The SMAD4 gene (SMAD4 stands for SMAD Family Member 4) is a protein-coding gene (see also SMAD proteins) located on chromosome 18q21.2. An important paralog of this gene is SMAD2.
SMAD4 gene
DefinitionThis section has been translated automatically.
PathophysiologyThis section has been translated automatically.
The encoded Smad4 protein plays a central role in muscle physiology for the balance between atrophy and hypertrophy. When recruited by MSTN, it promotes the atrophy response via phosphorylated SMAD2/4. A decrease in MSTN causes the release of SMAD4 and subsequent recruitment by the BMP signaling pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in BMP (bone morphogenetic protein)-mediated cardiac-specific gene expression. Binds to SMAD-binding elements (SBEs) (5'-GTCT/AGAC-3') within the BMP response element (BMPRE) of cardiac activation regions.
Common SMAD (co-SMAD) is the co-activator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex that forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates the activity of PDPK1 kinase by stimulating its dissociation from the 14-3-3 protein YWHAQ, which acts as a negative regulator.
Clinical pictureThis section has been translated automatically.
Diseases associated with SMAD4 include:
- Myhre syndrome (very rare congenital disorder with a combination of short stature, muscular physique, restricted movement, hearing loss and mental retardation).
- and
- Juvenile polyposis syndrome.
LiteratureThis section has been translated automatically.
- Cavalli G (2017). SMAD4 gene mutation and risk of aortic dilation: Lessons from hereditary hemorrhagic telangiectasia. Int J Cardio 245:145-146.
- Lin AE et al. (2004) Myhre syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2024.
- Schutte M (1999) DPC4/SMAD4 gene alterations in human cancer, and their functional implications. Ann Oncol 10 Suppl 4:56-59.