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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)

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: a) activating transcription factor 2 (ATF2) b) CREB-binding protein c) p300 transcriptional adaptor protein - 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

Interactions

molecular events

Related

SMAD4 gene mutation SMAD4/MADH4/DPC4 gene

General

SMAD protein

Properties

SIZE: entity length = 552 aa MW = 60 kD MOTIF: MH1 domain {N-TERMINUS} MH1 domain {18-142} proline-rich region MOTIF: proline residue (SEVERAL) SAD {275-320} MH2 domain {323-552} MOTIF: alanine-rich region {451-466} MOTIF: alanine residue (SEVERAL) MH2 domain {C-TERMINUS}

Database Correlations

OMIM correlations MORBIDMAP 600993 UniProt Q13485 PFAM correlations Entrez Gene 4089 Kegg hsa:4089

References

  1. UniProt :accession Q13485
  2. Izzi L & Attisano L Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 23:2071-8, 2004 PMID: 15021894
  3. Derynck R et al. TGF-beta signaling in tumor suppression and cancer progression. Nature genetics 29:17-129, 2001 PMID: 11586292
  4. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/SMAD4ID371.html
  5. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/SMAD4

Component-of

molecular complex