SMAD6
entrez
4091
canonical
uniprot
O43541
canonical
ensembl
ENSG00000137834
resolver
ensp
ENSP00000288840
resolver
genesymbol
SMAD6
resolver
genesymbol_syn
MADH6
resolver
hgnc
HGNC:6772
resolver
uniprot
A9J6M5
resolver
uniprot
O43654
resolver
uniprot
Q15799
resolver
uniprot
Q7Z7L4
resolver
uniprot
Q96E31
resolver
uniprot
Q9UKZ3
resolver
uniprot_entry
SMAD6_HUMAN
resolver
uniprot_sec
A9J6M5
resolver
uniprot_sec
O43654
resolver
uniprot_sec
Q15799
resolver
uniprot_sec
Q7Z7L4
resolver
uniprot_sec
Q96E31
resolver
uniprot_sec
Q9UKZ3
resolver
amino_acid_sequence
MFRSKRSGLVRRLWRSRVVPDREEGGSGGGGGGDEDGSLGSRAEPAPRAREGGGCGRSEVRPVAPRRPRDAVGQRGAQGAGRRRRAGGPPRPMSEPGAGAGSSLLDVAEPGGPGWLPESDCETVTCCLFSERDAAGAPRDASDPLAGAALEPAGGGRSREARSRLLLLEQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAVELKPLCGCHSFAAAADGPTVCCNPYHFSRLCGPESPPPPYSRLSPRDEYKPLDLSDSTLSYTETEATNSLITAPGEFSDASMSPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGEHPIFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSGLQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQFITSCPCWLEILLNNPR
uniprot
proteins
disease_involvement
DISEASE: Aortic 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, ECO:0000269|PubMed:30796334, ECO:0000269|PubMed:30848080}. Note=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). {ECO:0000269|PubMed:22275001}.; DISEASE: Craniosynostosis 7 (CRS7) [MIM:617439]: 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. {ECO:0000269|PubMed:27606499, ECO:0000269|PubMed:32499606}. Note=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, conferring 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). {ECO:0000269|PubMed:27606499, ECO:0000269|PubMed:32499606}.; DISEASE: Radioulnar synostosis, non-syndromic (RUS) [MIM:179300]: 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. {ECO:0000269|PubMed:31138930}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: Acts as an inhibitory regulator of signaling mediated by the TGF-beta superfamily, with strong selectivity toward BMP-dependent pathways (PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:16951688, PubMed:22275001, PubMed:30848080, PubMed:9436979, PubMed:9759503). Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear translocation 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). Associates with regulatory elements in target promoter regions (PubMed:16491121). Functions as an adapter protein that recruits ubiquitin ligases, including SMURF1 and, in some contexts, SMURF2, promoting proteasomal degradation of signaling components and transcription factors such as RUNX2, TBX6, BMPR1A and MYD88 (PubMed:16299379, PubMed:19561075, PubMed:28847510). {ECO:0000269|PubMed:16299379, ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:19561075, ECO:0000269|PubMed:22275001, ECO:0000269|PubMed:28847510, ECO:0000269|PubMed:30848080, ECO:0000269|PubMed:9436979, ECO:0000303|PubMed:10647776, ECO:0000303|PubMed:10708948, ECO:0000303|PubMed:10708949, ECO:0000303|PubMed:9759503}.
uniprot
proteins
mass_dalton
53497
uniprot
proteins
mutagenesis
MUTAGEN 173; /note="K->R: Abolishes monoubiquitination by UBE2O."; /evidence="ECO:0000269|PubMed:23455153"; MUTAGEN 435; /note="S->A: Loss of in vitro phosphorylation by PRKX."; /evidence="ECO:0000269|PubMed:16491121"; MUTAGEN 471; /note="G->S: Loss of SMAD1-binding and of inhibition of BMP-SMAD1 signaling. No effect on interaction with BMPR1B and TGFBR1."; /evidence="ECO:0000269|PubMed:9436979"; MUTAGEN 478..496; /note="Missing: Loss of interaction with BMPR1B, TGFBR1 and SMAD1."; /evidence="ECO:0000269|PubMed:9436979
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by BMP type 1 receptor kinase and by PRKX. {ECO:0000269|PubMed:16491121}.; PTM: 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). {ECO:0000250|UniProtKB:O35182, ECO:0000269|PubMed:23455153}.; PTM: 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. {ECO:0000250|UniProtKB:O35182}.
uniprot
proteins
protein_family
Dwarfin/SMAD family
uniprot
proteins
pubmed
10647776
uniprot
proteins
pubmed
10708948
uniprot
proteins
pubmed
10708949
uniprot
proteins
pubmed
10722652
uniprot
proteins
pubmed
11284962
uniprot
proteins
pubmed
11483516
uniprot
proteins
pubmed
14657019
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16299379
uniprot
proteins
pubmed
16491121
uniprot
proteins
pubmed
16601693
uniprot
proteins
pubmed
16951688
uniprot
proteins
pubmed
19561075
uniprot
proteins
pubmed
21791611
uniprot
proteins
pubmed
22275001
uniprot
proteins
pubmed
23455153
uniprot
proteins
pubmed
27606499
uniprot
proteins
pubmed
28847510
uniprot
proteins
pubmed
30796334
uniprot
proteins
pubmed
30848080
uniprot
proteins
pubmed
31138930
uniprot
proteins
pubmed
32499606
uniprot
proteins
pubmed
32636483
uniprot
proteins
pubmed
38290823
uniprot
proteins
pubmed
8673135
uniprot
proteins
pubmed
9436979
uniprot
proteins
pubmed
9712726
uniprot
proteins
pubmed
9759503
uniprot
proteins
sequence_length
496
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:19561075}. Cytoplasm {ECO:0000250|UniProtKB:O35182}.
uniprot
proteins