SMAD4 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the SMAD4 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | SMAD4 |
|---|---|
| Full Name | SMAD family member 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 18q21.2 |
| NCBI Gene ID | 4089 ncbi.nlm.nih.gov/gene/4089 |
| Ensembl ID | ENSG00000141646 |
| UniProt ID | Q13485 |
| OMIM ID | 600993 |
| HGNC ID | 6770 |
| Aliases | DPC4, MADH4, MYHRS |
Description
The SMAD4 gene encodes a critical intracellular mediator of the transforming growth factor-beta (TGF-beta) signaling pathway. SMAD4 forms complexes with receptor-regulated SMADs (R-SMADs) and translocates to the nucleus to regulate gene transcription. It acts as a tumor suppressor, and its loss or mutation is implicated in various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Juvenile polyposis syndrome | Germline mutations in SMAD4 lead to haploinsufficiency or dominant-negative effects, disrupting TGF-beta signaling and promoting intestinal polyp formation. | OMIM #174900; ClinVar |
| Pancreatic cancer | Somatic loss or mutation of SMAD4 (often homozygous deletion) inactivates TGF-beta tumor suppressor activity, contributing to tumor progression and metastasis. | COSMIC; ClinVar |
| Colorectal cancer | SMAD4 mutations or loss of heterozygosity at 18q21 are frequent, impairing TGF-beta-mediated growth inhibition and promoting tumor invasion. | COSMIC; ClinVar |
| Myhre syndrome | Specific missense mutations in SMAD4 (e.g., p.Ile500Val, p.Arg496Cys) cause gain-of-function or dominant-negative effects, leading to connective tissue and skeletal abnormalities. | OMIM #139210; ClinVar |
| Hereditary hemorrhagic telangiectasia | Some SMAD4 mutations cause combined juvenile polyposis and hereditary hemorrhagic telangiectasia, affecting vascular development. | OMIM #175050; ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Pancreas | High | High |
| Small intestine | High | High |
| Colon | High | High |
| Stomach | High | High |
| Liver | Medium | Medium |
| Lung | Medium | Medium |
| Kidney | Medium | Medium |
| Brain | Low | Low |
| Heart | Low | Low |
| Skeletal muscle | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | High | Ubiquitous expression; used in TGF-beta studies |
| A549 (lung cancer) | Medium | SMAD4 expression present; responsive to TGF-beta |
| MCF7 (breast cancer) | Medium | Expression varies; involved in estrogen/TGF-beta crosstalk |
| HCT116 (colorectal cancer) | High | Wild-type SMAD4; used in SMAD4 functional assays |
| PANC-1 (pancreatic cancer) | Low | Reduced SMAD4 expression; reflects pancreatic cancer phenotype |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1244_1245delAG (p.Glu415Valfs*3) | Frameshift | Rare | Loss of function; truncates protein, impairing SMAD complex formation |
| c.1082G>A (p.Arg361His) | Missense | Rare | Dominant-negative; disrupts DNA binding and transcriptional activity |
| c.1498A>G (p.Ile500Val) | Missense | Rare | Gain-of-function; associated with Myhre syndrome |
| c.1486C>T (p.Arg496Cys) | Missense | Rare | Gain-of-function; associated with Myhre syndrome |
| Whole gene deletion | Copy number loss | Common in pancreatic cancer | Loss of function; complete loss of SMAD4 protein |
Mutation functional classification
Loss of Function (LOF)
Most SMAD4 mutations in cancer are loss-of-function, including frameshift, nonsense, and homozygous deletions, leading to reduced or absent protein and impaired TGF-beta signaling.
Gain of Function (GOF)
Specific missense mutations (e.g., p.Ile500Val, p.Arg496Cys) in Myhre syndrome result in gain-of-function, enhancing SMAD4 transcriptional activity and causing abnormal TGF-beta responses.
Dominant Negative (DN)
Some missense mutations (e.g., p.Arg361His) act as dominant-negative, interfering with wild-type SMAD4 function by forming non-functional complexes with R-SMADs.
View complete mutation data：
Gene Ontology (GO)
| • DNA binding | • Transcription factor activity |
| • Protein binding | • Signal transducer activity |
| • TGF-beta receptor signaling pathway | • Regulation of transcription by RNA polymerase II |
| • Cell cycle arrest | • Apoptotic process |
| • Epithelial to mesenchymal transition | • SMAD protein complex |
Pathways
• TGF-beta signaling pathway
• Activin signaling pathway
• BMP signaling pathway
• Regulation of epithelial to mesenchymal transition
• Colorectal cancer pathway
• Pancreatic cancer pathway
Protein Summary
SMAD4 is a 552-amino acid protein with two conserved domains: MH1 (MAD homology 1) and MH2 (MAD homology 2), connected by a linker region. The MH1 domain mediates DNA binding, while the MH2 domain is involved in protein-protein interactions and transcriptional activation. SMAD4 acts as a common mediator SMAD (co-SMAD) that partners with receptor-regulated SMADs (SMAD1/2/3/5/8) to transduce TGF-beta family signals. It shuttles between cytoplasm and nucleus, and its activity is regulated by phosphorylation, ubiquitination, and interaction with various cofactors. Loss of SMAD4 function is a hallmark of several cancers, while gain-of-function mutations cause developmental syndromes.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SMAD4 Knockout HEK293 Cell Line | EDJ-KQ401 | Human | 4089 | Details Get a Quote |
| SMAD4 Knockout A-549 Cell Line | EDJ-KQ18640 | Human | 4089 | Details Get a Quote |
| SMAD4 Knockout HCT 116 Cell Line | EDJ-KQ18641 | Human | 4089 | Details Get a Quote |
| SMAD4 Knockout HeLa Cell Line | EDJ-KQ18642 | Human | 4089 | Details Get a Quote |
| SMAD4 Knockout HTR-8/SVneo Cell Line | EDJ-KZ479 | Human | 4089 | Details Get a Quote |
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