Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0007147
UniProt IDQ13485
Primary gene name(s)SMAD4
Synonym gene name(s)DPC4, MADH4
Protein nameMothers against decapentaplegic homolog 4
Protein functionIn 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. 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. {ECO:0000250, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9389648}.
Subcellular locationCytoplasm {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236}. Nucleus {ECO:0000269|PubMed:15799969}. Note=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. {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: Q13485
Gene Ontology
(Biological Process)
Complete annatation
atrioventricular canal development [GO:0036302];
atrioventricular valve formation [GO:0003190];
axon guidance [GO:0007411];
BMP signaling pathway [GO:0030509];
brainstem development [GO:0003360];
branching involved in ureteric bud morphogenesis [GO:0001658];
cell proliferation [GO:0008283];
cellular iron ion homeostasis [GO:0006879];
cellular response to BMP stimulus [GO:0071773];
developmental growth [GO:0048589];
embryonic digit morphogenesis [GO:0042733];
endocardial cell differentiation [GO:0060956];
endoderm development [GO:0007492];
endothelial cell activation [GO:0042118];
epithelial to mesenchymal transition involved in endocardial cushion formation [GO:0003198];
female gonad morphogenesis [GO:0061040];
formation of anatomical boundary [GO:0048859];
gastrulation with mouth forming second [GO:0001702];
interleukin-6-mediated signaling pathway [GO:0070102];
intracellular signal transduction [GO:0035556];
in utero embryonic development [GO:0001701];
left ventricular cardiac muscle tissue morphogenesis [GO:0003220];
mesoderm development [GO:0007498];
metanephric mesenchyme morphogenesis [GO:0072133];
negative regulation of cardiac muscle hypertrophy [GO:0010614];
negative regulation of cardiac myofibril assembly [GO:1905305];
negative regulation of cell death [GO:0060548];
negative regulation of cell growth [GO:0030308];
negative regulation of cell proliferation [GO:0008285];
negative regulation of ERK1 and ERK2 cascade [GO:0070373];
negative regulation of transcription, DNA-templated [GO:0045892];
negative regulation of transcription from RNA polymerase II promoter [GO:0000122];
nephrogenic mesenchyme morphogenesis [GO:0072134];
neural crest cell differentiation [GO:0014033];
neuron fate commitment [GO:0048663];
outflow tract septum morphogenesis [GO:0003148];
ovarian follicle development [GO:0001541];
palate development [GO:0060021];
positive regulation of BMP signaling pathway [GO:0030513];
positive regulation of cell proliferation involved in heart valve morphogenesis [GO:0003251];
positive regulation of epithelial to mesenchymal transition [GO:0010718];
positive regulation of follicle-stimulating hormone secretion [GO:0046881];
positive regulation of histone H3-K4 methylation [GO:0051571];
positive regulation of histone H3-K9 acetylation [GO:2000617];
positive regulation of luteinizing hormone secretion [GO:0033686];
positive regulation of pathway-restricted SMAD protein phosphorylation [GO:0010862];
positive regulation of SMAD protein import into nucleus [GO:0060391];
positive regulation of transcription, DNA-templated [GO:0045893];
positive regulation of transcription from RNA polymerase II promoter [GO:0045944];
positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus [GO:1901522];
positive regulation of transforming growth factor beta receptor signaling pathway [GO:0030511];
regulation of binding [GO:0051098];
regulation of hair follicle development [GO:0051797];
regulation of transforming growth factor beta2 production [GO:0032909];
regulation of transforming growth factor beta receptor signaling pathway [GO:0017015];
response to hypoxia [GO:0001666];
response to transforming growth factor beta [GO:0071559];
sebaceous gland development [GO:0048733];
seminiferous tubule development [GO:0072520];
single fertilization [GO:0007338];
SMAD protein complex assembly [GO:0007183];
SMAD protein signal transduction [GO:0060395];
somatic stem cell population maintenance [GO:0035019];
somite rostral/caudal axis specification [GO:0032525];
spermatogenesis [GO:0007283];
transforming growth factor beta receptor signaling pathway [GO:0007179];
uterus development [GO:0060065];
ventricular septum morphogenesis [GO:0060412]
Gene Ontology
(Molecular Function)
Complete annatation
chromatin binding [GO:0003682];
core promoter proximal region sequence-specific DNA binding [GO:0000987];
identical protein binding [GO:0042802];
I-SMAD binding [GO:0070411];
metal ion binding [GO:0046872];
protein homodimerization activity [GO:0042803];
RNA polymerase II core promoter proximal region sequence-specific DNA binding [GO:0000978];
R-SMAD binding [GO:0070412];
transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding [GO:0001077];
transcription factor activity, RNA polymerase II transcription factor binding [GO:0001076];
transcription regulatory region DNA binding [GO:0044212];
transforming growth factor beta receptor, common-partner cytoplasmic mediator activity [GO:0030616]
Gene Ontology
(Cellular Component)
Complete annatation
activin responsive factor complex [GO:0032444];
cytoplasm [GO:0005737];
cytosol [GO:0005829];
nuclear chromatin [GO:0000790];
nucleoplasm [GO:0005654];
nucleus [GO:0005634];
SMAD protein complex [GO:0071141];
transcription factor complex [GO:0005667]
Protein-protein interaction110264
Phylogenetic treeQ13485
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-0.1172445955372010.720147093704410.802340109130164
AZA vs. DISU0.2699535222094590.2890028778202110.85676070959683
AZA vs. IL7-0.06687270336514030.7282859456298370.999311006273513
AZA vs. SAHA-0.1458648807078410.5502789503464930.847319150875362
DISU vs. CD30.3746145971556550.3040979855690430.435614656891357
DISU vs. IL7-0.3456647601320190.1724068415711560.537240320818655
DISU vs. SAHA-0.415038478323150.156126864270090.508974252955769
DMSO vs. AZA-0.06336006283801430.7058038733910591
DMSO vs. CD30.04238949246332420.8944661342145510.928295144112856
DMSO vs. DISU-0.3351913341169080.1724749379127760.684995645850879
DMSO vs. IL70.003726006905465750.9834902887929410.998221026906907
DMSO vs. SAHA-0.08983093692910120.703404839687250.910949929796312
HIV vs. Mock in Activation-0.05823194326222870.9254993426835520.999983755607037
HIV vs. Mock in Latency-0.01736520166588440.9162693478445930.999834320637052
IL7 vs. CD30.05868332332186550.8549579690722880.906770496900004
SAHA vs. CD3-0.05402235870206360.8783948115729860.914880766494223
SAHA vs. IL7-0.08349603196563090.7318044807957680.878024241602841
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK -0.360006 0.0325783
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
0.976 0.879 0.977 0.874 0.861
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
1DD1 X-ray 2.6Å A/B/C=285-552.
1G88 X-ray 3.0Å A/B/C=285-552.
1MR1 X-ray 2.8Å A/B=319-552.
1U7F X-ray 2.6Å B=314-552.
1U7V X-ray 2.7Å B=314-549.
1YGS X-ray 2.1Å A=319-552.
5C4V X-ray 2.6Å A/C/E=314-549.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
Tat enhances 19420158
Tat modulates 23152365
Tat inhibited by 12202226
Tat downregulates 24008158

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04068 FoxO signaling pathway - Homo sapiens (human)
hsa04110 Cell cycle - Homo sapiens (human)
hsa04310 Wnt signaling pathway - Homo sapiens (human)
hsa04350 TGF-beta signaling pathway - Homo sapiens (human)
hsa04390 Hippo signaling pathway - Homo sapiens (human)
hsa04520 Adherens junction - Homo sapiens (human)
hsa04550 Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
hsa04659 Th17 cell differentiation - Homo sapiens (human)
hsa04933 AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
hsa05161 Hepatitis B - Homo sapiens (human)
hsa05166 HTLV-I infection - Homo sapiens (human)
hsa05200 Pathways in cancer - Homo sapiens (human)
hsa05210 Colorectal cancer - Homo sapiens (human)
hsa05212 Pancreatic cancer - Homo sapiens (human)
hsa05220 Chronic myeloid leukemia - Homo sapiens (human)