SMAD4

SMAD4 is a human gene that encodes a central mediator protein in the transforming growth factor beta (TGF-β) signaling pathway. Also known as DPC4 (deleted in pancreatic cancer, locus 4), the gene is located on chromosome 18q21.1. The SMAD4 protein acts as a common mediator (co-SMAD) for TGF-β and bone morphogenetic protein (BMP) signaling, forming complexes with receptor-regulated SMADs (R-SMADs) after they are phosphorylated by TGF-β or BMP receptors. The SMAD4-containing complex then translocates to the nucleus to regulate transcription of target genes involved in cell cycle control, differentiation, and apoptosis.

SMAD4 contains an N-terminal MH1 (MAD homology 1) DNA-binding domain and a C-terminal MH2 (MAD homology 2) domain. It is a cytoplasmic/nuclear shuttling protein that does not have a membrane anchor. As a co-SMAD, SMAD4 is essential for the transcriptional response to TGF-β signals; without SMAD4, signaling through these pathways is impaired and downstream gene regulation is disrupted.

Clinically, SMAD4 functions as a tumor suppressor gene. Somatic mutations or deletions of SMAD4 are common in pancreatic ductal adenocarcinoma and appear in other cancers as well. Germline mutations in SMAD4 cause juvenile polyposis syndrome, a hereditary condition associated with increased cancer risk. Loss or inactivation of SMAD4 can reduce TGF-β–mediated growth inhibition and contribute to oncogenesis, while in some contexts TGF-β signaling may promote tumor progression via non-canonical pathways.