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 SMAD4 gene functions as a tumor suppressor gene. The encoded Smad4 protein belongs to a family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to the signaling of transforming growth factor beta (TGF-β) via various signaling pathways (McCarthy AJ et al. 2018).
Co-SMAD is the co-activator and mediator of signal transduction by TGF-beta (transforming growth factor). It is a component of the heterotrimeric SMAD2/SMAD3/SMAD4 complex, which forms in the cell nucleus and is required for TGF-mediated signal transduction. Promotes the binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activating function required for SMAD1 or SMAD2 to stimulate transcription. A component of the multimeric SMAD3/SMAD4/JUN/FOS complex, which 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 the PDPK1 kinase by stimulating its dissociation from the 14-3-3 protein YWHAQ, which acts as a negative regulator.

Smad4/DPC4 also plays a role in cancers such as colorectal and prostate carcinomas. In normal and reactive states, the protein is localized in the cytoplasm and the cell nucleus, whereas it is lost in high-grade pancreatic intraepithelial neoplasia/carcinoma in situ as well as in pancreatic carcinoma.

Smad4 acts synergistically with SMAD1 and YY1 in BMP (bone morphogenetic protein)-mediated cardiac-specific gene expression. It binds to SMAD-binding elements (SBEs) (5'-GTCT/AGAC-3') within the BMP response element (BMPRE) of the cardiac activation regions.

Furthermore, the encoded Smad4 protein plays a central role in muscle physiology by maintaining the balance between atrophy and hypertrophy. When recruited by MSTN, it promotes the atrophy response via phosphorylated SMAD2/4. A decrease in MSTN leads to the release of SMAD4 and its subsequent recruitment by the BMP signaling pathway to promote hypertrophy via phosphorylated SMAD1/5/8.

Diseases associated with SMAD4 include:

• Myhre syndrome (a very rare congenital disorder characterized by a combination of short stature, muscular build, limited mobility, hearing loss, and intellectual disability).
•  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. McCarthy AJ et al. (2018) Smad4/DPC4. J Clin Pathol 71:661–664.
4. Schutte M (1999) DPC4/SMAD4 gene alterations in human cancer, and their functional implications. Ann Oncol 10 Suppl 4:56–59.