SMAD6
Function
Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta (PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:16951688, PubMed:22275001, PubMed:30848080, PubMed:9436979, PubMed:9759503). Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of pro-inflammatory genes (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding (PubMed:30848080, PubMed:9436979). Binds to regulatory elements in target promoter regions (PubMed:16491121).
Involvement in disease
Aortic valve disease 2
AOVD2
A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.
None
The disease is caused by variants affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001).
Craniosynostosis 7
CRS7
A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry. Rare heterozygous SMAD6 variants have been reported to be strongly associated with non-syndromic midline craniosynostosis, confering a very high risk for disease development in the presence of a common risk allele (rs1884302) near the BMP2 locus (PubMed:27606499). The modifier role of rs1884302 SNP on craniosynostosis development associated with SMAD6 variants has not been confirmed in further studies (PubMed:32499606).
Radioulnar synostosis, non-syndromic
RUS
An autosomal dominant disease characterized by proximal fusion of the radius and ulna resulting in extremely limited pronation and supination of the forearm. There are two disease forms. Radioulnar synostosis type 1 is characterized by a proximal fusion between the radius and ulna, and the radial head is absent. Radioulnar synostosis type 2 is characterized by a fusion just distal to the proximal radial epiphysis, and congenital dislocation of the radial head. In radioulnar synostosis type 2 there is also a restriction of extension at the elbow.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylated by BMP type 1 receptor kinase and by PRKX.
Monoubiquitinated at Lys-173 by the E2/E3 hybrid ubiquitin-protein ligase UBE2O, leading to reduced binding affinity for the activated BMP type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating adipocyte differentiation (PubMed:23455153). Ubiquitinated by WWP1 (By similarity). Ubiquitinated by ARK2C, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling (By similarity).
Arginine methylation by PRMT1, which is recruited by BMPR2, initiates BMP-Induced signaling and induces dissociation from the BMPR1B receptor at the cell surface leading to derepress downstream Smad1/Smad5 signaling.
Sequence Similarities
Belongs to the dwarfin/SMAD family.
Tissue Specificity
Isoform B
Expressed in the brain, heart, ovary, peripheral blood leukocytes, small intestine, spleen, thymus, bone marrow, fetal liver and lymph nodes.
Cellular localization
- Nucleus
Alternative names
MADH6, SMAD6, Mothers against decapentaplegic homolog 6, MAD homolog 6, Mothers against DPP homolog 6, SMAD family member 6, SMAD 6, Smad6, hSMAD6