SMAD3: A Key Mediator of TGF-β Signaling in Development and Disease
Comprehensive genomic and functional analysis of the SMAD3 gene, its role in TGF-β signaling, associated disorders, and clinical relevance.
Gene Information Card
| Symbol | SMAD3 |
|---|---|
| Full Name | SMAD family member 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 15q22.33 |
| NCBI Gene ID | 4087 ncbi.nlm.nih.gov/gene/4087 |
| Ensembl ID | ENSG00000166949 |
| UniProt ID | P84022 |
| OMIM ID | 603109 |
| HGNC ID | 6769 |
| Aliases | MADH3, JV15-2, hSMAD3, LDS1C |
Description
SMAD3 (SMAD family member 3) is a protein-coding gene that encodes a key intracellular mediator of the transforming growth factor-beta (TGF-β) signaling pathway. Upon TGF-β receptor activation, SMAD3 is phosphorylated, forms a complex with SMAD4, and translocates to the nucleus to regulate transcription of target genes involved in cell growth, differentiation, apoptosis, and extracellular matrix homeostasis. Mutations in SMAD3 are associated with Loeys-Dietz syndrome type 1C, aortic aneurysms, and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Loeys-Dietz syndrome 1C (LDS1C) | Loss-of-function or dominant-negative mutations impair TGF-β signaling, leading to aortic root dilation, arterial tortuosity, and craniofacial abnormalities. | OMIM #613795; ClinVar |
| Aortic aneurysm, familial thoracic 1 | Heterozygous missense mutations disrupt SMAD3 function, causing weakened aortic wall integrity and predisposition to dissection. | OMIM #607086; NCBI GeneReviews |
| Colorectal cancer | Somatic mutations and loss of heterozygosity in SMAD3 contribute to TGF-β resistance and tumor progression. | COSMIC; PMID: 22610119 |
| Pancreatic cancer | SMAD3 inactivation via mutation or deletion promotes epithelial-mesenchymal transition and metastasis. | COSMIC; PMID: 28481359 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.5 | Medium |
| Aorta | 15.3 | Medium |
| Lung | 10.8 | Medium |
| Colon | 9.2 | Low |
| Pancreas | 7.1 | Low |
| Brain | 5.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 18.2 | High expression in embryonic kidney cells |
| HeLa | 14.6 | Moderate expression in cervical cancer cells |
| A549 | 11.3 | Moderate expression in lung adenocarcinoma cells |
| HCT 116 | 8.9 | Low expression in colorectal carcinoma cells |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.859C>T (p.Arg287Trp) | Missense | <0.01% in general population | Dominant-negative; reduces SMAD3 transcriptional activity; associated with LDS1C (ClinVar) |
| c.1132C>T (p.Arg378Cys) | Missense | <0.01% | Loss-of-function; impairs SMAD3-SMAD4 complex formation (ClinVar) |
| c.1055_1056delAG (p.Glu352Valfs*12) | Frameshift | Rare | Loss-of-function; truncation leads to nonsense-mediated decay (COSMIC) |
| c.1066G>A (p.Gly356Arg) | Missense | Somatic in colorectal cancer | Gain-of-function?; altered DNA binding (COSMIC) |
Mutation functional classification
Loss of Function (LOF)
Missense mutations (e.g., p.Arg378Cys) and frameshift deletions that impair SMAD3 phosphorylation, nuclear translocation, or transcriptional activity. Associated with Loeys-Dietz syndrome and aortic aneurysms.
Gain of Function (GOF)
Rare somatic missense mutations (e.g., p.Gly356Arg) reported in colorectal cancer that may enhance TGF-β signaling or alter target gene specificity; functional validation pending.
Dominant Negative (DN)
Mutations such as p.Arg287Trp that produce a protein capable of binding SMAD4 but failing to activate transcription, thereby interfering with wild-type SMAD3 function. Common in LDS1C.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity (GO:0003700) | • SMAD binding (GO:0046332) |
| • TGF-beta receptor signaling pathway (GO:0007179) | • Regulation of cell population proliferation (GO:0042127) |
| • Negative regulation of cell cycle (GO:0045786) | • Positive regulation of epithelial to mesenchymal transition (GO:0010718) |
Pathways
• TGF-beta signaling pathway (KEGG hsa04350)
• Signaling pathways regulating pluripotency of stem cells (KEGG hsa04550)
• Colorectal cancer (KEGG hsa05210)
• Pancreatic cancer (KEGG hsa05212)
• Chronic myeloid leukemia (KEGG hsa05220)
Protein Summary
SMAD3 is a 425-amino acid protein (UniProt P84022) containing an N-terminal MH1 domain for DNA binding, a linker region, and a C-terminal MH2 domain for receptor interaction and oligomerization. It is phosphorylated at Ser423/425 by TGF-β receptor type I, enabling complex formation with SMAD4. The protein acts as a tumor suppressor in epithelial tissues but can promote fibrosis and metastasis in certain contexts. Structural mutations in the MH2 domain are common in hereditary aortopathies.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SMAD3 Knockout HEK293 Cell Line | EDJ-KQ400 | Human | 4088 | Details Get a Quote |
| SMAD3 Knockout HeLa Cell Line | EDJ-KQ17985 | Human | 4088 | Details Get a Quote |
| SMAD3 Knockout A-549 Cell Line | EDJ-KQ18637 | Human | 4088 | Details Get a Quote |
| SMAD3 Knockout HCT 116 Cell Line | EDJ-KQ18638 | Human | 4088 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
