SMAD4/MADH4; mothers against decapentaplegic homolog 4; mothers against DPP homolog 4; MAD homolog 4; SMAD family member 4; SMAD 4; smad4; hSMAD4; deletion target in pancreatic carcinoma 4 (SMAD4, DPC4, MADH4)
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Function
- common mediator of signal transduction by TGF-beta superfamily
- SMAD4 is the common SMAD (co-SMAD)
binds phosphorylated R-SMADs; complex translocates to the nucleus; has intrinsic DNA binding capability[3].
- promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA & provides an activation function required for SMAD1 or SMAD2 to stimulate transcription
- may act as a tumor suppressor
- 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 may form trimers with receptor-regulated SMAD (R-SMAD)
- found in a ternary complex composed of SMAD4, STK11 & STK11IP
- interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11, STK11IP & TRIM33
- associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes
- interacts with USP9X
- interacts with RBPMS
- SMAD2/SMAD4 & SMAD3/SMAD4 complexes interact with transcription factors:
- SMAD2/SMA4 interacts with forkhead activin signal transducer 2
- ubiquitination regulates proteasomal degradation & possibly modulates function
Structure
- the MH1 & MH2 domains are necessary for interaction with RBPMS
- belongs to the dwarfin/SMAD family
- contains 1 MH1 (MAD homology 1) domain
- contains 1 MH2 (MAD homology 2) domain
Compartment
- cytoplasm, nucleus
- cytoplasmic in the absence of ligand
- migrates to the nucleus when complexed with R-SMAD
Pathology
- deleted or mutated in some pancreatic carcinomas
- mutations in gene associated with some cases of juvenile polyposis coli & correspondingly juvenile polyposis/ hereditary hemorrhagic telangiectasia syndrome
- defects in SMAD4 may be a cause of colorectal cancer
More general terms
Component of
References
- ↑ UniProt http://www.uniprot.org/uniprot/Q13485.html
- ↑ Izzi L & Attisano L Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 23:2071-8, 2004 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15021894
- ↑ 3.0 3.1 Derynck R et al. TGF-beta signaling in tumor suppression and cancer progression. Nature genetics 29:17-129, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11586292
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/SMAD4ID371.html
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/SMAD4
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4089
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4089
- OMIM: https://mirror.omim.org/entry/114500
- OMIM: https://mirror.omim.org/entry/174900
- OMIM: https://mirror.omim.org/entry/175050
- OMIM: https://mirror.omim.org/entry/260350
- OMIM: https://mirror.omim.org/entry/600993
- UniProt: http://www.uniprot.org/uniprot/Q13485.html