | Structural, Embedding |
| 3 | SMAD3 | SMAD family member 3 | P84022 | Structural, Embedding |
| 4 | SMAD5 | SMAD family member 5 | Q99717 | Structural, Embedding |
| 5 | SMAD6 | SMAD family member 6 | O43541 | Structural, Embedding |
| 6 | SMAD7 | SMAD family member 7 | O15105 | Structural, Embedding |
| 7 | SMAD9 | SMAD family member 9 | O15198 | Structural, Embedding |
| 8 | NFXL1 | Nuclear factor 1 X-type | Q14938 | Embedding |
| 9–44 | Orthologs from non-human species | Various Smad4 homologs | Various | Structural |
Sequence homology notes:
- SMAD4 belongs to the SMAD family of signal transduction proteins with 9 human members (SMAD1–9)
- Highest sequence identity with SMAD2, SMAD3 (TGF-β pathway SMADs)
- Cross-species orthologs identified in mammals, birds, fish, and invertebrates
- Core conserved domains: MH1 (DNA-binding), MH2 (protein-protein interaction)
Summary: SMAD4 functions as the central hub of TGF-β/BMP signaling, interacting with R-SMADs (1, 2, 3, 5, 8, 9) and I-SMADs (6, 7), as well as transcriptional regulators (RUNX2, E2F, Forkhead/FOX family, Snail-family zinc fingers). The extensive STRING network (4,822 interactions) reflects its pivotal role as a common mediator in diverse developmental and disease pathways.
Transcription factor regulatory data
SMAD4 is a transcription factor with DNA binding capability.
DNA Binding Motifs (JASPAR)
SMAD4 has 2 known DNA binding motifs:
- MA1153.2 (SMAD factors family, SMAD/NF-1 DNA-binding domain factors, SMiLE-seq, version 2)
- MA1153.1 (SMAD factors family, SMAD/NF-1 DNA-binding domain factors, SMiLE-seq, version 1)
Both motifs are from the JASPAR CORE collection for vertebrates and derived from mouse (Mus musculus) SMiLE-seq data.
Downstream Targets
Total count: 100 genes
Top 30 with regulation type and evidence confidence:
| Target Gene | Regulation | Confidence |
|---|---|---|
| ADAM2 | Unknown | High |
| ALPI | Activation | High |
| ANKRD1 | Activation | High |
| APOC3 | Activation | High |
| BAMBI | Activation | High |
| BBC3 | Activation | High |
| CDH2 | Activation | High |
| CDKN1A | Activation | High |
| CDX2 | Activation | High |
| COL1A2 | Unknown | High |
| COL7A1 | Unknown | High |
| DLX3 | Activation | High |
| DMP1 | Activation | High |
| DSPP | Activation | High |
| FSCN1 | Activation | High |
| FSHB | Activation | High |
| GADD45B | Activation | High |
| HAMP | Activation | High |
| IHH | Activation | High |
| IL10 | Activation | High |
| ITGB5 | Activation | High |
| LAMA3 | Activation | High |
| LAMB3 | Repression | High |
| LAMC2 | Activation | High |
| MET | Activation | High |
| MST1R | Activation | High |
| MSX2 | Activation | High |
| MUC4 | Unknown | High |
| MYC | Unknown | High |
| MYCN | Activation | High |
Upstream Regulators (TFs that regulate SMAD4)
| Upstream TF | Evidence Type |
|---|---|
| SMAD2 | Activation (curated) |
| KLF10 | Repression (curated, High confidence) |
| HIF1A | Activation (curated) |
| FOXO1 | Activation (curated, Low confidence) |
| FOXO3 | Activation (curated, Low confidence) |
| KAT2B | Activation (curated) |
| TGFB2 | Activation (curated) |
| ZNF451 | Repression (curated) |
| ETS1 | Unknown (curated) |
| FOS | Unknown (curated) |
| GLI1 | Unknown (curated) |
| HDAC4 | Unknown (curated) |
| JUNB | Unknown (curated) |
| OVOL2 | Repression (curated) |
| SP1 | Unknown (curated) |
Evidence sourced from CollectRI transcriptional regulatory network database
Drug & pharmacology data
SMAD4 is not currently an established drug target with marketed or clinical-stage therapeutics.
Available evidence:
- ChEMBL target registration: SMAD4 is registered as a ChEMBL target (CHEMBL5725109), but contains only 6 experimental research assays for SMAD4 inhibition using compounds of unknown origin—no documented molecules with development phases.
- No clinical candidates: No molecules with developmental stage information (Phase I-IV) targeting SMAD4 identified in ChEMBL, DrugBank, or other major databases.
- Clinical trials: Zero documented clinical trials for SMAD4-targeting agents.
- Pharmacogenomics: PharmGKB lists SMAD4 as a VIP gene but shows no CPIC dosing guidelines or pharmacogene interaction data.
Conclusion: While SMAD4 is a well-characterized protein in TGF-β signaling pathways and has research-level assays, it lacks approved drugs, clinical candidates, or pharmacogenomic dosing guidance, indicating it has not yet been validated as a therapeutic target.
Expression profiles
Tissue Expression (Bgee)
SMAD4 shows ubiquitous expression across human tissues with an average expression score of 88.1 (range 0-100). All 288 tissue conditions show presence, indicating broad tissue distribution. Below are the top 30 tissues with highest expression scores:
| Tissue | Expression Score | Quality |
|---|---|---|
| Ventricular zone | 98.52 | Gold |
| Ganglionic eminence | 97.77 | Gold |
| Calcaneal tendon | 97.63 | Gold |
| Adrenal tissue | 96.97 | Gold |
| Colonic epithelium | 96.66 | Gold |
| Stromal cell of endometrium | 96.05 | Gold |
| Tendon | 95.93 | Gold |
| Cortical plate | 95.88 | Gold |
| Left ovary | 95.79 | Gold |
| Gall bladder | 95.77 | Gold |
| Rectum | 95.74 | Gold |
| Popliteal artery | 95.65 | Gold |
| Tibial artery | 95.63 | Gold |
| Embryo | 95.54 | Gold |
| Body of uterus | 95.38 | Gold |
| Endocervix | 95.35 | Gold |
| Islet of Langerhans | 95.31 | Gold |
| Descending thoracic aorta | 95.23 | Gold |
| Right ovary | 95.18 | Gold |
| Mucosa of stomach | 94.97 | Gold |
| Aorta | 94.95 | Gold |
| Left lobe of thyroid gland | 94.90 | Gold |
| Right lobe of thyroid gland | 94.88 | Gold |
| Parietal pleura | 94.86 | Gold |
| Right coronary artery | 94.83 | Gold |
| Thyroid gland | 94.79 | Gold |
| Endometrium | 94.78 | Gold |
| Ovary | 94.70 | Gold |
| Gastrocnemius | 94.66 | Gold |
| Muscle of leg | 94.64 | Gold |
Pattern: Prominent expression in developing CNS tissues (ventricular zone, ganglionic eminence, cortical plate), connective tissues (tendons, arteries), endocrine tissues (adrenal, thyroid, ovary, islet), and reproductive tissues (uterus, endometrium).
Single-Cell Expression (Single Cell Expression Atlas)
SMAD4 was identified as a marker gene in 2 experiments from the Single Cell Expression Atlas:
- E-MTAB-6142: Transcriptomic characterization of the human cell cycle in individual unsynchronized cells (96 cells)
- Across 146 cell clusters analyzed
- Max mean expression: 38.79
- Average mean expression: 0.87
Expression is distributed across multiple cell populations in this cell cycle dataset, consistent with SMAD4’s role in cell proliferation and differentiation pathways.
Disease associations
Mendelian / Monogenic Diseases
SMAD4 mutations cause autosomal dominant inheritance patterns in the following conditions:
| Disease | Disease ID | Inheritance | Evidence Level |
|---|---|---|---|
| Juvenile polyposis syndrome | OMIM:174900, MONDO:0017380, Orphanet:2929 | Autosomal dominant | Definitive/Strong |
| Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | OMIM:175050, MONDO:0008278 | Autosomal dominant | Definitive/Strong |
| Myhre syndrome | OMIM:139210, MONDO:0007688, Orphanet:2588 | Autosomal dominant | Definitive/Strong |
| Hereditary hemorrhagic telangiectasia | MONDO:0019180, Orphanet:774 | Autosomal dominant | Supportive |
| Familial thoracic aortic aneurysm and aortic dissection | MONDO:0019625, Orphanet:91387 | Autosomal dominant | Supportive |
| Generalized juvenile polyposis/juvenile polyposis coli | MONDO:0008276, Orphanet:329971 | Autosomal dominant | Supportive |
| Familial pancreatic carcinoma | MONDO:0015278, Orphanet:1333 | Autosomal dominant | Inferred |
Cancer associations:
- Exocrine pancreatic carcinoma (MONDO:0009831)
- Breast cancer (MONDO:0007254)
- Colon carcinoma (MONDO:0002032)
- Gastric cancer (MONDO:0001056)
- Gallbladder cancer (MONDO:0005411)
- Lung cancer (MONDO:0008903)
- Colorectal cancer (MONDO:0005575)
- Wilms tumor (MONDO:0006058)
- Ovarian carcinoma (inferred from HPO associations)
Other conditions:
- Pulmonary arterial hypertension (MONDO:0015924, Orphanet:422)
- Intellectual disability (MONDO:0001071)
- Familial renal glucosuria (MONDO:0009297, Orphanet:69076)
- Thrombocytopenia (MONDO:0002049)
- Vascular dementia (MONDO:0004648)
Phenotype Associations (Top 30 HPO Terms)
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0001009 | Telangiectasia |
| HP:0000421 | Epistaxis |
| HP:0002092 | Pulmonary arterial hypertension |
| HP:0002647 | Aortic dissection |
| HP:0002616 | Aortic root aneurysm |
| HP:0002239 | Gastrointestinal hemorrhage |
| HP:0001892 | Abnormal bleeding |
| HP:0002629 | Gastrointestinal arteriovenous malformation |
| HP:0004936 | Venous thrombosis |
| HP:0002040 | Esophageal varix |
| HP:0004406 | Spontaneous, recurrent epistaxis |
| HP:0100579 | Mucosal telangiectasiae |
| HP:0100761 | Visceral angiomatosis |
| HP:0100100 | Arteriovenous malformation |
| HP:0006548 | Pulmonary arteriovenous malformation |
| HP:0006574 | Hepatic arteriovenous malformation |
| HP:0006725 | Pancreatic adenocarcinoma |
| HP:0003003 | Colon cancer |
| HP:0002894 | Neoplasm of the pancreas |
| HP:0004783 | Duodenal polyposis |
| HP:0005227 | Adenomatous colonic polyposis |
| HP:0200008 | Intestinal polyposis |
| HP:0030256 | Small intestinal polyposis |
| HP:0004394 | Multiple gastric polyps |
| HP:0001738 | Exocrine pancreatic insufficiency |
| HP:0001394 | Cirrhosis |
| HP:0001399 | Hepatic failure |
| HP:0002910 | Elevated circulating hepatic transaminase concentration |
| HP:0004933 | Ascending aortic dissection |
Complex Disease / GWAS Associations (Top 7)
| Trait | Variant | P-value | Chromosome |
|---|---|---|---|
| Asthma (childhood onset) | SMAD4 - SRSF10P1 | 4×10⁻¹³ | 18 |
| Asthma | SMAD4 | 2×10⁻⁹ | 18 |
| Asthma | SMAD4 - SRSF10P1 | 6×10⁻⁸ | 18 |
| Oligoclonal band status in multiple sclerosis | ELAC1 - SMAD4 | 8×10⁻⁷ | 18 |
| Asthma onset (childhood vs adult) | SMAD4 - SRSF10P1 | 5×10⁻⁶ | 18 |
| Immune response to anthrax vaccine | SRSF10P1 - MEX3C | 1×10⁻⁶ | 18 |
| Metabolite levels | SRSF10P1 - MEX3C | 5×10⁻⁶ | 18 |