SMAD1

The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

SMAD1

Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. May act synergistically with SMAD4 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression.

Anatomical structure morphogenesisManual Assertion Based On ExperimentIBA:GO_Central
BMP signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Bone developmentIEA:Ensembl
Cardiac conduction system development1 PublicationNAS:BHF-UCL
Cardiac muscle cell proliferationIEA:Ensembl
Cartilage developmentIEA:Ensembl
Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cellular response to organic cyclic compoundIEA:Ensembl
Embryonic pattern specificationISS:UniProtKB
Gamete generationIEA:Ensembl
Hindbrain developmentIEA:Ensembl
Homeostatic processIEA:Ensembl
Inflammatory responseIEA:Ensembl
MAPK cascadeIEA:Ensembl
Mesodermal cell fate commitmentIEA:Ensembl
Midbrain developmentIEA:Ensembl
Negative regulation of cell population proliferationIEA:Ensembl
Negative regulation of muscle cell differentiationIEA:Ensembl
Osteoblast fate commitmentIEA:Ensembl
Positive regulation of cartilage developmentIEA:Ensembl
Positive regulation of gene expressionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of miRNA transcriptionIEA:Ensembl
Positive regulation of osteoblast differentiationIEA:Ensembl
Positive regulation of sprouting angiogenesisManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:NTNU_SB
Positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulusISS:BHF-UCL
Primary miRNA processingManual Assertion Based On ExperimentTAS:BHF-UCL
Protein phosphorylationIEA:Ensembl
Signal transduction1 PublicationNAS:UniProtKB
SMAD protein complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
SMAD protein signal transductionISS:BHF-UCL
Transcription, DNA-templatedManual Assertion Based On ExperimentIDA:ComplexPortal
Transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:ComplexPortal
Ureteric bud developmentIEA:Ensembl

Cytoplasm
Nucleus
Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with SMAD4 (PubMed:15647271).
Co-localizes with LEMD3 at the nucleus inner membrane (PubMed:15647271).
Exported from the nucleus to the cytoplasm when dephosphorylated (By similarity).

SMAD1 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.

Phosphorylation of the C-terminal SVS motif by BMP type 1 receptor kinase activates SMAD1 by promoting dissociation from the receptor and trimerization with SMAD4.
Ubiquitinated by SMAD-specific E3 ubiquitin ligase SMURF1, leading to its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm (By similarity).