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MGP001858

UniProt Annotations

Entry Information
Gene NameSMAD family member 6
Protein EntrySMAD6_HUMAN
UniProt IDO43541
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=3; Name=A; IsoId=O43541-1; Sequence=Displayed; Name=B; Synonyms=Smad 6S; IsoId=O43541-2; Sequence=VSP_006179, VSP_006180; Name=D; IsoId=O43541-4; Sequence=VSP_035489, VSP_035490;
DiseaseAortic valve disease 2 (AOVD2) [MIM:614823]: 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. {ECO:0000269|PubMed:22275001}. Note=The disease is caused by mutations 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). {ECO:0000269|PubMed:22275001}.
FunctionActs as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions. {ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:9436979}.
InteractionSelf; NbExp=2; IntAct=EBI-976374, EBI-976374; P51817:PRKX; NbExp=5; IntAct=EBI-976374, EBI-4302903; Q13950:RUNX2; NbExp=3; IntAct=EBI-976374, EBI-976402; Q15797:SMAD1; NbExp=4; IntAct=EBI-976374, EBI-1567153; O95630:STAMBP; NbExp=2; IntAct=EBI-4324970, EBI-396676;
PtmArginine 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. {ECO:0000250}.
PtmPhosphorylated by BMP type 1 receptor kinase and by PRKX. {ECO:0000269|PubMed:16491121}.
PtmUbiquitinated by WWP1 (By similarity). 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. {ECO:0000250, ECO:0000269|PubMed:23455153}.
SimilarityBelongs to the dwarfin/SMAD family. {ECO:0000305}.
SimilarityContains 1 MH1 (MAD homology 1) domain. {ECO:0000255|PROSITE-ProRule:PRU00438}.
SimilarityContains 1 MH2 (MAD homology 2) domain. {ECO:0000255|PROSITE-ProRule:PRU00439}.
Subcellular LocationNucleus {ECO:0000269|PubMed:16491121}.
SubunitInteracts with NEDD4L (By similarity). Interacts with WWP1 (By similarity). Interacts with STAMBP and PRKX. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in response to IL1B and hence negatively regulates IL1R-TLR signaling. {ECO:0000250, ECO:0000269|PubMed:10722652, ECO:0000269|PubMed:11483516, ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:9436979}.
Tissue SpecificityUbiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.
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