SMAD4 gene

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.

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.

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.

1. Cavalli G (2017). SMAD4 gene mutation and risk of aortic dilation: Lessons from hereditary hemorrhagic telangiectasia. Int J Cardio 245:145-146.
2. 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.
3. Schutte M (1999) DPC4/SMAD4 gene alterations in human cancer, and their functional implications. Ann Oncol 10 Suppl 4:56-59.