Search by BoMiProt ID - Bomi7214


Primary Information

BoMiProt ID Bomi7214
Protein Name Mothers against decapentaplegic homolog 4/MAD homolog 4/ Mothers against DPP homolog 4/SMAD family member 4/SMAD 4/Smad4
Organism Bos taurus
Uniprot IdQ1HE26
Milk FractionWhey,MFGM
Ref Sequence Id NP_001069677.1
Aminoacid Length 553
Molecular Weight 60542
Fasta Sequence https://www.uniprot.org/uniprot/Q1HE26.fasta
Gene Name SMAD4
Gene Id 540248
Protein Existence Status reviewed

Secondary Information

Protein Function SMAD4 functions at the G1/S checkpoint to make cells stay at the G1 phase, thus leading to cell cycle arrest.Acts as tumor suppressor protein.Also serve as a prognostic indicator.
Biochemical Properties onsists of three major parts, including the N-terminal MH1 domain, the C-terminal MH2 domain and the linker region between them.The MH1 domain is responsible for DNA binding by recognizing the SMAD-binding DNA element (SBE).MH2 domain is important for its transcriptional activity .The SMAD activation domain (SAD), locating at the C-terminal of linker region, is necessary for SMAD4 transcriptional activity.
PTMs Phosphorylation,Ubl conjugation,sumoylation,ADP ribosylation
Site(s) of PTM(s)

N-glycosylation, O-glycosylation,
Phosphorylation
NA
Predicted Disorder Regions 152-258, 269-315, 462-477
DisProt Annotation
TM Helix Prediction No TM helices
Significance of PTMs Smad4 is ADP-ribosylated by PARP-1 in its DNA-binding MH1 domain, which interferes with Smad4 DNA binding and attenuates Smad-mediated transcription and induction of EMT. SMAD4 sumoylation by PIAS family of E3 ligase which facilitates SMAD4 dependent transcription.Smad4 sumoylation may prevent Smad4 from ubiquitylation, thus protecting Smad4 from degradation to enhance TGF-β-induced Smad signaling.Monoubiquitinated on Lys-520 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.Erk kinases phosphorylate Smad4 specifically at Thr276 in the linker region, and this phosphorylation stabilizes the binding of the coactivators p300 and CBP to the heteromeric Smad complex. Liver kinase B1 (LKB1), also known as STK11, phosphorylates Thr77 in the MH1 domain of Smad4,which regulates cell polarity and is required in the control of cell metabolism.Also it interferes with Smad4 binding to either TGF-β or BMP-specific promoter sequences, and inhibits Smad-mediated gene expression and TGF-β-induced EMT.Phosphorylation of Smad4 by the serine/threonine kinase MPK38, known to activate p53 function, is thought to enhance TGF-β signaling and TGF-β-induced apoptosis and cell growth arrest.
Additional Comments ERK pathway inhibits the TGF-β/SMAD4 pathway by phosphorylating SMAD2 and SMAD3 at the serine or threonine residues in the linker region, thus preventing its translocation into the nucleus
Bibliography Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci. 2018 Jan 12;14(2):111-123. doi: 10.7150/ijbs.23230. PMID: 29483830; PMCID: PMC5821033.