Hmdb loader
Identification
HMDB Protein ID HMDBP14461
Secondary Accession Numbers None
Name Mothers against decapentaplegic homolog 4
Synonyms
  1. MAD homolog 4
  2. Mothers against DPP homolog 4
  3. Deletion target in pancreatic carcinoma 4 homolog
  4. SMAD family member 4
  5. SMAD 4
  6. Smad4
Gene Name SMAD4
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function 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. 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 (By similarity). Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (PubMed:15329343). 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.
Pathways
  • Adherens junction
  • AGE-RAGE signaling pathway in diabetic complications
  • Apelin signaling pathway
  • Cell cycle
  • Chronic myeloid leukemia
  • Colorectal cancer
  • FoxO signaling pathway
  • Gastric cancer
  • Hepatitis B
  • Hepatocellular carcinoma
  • Hippo signaling pathway
  • Human T-cell leukemia virus 1 infection
  • Pancreatic cancer
  • Signaling pathways regulating pluripotency of stem cells
  • TGF-beta signaling pathway
  • Th17 cell differentiation
  • Wnt signaling pathway
Reactions Not Available
GO Classification
Biological Process
cellular response to glucose stimulus
cell differentiation
spermatogenesis
regulation of cell proliferation
cell proliferation
cellular iron ion homeostasis
response to hypoxia
intracellular signal transduction
male gonad development
anterior/posterior pattern specification
kidney development
negative regulation of cell proliferation
developmental growth
in utero embryonic development
negative regulation of transcription, DNA-dependent
positive regulation of transcription, DNA-dependent
endothelial cell activation
negative regulation of transcription from RNA polymerase II promoter
negative regulation of cell growth
regulation of binding
embryonic digit morphogenesis
anatomical structure morphogenesis
regulation of transcription from RNA polymerase II promoter
positive regulation of transcription from RNA polymerase II promoter
osteoblast differentiation
gastrulation
positive regulation of histone H3-K4 methylation
transforming growth factor beta receptor signaling pathway
negative regulation of ERK1 and ERK2 cascade
ventricular septum morphogenesis
axon guidance
endoderm development
mesoderm development
branching involved in ureteric bud morphogenesis
wound healing
tissue morphogenesis
single fertilization
regulation of hair follicle development
gastrulation with mouth forming second
ovarian follicle development
negative regulation of protein catabolic process
female gonad development
BMP signaling pathway
sebaceous gland development
ERK1 and ERK2 cascade
positive regulation of pri-miRNA transcription by RNA polymerase II
positive regulation of BMP signaling pathway
negative regulation of cell death
positive regulation of epithelial to mesenchymal transition
interleukin-6-mediated signaling pathway
SMAD protein signal transduction
neuron fate commitment
positive regulation of pathway-restricted SMAD protein phosphorylation
epithelial to mesenchymal transition involved in endocardial cushion formation
negative regulation of cardiac muscle hypertrophy
atrioventricular canal development
atrioventricular valve formation
brainstem development
cardiac septum development
endocardial cell differentiation
female gonad morphogenesis
formation of anatomical boundary
left ventricular cardiac muscle tissue morphogenesis
mesendoderm development
metanephric mesenchyme morphogenesis
negative regulation of cardiac myofibril assembly
nephrogenic mesenchyme morphogenesis
neural crest cell differentiation
outflow tract septum morphogenesis
positive regulation of cardiac muscle cell apoptotic process
positive regulation of cell proliferation involved in heart valve morphogenesis
positive regulation of follicle-stimulating hormone secretion
positive regulation of histone H3-K9 acetylation
positive regulation of luteinizing hormone secretion
positive regulation of SMAD protein signal transduction
positive regulation of transforming growth factor beta receptor signaling pathway
regulation of transforming growth factor beta receptor signaling pathway
regulation of transforming growth factor beta2 production
response to transforming growth factor beta
secondary palate development
seminiferous tubule development
SMAD protein complex assembly
somite rostral/caudal axis specification
uterus development
Cellular Component
cytosol
cytoplasm
nucleus
nucleoplasm
chromatin
transcription factor complex
centrosome
protein-containing complex
RNA polymerase II transcription regulator complex
activin responsive factor complex
heteromeric SMAD protein complex
SMAD protein complex
Molecular Function
metal ion binding
protein homodimerization activity
identical protein binding
collagen binding
chromatin binding
DNA binding
sequence-specific DNA binding transcription factor activity
RNA polymerase II core promoter proximal region sequence-specific DNA binding
sulfate binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
transcription regulatory region sequence-specific DNA binding
filamin binding
RNA polymerase II transcription regulatory region sequence-specific DNA binding
R-SMAD binding
SMAD binding
I-SMAD binding
RNA polymerase II transcription factor binding
transcription coactivator binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 551
Molecular Weight 60341.65
Theoretical pI 6.984
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P97471
UniProtKB/Swiss-Prot Entry Name SMAD4_MOUSE
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  3. Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP: A tissue-specific atlas of mouse protein phosphorylation and expression. Cell. 2010 Dec 23;143(7):1174-89. doi: 10.1016/j.cell.2010.12.001. [PubMed:21183079 ]
  4. Anna CH, Devereux TR: Sequence and chromosomal mapping of the mouse homolog (Madh4) of the human DPC4/MADH4 gene. Mamm Genome. 1997 Jun;8(6):443-4. doi: 10.1007/s003359900465. [PubMed:9166592 ]
  5. Jiao K, Zhou Y, Hogan BL: Identification of mZnf8, a mouse Kruppel-like transcriptional repressor, as a novel nuclear interaction partner of Smad1. Mol Cell Biol. 2002 Nov;22(21):7633-44. doi: 10.1128/MCB.22.21.7633-7644.2002. [PubMed:12370310 ]
  6. Lee KH, Evans S, Ruan TY, Lassar AB: SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer. Development. 2004 Oct;131(19):4709-23. doi: 10.1242/dev.01344. Epub 2004 Aug 25. [PubMed:15329343 ]
  7. Collart C, Remacle JE, Barabino S, van Grunsven LA, Nelles L, Schellens A, Van de Putte T, Pype S, Huylebroeck D, Verschueren K: Smicl is a novel Smad interacting protein and cleavage and polyadenylation specificity factor associated protein. Genes Cells. 2005 Sep;10(9):897-906. doi: 10.1111/j.1365-2443.2005.00887.x. [PubMed:16115198 ]
  8. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J, Wrana JL: The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell. 2010 Dec 14;19(6):831-44. doi: 10.1016/j.devcel.2010.11.012. [PubMed:21145499 ]
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