SMAD4
GeneName
SMAD4
Summary
SMAD4, also known as DPC4 or Smad 4, is a 60kDa protein that functions as a key transcription factor in the TGF-beta signalling pathway. It is predominantly expressed in the nucleus and cytoplasm, where it forms heteromeric complexes with other SMAD proteins to regulate gene expression. SMAD4 plays a crucial role in various biological processes, including cell differentiation, morphogenesis, and response to extracellular signals. It is involved in the regulation of numerous developmental pathways, such as cardiac and adrenal gland development, and is essential for the transcriptional activation of target genes in response to TGF-beta and BMP signals.
Importance
SMAD4 is relevant to: - Tumourigenesis, particularly in pancreatic and colorectal cancers, where mutations in SMAD4 are frequently observed. - Developmental biology, due to its role in embryonic development and organogenesis. - Disease mechanisms involving fibrosis and inflammation, as it mediates the effects of TGF-beta in tissue repair and scarring. - Understanding cellular processes like epithelial to mesenchymal transition, which is critical in cancer metastasis and tissue regeneration.
Top Products
For researchers investigating SMAD4, we highly recommend the top-selling recombinant antibody, Anti-Smad4 antibody [EP618Y] (ab40759). This well-cited product has garnered 192 citations, reflecting its strong reputation in the field. It has been validated in knockout models, ensuring reliable performance in various applications, particularly in Western blotting (WB) and immunohistochemistry (IHC). The consistency and reliability of this recombinant antibody make it an excellent choice for those studying SMAD4. The Human SMAD4 ELISA Kit (ab253211), supported by 2 citations, is an excellent option for researchers looking to accurately measure SMAD4 levels in their samples.
Abcam Product Citation Summary
The data indicates that SMAD4 is a significant target in various cancer studies, particularly in human tissues such as bladder cancer, cervical carcinoma, and colorectal cancer. The use of multiple applications, primarily Western blotting, highlights its role in understanding signaling pathways and tumor growth regulation. Additionally, studies involving mouse and rat models suggest a broader relevance in developmental and differentiation processes.
Abcam Product Citation Table
Domain
The MH1 domain is required for DNA binding.
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.
Function
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 (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. 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 PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
Involvement in disease
Pancreatic cancer
PNCA
A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
None
The gene represented in this entry may be involved in disease pathogenesis.
Juvenile polyposis syndrome
JPS
Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.
None
The disease is caused by variants affecting the gene represented in this entry.
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
JP/HHT
JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.
None
The disease is caused by variants affecting the gene represented in this entry.
Colorectal cancer
CRC
A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
None
The disease may be caused by variants affecting the gene represented in this entry.
SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.
Myhre syndrome
MYHRS
An autosomal dominant syndrome characterized by pre- and postnatal growth deficiency, intellectual disability, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylated by PDPK1.
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.
Sequence Similarities
Belongs to the dwarfin/SMAD family.
Cellular localization
- Cytoplasm
- Nucleus
- Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD (PubMed:15799969). PDPK1 prevents its nuclear translocation in response to TGF-beta (PubMed:17327236).
Alternative names
DPC4, MADH4, SMAD4, SMAD family member 4, SMAD 4, hSMAD4, Deletion target in pancreatic carcinoma 4, Mothers against decapentaplegic homolog 4, MAD homolog 4, Mothers against DPP homolog 4
Database links
swissprot:Q13485 omim:600993 entrezGene:4089
Other research areas
- Oncology