SMAD6: A Key Regulator of BMP/TGF-β Signaling
SMAD6 Gene - Function, Expression, and Clinical Significance
Gene Information Card
| Symbol | SMAD6 |
|---|---|
| Full Name | SMAD family member 6 |
| Gene Type | Protein coding |
| Chromosomal Location | 15q22.31 |
| NCBI Gene ID | 4091 ncbi.nlm.nih.gov/gene/4091 |
| Ensembl ID | ENSG00000137834 |
| UniProt ID | O43541 |
| OMIM ID | 602931 |
| HGNC ID | 6772 |
| Aliases | MADH6, MADH7, SMAD6 |
Description
SMAD6 encodes a member of the SMAD family of proteins, which are intracellular signal transducers of the transforming growth factor-beta (TGF-β) superfamily. SMAD6 functions as an inhibitory SMAD (I-SMAD) that negatively regulates bone morphogenetic protein (BMP) signaling by competing with receptor-regulated SMADs (R-SMADs) for receptor interaction or by targeting receptors for degradation. It plays critical roles in development, immune response, and tissue homeostasis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cardiovascular malformations (e.g., aortic valve disease) | SMAD6 loss-of-function mutations disrupt BMP signaling, leading to abnormal cardiac development and valve calcification. | ClinVar, OMIM |
| Craniosynostosis | SMAD6 mutations impair BMP pathway regulation, causing premature fusion of cranial sutures. | ClinVar, OMIM |
| Hereditary hemorrhagic telangiectasia (HHT)-like phenotype | SMAD6 deficiency alters TGF-β/BMP signaling in vascular endothelium, contributing to vascular malformations. | ClinVar, OMIM |
| Cancer (e.g., colorectal, breast) | SMAD6 overexpression or mutation can dysregulate TGF-β signaling, promoting tumor progression and metastasis. | COSMIC, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.5 | Medium |
| Lung | 8.3 | Low |
| Liver | 6.1 | Low |
| Kidney | 9.7 | Low |
| Brain | 4.2 | Not detected |
| Testis | 15.8 | Medium |
| Placenta | 18.2 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (umbilical vein endothelial) | 14.5 | High expression |
| HeLa (cervical carcinoma) | 8.2 | Moderate expression |
| A549 (lung carcinoma) | 6.7 | Low expression |
| MCF7 (breast carcinoma) | 5.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1153C>T (p.Arg385*) | Nonsense | Rare | Loss of function; associated with cardiovascular malformations |
| c.788G>A (p.Arg263Gln) | Missense | Rare | Impaired BMP inhibition; linked to craniosynostosis |
| c.1045_1046del (p.Leu349Valfs*2) | Frameshift | Rare | Loss of function; reported in HHT-like phenotype |
Mutation functional classification
Loss of Function (LOF)
Most SMAD6 mutations are loss-of-function, reducing its ability to inhibit BMP signaling, leading to overactive BMP pathways and developmental defects.
Gain of Function (GOF)
Gain-of-function mutations are rare but may enhance SMAD6 inhibitory activity, potentially suppressing TGF-β signaling and contributing to certain cancers.
Dominant Negative (DN)
Dominant-negative SMAD6 variants can interfere with wild-type SMAD6 function, exacerbating BMP pathway dysregulation.
View complete mutation data：
Gene Ontology (GO)
| • GO:0007179 - transforming growth factor beta receptor signaling pathway | • GO:0030510 - regulation of BMP signaling pathway |
| • GO:0005515 - protein binding | • GO:0005634 - nucleus |
| • GO:0005737 - cytoplasm | • GO:0046872 - metal ion binding |
Pathways
• TGF-beta signaling pathway (KEGG: hsa04350)
• Signaling pathways regulating pluripotency of stem cells (KEGG: hsa04550)
• BMP signaling pathway (Reactome: R-HSA-201451)
Protein Summary
SMAD6 is a 496-amino acid protein containing an N-terminal MH1 domain and a C-terminal MH2 domain. It acts as an intracellular antagonist of BMP signaling by binding to BMP type I receptors or competing with SMAD1/5/8 for SMAD4 interaction. SMAD6 is also involved in transcriptional repression and can interact with other signaling pathways, including Wnt and MAPK. Its expression is regulated by multiple stimuli, and its dysregulation is implicated in developmental disorders and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SMAD6 Knockout HEK293 Cell Line | EDJ-KQ126 | Human | 4091 | Details Get a Quote |
| SMAD6 Knockout A-549 Cell Line | EDJ-KQ18646 | Human | 4091 | Details Get a Quote |
| SMAD6 Knockout HCT 116 Cell Line | EDJ-KQ18648 | Human | 4091 | Details Get a Quote |
| SMAD6 Knockout HeLa Cell Line | EDJ-KQ18649 | Human | 4091 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
