Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0010410
UniProt IDP84022
Primary gene name(s)SMAD3
Synonym gene name(s)MADH3
Protein nameMothers against decapentaplegic homolog 3
Protein functionReceptor-regulated SMAD, R-SMAD that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta, transforming growth factor and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:10995748, ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:15588252, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9732876, ECO:0000269|PubMed:9892009}.
Subcellular locationCytoplasm {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:22781750}. Nucleus {ECO:0000269|PubMed:15601644, ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:22781750}. Note=Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4, PubMed:15799969. Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1, PubMed:16751101, PubMed:19289081. Co-localizes with LEMD3 at the nucleus inner membrane, PubMed:15601644. MAPK-mediated phosphorylation appears to have no effect on nuclear import, PubMed:19218245. PDPK1 prevents its nuclear translocation in response to TGF-beta, PubMed:17327236. {ECO:0000269|PubMed:15601644, ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P84022
Gene Ontology
(Biological Process)
Complete annatation
activation of cysteine-type endopeptidase activity involved in apoptotic process [GO:0006919];
activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway [GO:0097296];
activin receptor signaling pathway [GO:0032924];
canonical Wnt signaling pathway [GO:0060070];
cell-cell junction organization [GO:0045216];
cell cycle arrest [GO:0007050];
developmental growth [GO:0048589];
embryonic cranial skeleton morphogenesis [GO:0048701];
embryonic foregut morphogenesis [GO:0048617];
embryonic pattern specification [GO:0009880];
endoderm development [GO:0007492];
evasion or tolerance of host defenses by virus [GO:0019049];
extrinsic apoptotic signaling pathway [GO:0097191];
heart looping [GO:0001947];
immune response [GO:0006955];
immune system development [GO:0002520];
in utero embryonic development [GO:0001701];
lens fiber cell differentiation [GO:0070306];
liver development [GO:0001889];
mesoderm formation [GO:0001707];
negative regulation of apoptotic process [GO:0043066];
negative regulation of cell growth [GO:0030308];
negative regulation of cytosolic calcium ion concentration [GO:0051481];
negative regulation of fat cell differentiation [GO:0045599];
negative regulation of inflammatory response [GO:0050728];
negative regulation of mitotic cell cycle [GO:0045930];
negative regulation of osteoblast differentiation [GO:0045668];
negative regulation of osteoblast proliferation [GO:0033689];
negative regulation of protein catabolic process [GO:0042177];
negative regulation of transcription from RNA polymerase II promoter [GO:0000122];
negative regulation of transforming growth factor beta receptor signaling pathway [GO:0030512];
negative regulation of wound healing [GO:0061045];
nodal signaling pathway [GO:0038092];
osteoblast development [GO:0002076];
paraxial mesoderm morphogenesis [GO:0048340];
pericardium development [GO:0060039];
positive regulation of alkaline phosphatase activity [GO:0010694];
positive regulation of bone mineralization [GO:0030501];
positive regulation of catenin import into nucleus [GO:0035413];
positive regulation of cell migration [GO:0030335];
positive regulation of chondrocyte differentiation [GO:0032332];
positive regulation of epithelial to mesenchymal transition [GO:0010718];
positive regulation of extracellular matrix assembly [GO:1901203];
positive regulation of focal adhesion assembly [GO:0051894];
positive regulation of gene expression [GO:0010628];
positive regulation of interleukin-1 beta production [GO:0032731];
positive regulation of nitric oxide biosynthetic process [GO:0045429];
positive regulation of positive chemotaxis [GO:0050927];
positive regulation of pri-miRNA transcription from RNA polymerase II promoter [GO:1902895];
positive regulation of stress fiber assembly [GO:0051496];
positive regulation of transcription, DNA-templated [GO:0045893];
positive regulation of transcription factor import into nucleus [GO:0042993];
positive regulation of transcription from RNA polymerase II promoter [GO:0045944];
positive regulation of transforming growth factor beta3 production [GO:0032916];
primary miRNA processing [GO:0031053];
protein stabilization [GO:0050821];
regulation of binding [GO:0051098];
regulation of epithelial cell proliferation [GO:0050678];
regulation of immune response [GO:0050776];
regulation of striated muscle tissue development [GO:0016202];
regulation of transcription from RNA polymerase II promoter [GO:0006357];
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];
signal transduction involved in regulation of gene expression [GO:0023019];
SMAD protein complex assembly [GO:0007183];
SMAD protein signal transduction [GO:0060395];
somitogenesis [GO:0001756];
T cell activation [GO:0042110];
thyroid gland development [GO:0030878];
transcription, DNA-templated [GO:0006351];
transdifferentiation [GO:0060290];
transforming growth factor beta receptor signaling pathway [GO:0007179];
transport [GO:0006810];
ureteric bud development [GO:0001657];
wound healing [GO:0042060]
Gene Ontology
(Molecular Function)
Complete annatation
beta-catenin binding [GO:0008013];
bHLH transcription factor binding [GO:0043425];
chromatin DNA binding [GO:0031490];
core promoter proximal region sequence-specific DNA binding [GO:0000987];
co-SMAD binding [GO:0070410];
enhancer binding [GO:0035326];
identical protein binding [GO:0042802];
phosphatase binding [GO:0019902];
protein homodimerization activity [GO:0042803];
protein kinase binding [GO:0019901];
RNA polymerase II activating transcription factor binding [GO:0001102];
RNA polymerase II core promoter proximal region sequence-specific DNA binding [GO:0000978];
R-SMAD binding [GO:0070412];
sequence-specific DNA binding [GO:0043565];
transcription factor activity, RNA polymerase II core promoter sequence-specific [GO:0000983];
transcription factor activity, sequence-specific DNA binding [GO:0003700];
transcription factor binding [GO:0008134];
transcription regulatory region DNA binding [GO:0044212];
transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity [GO:0030618];
transforming growth factor beta receptor binding [GO:0005160];
ubiquitin binding [GO:0043130];
ubiquitin protein ligase binding [GO:0031625];
zinc ion binding [GO:0008270]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytosol [GO:0005829];
nuclear chromatin [GO:0000790];
nuclear inner membrane [GO:0005637];
nucleoplasm [GO:0005654];
nucleus [GO:0005634];
plasma membrane [GO:0005886];
receptor complex [GO:0043235];
SMAD2-SMAD3 protein complex [GO:0071144];
SMAD protein complex [GO:0071141];
transcription factor complex [GO:0005667]
Protein-protein interaction110263
Phylogenetic treeP84022
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. CD3-0.5285983989051690.4127539995035550.534314891395481
AZA vs. DISU0.4360124206975060.08535314198421570.612672982033366
AZA vs. IL7-0.494029769293420.01028656057518730.331301981944013
AZA vs. SAHA-0.1294414338576070.5956701981028990.867158208964865
DISU vs. CD30.9511713807483590.1502643726482220.256550589341862
DISU vs. IL7-0.9393824354208310.0002178370856701360.00949102331351822
DISU vs. SAHA-0.5635138625758630.05349011314787240.289981832824311
DMSO vs. AZA0.01513914898357030.9278653617322261
DMSO vs. CD30.5313874495493020.4102463280625430.524559576664592
DMSO vs. DISU-0.4229033620451420.08346812241074670.535720777090477
DMSO vs. IL7-0.5018218403587550.005322593830815790.149697951491694
DMSO vs. SAHA-0.1506408466946130.5226689756907870.82604279914386
HIV vs. Mock in Activation0.8074232142718170.5361687480680620.999983755607037
HIV vs. Mock in Latency0.2629658147614060.1659033857485940.999834320637052
IL7 vs. CD30.04046498097165250.9498910748944730.969434359771355
SAHA vs. CD30.3745618302202520.5630322675912650.665690904801535
SAHA vs. IL70.3608084969389250.1388236024135950.35046507834241
(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 -0.349086 0.00605069
(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
unknown unknown unknown unknown unknown
(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
1MHD X-ray 2.8Å A/B=1-132.
1MJS X-ray 1.9Å A=229-425.
1MK2 X-ray 2.7Å A=220-425.
1OZJ X-ray 2.4Å A/B=1-144.
1U7F X-ray 2.6Å A/C=228-425.
2LAJ NMR - B=202-211.
2LB2 NMR - B=178-189.

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

HIV Partner Interaction Type PubMed
Tat enhances 19420158
Tat inhibited by 16750572
Tat stimulated by 12202226
Tat downregulates 24008158
Vpr activates 18417583

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)
hsa04144 Endocytosis - 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)
hsa05142 Chagas disease (American trypanosomiasis) - 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)
hsa05321 Inflammatory bowel disease (IBD) - Homo sapiens (human)