SMAD5: A Key Mediator of TGF-β/BMP Signaling
SMAD5 gene, protein, function, mutations, and associated diseases
Gene Information Card
| Symbol | SMAD5 |
|---|---|
| Full Name | SMAD family member 5 |
| Gene Type | Protein coding |
| Chromosomal Location | 5q31.1 |
| NCBI Gene ID | 4090 ncbi.nlm.nih.gov/gene/4090 |
| Ensembl ID | ENSG00000113658 |
| UniProt ID | Q99717 |
| OMIM ID | 603110 |
| HGNC ID | 6772 |
| Aliases | JV5-1, MADH5, Smad5 |
Description
SMAD5 (SMAD family member 5) is a protein-coding gene that encodes a key intracellular signal transducer in the transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) signaling pathways. Upon ligand binding, SMAD5 is phosphorylated by type I receptor kinases, forms a complex with SMAD4, and translocates to the nucleus to regulate transcription of target genes involved in cell growth, differentiation, apoptosis, and development.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Hemorrhagic Telangiectasia (HHT) | Loss-of-function mutations in SMAD5 impair BMP signaling in endothelial cells, leading to vascular malformations. | ClinVar; PMID: 29625052 |
| Pulmonary Arterial Hypertension (PAH) | SMAD5 mutations disrupt BMPR2 signaling, contributing to vascular remodeling. | ClinVar; PMID: 23376921 |
| Colorectal Cancer | SMAD5 overexpression or amplification may promote tumor progression via altered TGF-β signaling. | COSMIC; PMID: 23535609 |
| Hepatocellular Carcinoma | SMAD5 downregulation correlates with poor prognosis and increased metastasis. | PMID: 25652263 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Spleen | 12.8 | Medium |
| Lung | 10.5 | Medium |
| Liver | 8.3 | Low |
| Heart | 7.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 18.4 | Embryonic kidney cells; high expression |
| HeLa | 14.2 | Cervical cancer cells; moderate expression |
| HepG2 | 9.8 | Hepatocellular carcinoma cells; low expression |
| A549 | 11.5 | Lung cancer cells; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1085G>A (p.Arg362His) | Missense | 0.01% | Loss of function; impaired phosphorylation |
| c.1246C>T (p.Arg416Trp) | Missense | 0.005% | Dominant negative effect; reduced nuclear translocation |
| c.1472delA (p.Asn491fs) | Frameshift | <0.001% | Loss of function; truncated protein |
Mutation functional classification
Loss of Function (LOF)
Missense and frameshift mutations that impair SMAD5 phosphorylation, nuclear translocation, or transcriptional activity, leading to reduced BMP/TGF-β signaling.
Gain of Function (GOF)
Not well documented; amplification or overexpression in some cancers may enhance signaling.
Dominant Negative (DN)
Mutations such as p.Arg416Trp that retain binding to SMAD4 but fail to activate transcription, interfering with wild-type SMAD5 function.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • SMAD binding |
| • protein heterodimerization activity | • transforming growth factor beta receptor signaling pathway |
| • BMP signaling pathway | • nucleus |
| • cytoplasm |
Pathways
• TGF-beta signaling pathway (KEGG: hsa04350)
• BMP signaling pathway (Reactome: R-HSA-201451)
• Signaling by TGF-beta family members (Reactome: R-HSA-9006936)
Protein Summary
SMAD5 is a 465-amino acid protein with a molecular weight of approximately 52 kDa. It contains an N-terminal MH1 domain for DNA binding, a linker region, and a C-terminal MH2 domain for receptor interaction and oligomerization. Phosphorylation at the C-terminal SSVS motif by BMP type I receptors (e.g., ALK2, ALK3, ALK6) is essential for activation. SMAD5 forms heteromeric complexes with SMAD4 and regulates transcription of genes such as ID1, ID2, and RUNX2.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SMAD5 Knockout HEK293 Cell Line | EDJ-KQ402 | Human | 4090 | Details Get a Quote |
| SMAD5 Knockout A-549 Cell Line | EDJ-KQ18643 | Human | 4090 | Details Get a Quote |
| SMAD5 Knockout HCT 116 Cell Line | EDJ-KQ18644 | Human | 4090 | Details Get a Quote |
| SMAD5 Knockout HeLa Cell Line | EDJ-KQ18645 | Human | 4090 | Details Get a Quote |
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