SMAD6

The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

SMAD Family Member 6

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:9436979, PubMed:16951688, PubMed:22275001, PubMed:9759503, PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:30848080).
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:9436979, PubMed:30848080).
Binds to regulatory elements in target promoter regions (PubMed:16491121).

Biological Process anatomical structure morphogenesisManual Assertion Based On ExperimentIBA:GO_Central
Biological Process aorta developmentIEA:Ensembl
Biological Process aortic valve morphogenesisManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process BMP signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process cell-substrate adhesionManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process coronary vasculature developmentIEA:Ensembl
Biological Process fat cell differentiationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process immune responseManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process mitral valve morphogenesisISS:BHF-UCL
Biological Process negative regulation of apoptotic processManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process negative regulation of BMP signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of cell population proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process negative regulation of ossificationISS:BHF-UCL
Biological Process negative regulation of osteoblast differentiationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process negative regulation of pathway-restricted SMAD protein phosphorylationManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of SMAD protein complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process outflow tract septum morphogenesisISS:BHF-UCL
Biological Process positive regulation of miRNA transcriptionIEA:Ensembl
Biological Process pulmonary valve morphogenesisISS:BHF-UCL
Biological Process response to estrogenIEA:Ensembl
Biological Process response to laminar fluid shear stressManual Assertion Based On ExperimentIEP:BHF-UCL
Biological Process response to lipopolysaccharideManual Assertion Based On ExperimentIDA:ARUK-UCL
Biological Process SMAD protein signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Biological Process transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Biological Process ureteric bud developmentIEA:Ensembl
Biological Process ventricular septum developmentIEA:Ensembl
Biological Process zygotic specification of dorsal/ventral axisManual Assertion Based On ExperimentIMP:BHF-UCL

Nucleus

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.
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.
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.

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 RNF165, 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.