Gene SMAD4
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Also known as
MADH4, DPC4, JIP, MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 4Overview
SMAD4 (SMAD Family Member 4) is a central mediator in both the TGF-beta and BMP (bone morphogenetic protein) signaling pathways, making it unique among SMAD proteins. Unlike receptor-regulated SMADs (R-SMADs) such as SMAD2 and SMAD3, SMAD4 functions as a common mediator SMAD (Co-SMAD) that forms complexes with activated R-SMADs and translocates to the nucleus to regulate transcription of target genes. This dual role in TGF-beta and BMP signaling makes SMAD4 essential for numerous developmental processes, including gastrointestinal tract formation, immune regulation, and tumor suppression.Germline mutations in SMAD4 are responsible for juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT), as well as a combined syndrome with features of both conditions. JPS is characterized by the development of hamartomatous polyps throughout the gastrointestinal tract, with significantly increased risk of colorectal cancer. Somatic SMAD4 mutations are also common in pancreatic adenocarcinoma, where loss of SMAD4 expression is associated with poor prognosis and is used as a diagnostic marker. Additionally, SMAD4 inactivation occurs in colorectal cancer and other malignancies, where it contributes to tumor progression by disrupting TGF-beta-mediated growth inhibition and promoting metastasis.