SMAD4

SMAD4
File:Smad4 protein structure.png Crystal structure of the SMAD4 protein
Identifiers
Symbol	?
NCBI gene	4089
HGNC	6770
OMIM	600993
RefSeq	NM_005359
UniProt	Q13485
Search for Structures Swiss-model Domains InterPro

SMAD4 (SMAD family member 4) is a protein encoded by the SMAD4 gene in humans. It is a member of the SMAD family of proteins, which are critical components of the TGF-beta signaling pathway. SMAD4 is also known as DPC4 (Deleted in Pancreatic Cancer 4) due to its frequent deletion in pancreatic cancer.

Function

SMAD4 is a signal transducer and transcriptional modulator that mediates multiple signaling pathways. It is a common-mediator SMAD (co-SMAD) that forms complexes with receptor-regulated SMADs (R-SMADs) to regulate the transcription of target genes. Upon activation by TGF-beta or BMP ligands, R-SMADs are phosphorylated and form a complex with SMAD4, which then translocates to the nucleus to influence gene expression.

Clinical Significance

Mutations or deletions of the SMAD4 gene are implicated in several types of cancer, including pancreatic cancer, colorectal cancer, and gastric cancer. SMAD4 mutations are also associated with juvenile polyposis syndrome, a hereditary condition that increases the risk of developing gastrointestinal polyps and cancer.

Pancreatic Cancer

SMAD4 is frequently inactivated in pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive forms of cancer. The loss of SMAD4 function disrupts TGF-beta signaling, which can lead to uncontrolled cell proliferation and tumor progression.

Juvenile Polyposis Syndrome

Germline mutations in SMAD4 are one of the causes of juvenile polyposis syndrome (JPS), a condition characterized by the development of numerous polyps in the gastrointestinal tract. Individuals with JPS have an increased risk of developing gastrointestinal cancers.

Structure

The SMAD4 protein consists of two main domains: the MH1 (MAD homology 1) domain, which is involved in DNA binding, and the MH2 (MAD homology 2) domain, which is responsible for protein-protein interactions. The linker region between these domains is subject to post-translational modifications that regulate SMAD4 activity.

Interactions

SMAD4 interacts with various proteins to exert its function. It forms complexes with R-SMADs such as SMAD2 and SMAD3 in the TGF-beta pathway, and with SMAD1, SMAD5, and SMAD8 in the BMP pathway. SMAD4 also interacts with transcription factors and co-activators to regulate gene expression.

Research Directions

Current research on SMAD4 focuses on understanding its role in cancer progression and metastasis, as well as its potential as a therapeutic target. Studies are also exploring the development of drugs that can modulate SMAD4 activity or compensate for its loss in cancer cells.

Also see

• TGF-beta signaling pathway
• Pancreatic cancer
• Juvenile polyposis syndrome
• SMAD family
• BMP signaling pathway