SMAD4
SMAD4 (SMAD family member 4) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer and 5 more.
Overview
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8.
CIViC holds 31 clinical evidence items and 0 assertions across 20 variants, naming Cetuximab, Trametinib, Bevacizumab and Panitumumab and others. Open Targets scores its association with cancer at 0.87 (direct and indirect evidence; datatypes genetic literature 0.56, affected pathway 0.61, literature 0.99, genetic association 0.89, somatic mutation 0.97, animal model 0.85). IntOGen calls it a driver in 37 cohorts (10 activating, 27 loss-of-function), covering Invasive Breast Carcinoma, Cervical Squamous Cell Carcinoma, Cholangiocarcinoma, Colon Adenocarcinoma, Colorectal Adenocarcinoma, Oesophageal Adenocarcinoma and others.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · SMAD4 (SMAD family member 4) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer and 5 more.
- 1 · What it is
SMAD4 (SMAD family member 4) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer and 5 more.
- 2 · What goes wrong in cancer
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4.
- 3 · How drugs use it
No product in this corpus aims at SMAD4 yet. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
External identifiers
Sources: HGNC HGNC:6770 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q13485 (protein name, function text, keywords and locations (REST API)); CIViC gene SMAD4 (31 evidence items, 0 assertions, 20 variants; diseases: Pancreatic Cancer, Colorectal Cancer, Prostate Cancer, Juvenile Polyposis Syndrome, Lung Non-small Cell Carcinoma and 3 more (GraphQL API, CC0)); Open Targets ENSG00000141646 (association with cancer (MONDO_0004992) 0.87; per-cancer scores at or above 0.5: non-small cell lung carcinoma 0.50, colorectal cancer 0.79, gastric cancer 0.62, oesophageal cancer 0.65, gallbladder cancer 0.50, lung cancer 0.56 (GraphQL API, CC0)); IntOGen SMAD4 (driver in 37 cohorts (Act 10, LoF 27); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)
Biology
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Location: Cytoplasm; Nucleus (UniProt). Locus 18q21.2 (HGNC).
- Colorectal cancer: Open Targets association 0.79 with colorectal cancer (MONDO_0005575); CIViC evidence names this disease
- Gastric & gastro-oesophageal junction cancer: Open Targets association 0.62 with gastric cancer (MONDO_0001056); IntOGen driver in 5 cohorts (STAD, STOMACH)
- Oesophageal cancer: Open Targets association 0.65 with oesophageal cancer (MONDO_0007576); IntOGen driver in 5 cohorts (ESCA, ESCC)
- Pancreatic ductal adenocarcinoma: CIViC evidence names this disease; IntOGen driver in 8 cohorts (PAAD, PANCREAS)
- Biliary tract cancer: Open Targets association 0.63 with biliary tract cancer (MONDO_0003060)
- Prostate cancer: CIViC evidence names this disease; IntOGen driver in 2 cohorts (PRAD, PROSTATE)
Notes
top- Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 11 therapies; IntOGen calls it an activating (Act) driver in 10 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 27 cohorts; CIViC holds 31 clinical evidence items on its variants. Evidence tier "clinical-evidence" is the strongest of those signals.
- Prevalence not recorded: none of the sources gives a positivity rate.
- Diseases the sources name that have no OnCo cancer page yet, so they are not linked: Juvenile Polyposis Syndrome.
Latest papers
topQuery for this target: (TITLE:"SMAD4" OR ABSTRACT:"SMAD4" OR TITLE:"SMAD family member 4" OR ABSTRACT:"SMAD family member 4" OR TITLE:"DPC4" OR ABSTRACT:"DPC4" OR TITLE:"MADH4" OR ABSTRACT:"MADH4") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about SMAD4, not a curated reading list.
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