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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

SMAD3 Gene

protein-coding GIFtS: 69
GCID: GC15P067358

SMAD family member 3

(Previous names: MAD, mothers against decapentaplegic homolog 3 (Drosophila),...)
(Previous symbol: MADH3)

Explore 102 diseases affiliated with
SMAD3 via

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(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, and/or ¹⁰fRNAdb)
About This Section

Aliases
SMAD Family Member 3¹ ² ³		LDS3²
MADH3¹ ² ³ ⁵		Mad Homolog JV15-2²
JV15-2¹ ² ³		Mad Protein Homolog²
HsT17436¹ ²		MAD, Mothers Against Decapentaplegic Homolog 3²
Mothers Against DPP Homolog 3² ³		Mad3³
HMAD-3¹		Mothers Against Decapentaplegic Homolog 3²
HSMAD3¹		SMA- And MAD-Related Protein 3²
MAD Homolog 3² ³		SMAD, Mothers Against DPP Homolog 3²
MAD, Mothers Against Decapentaplegic Homolog 3 (Drosophila)¹		Mad3³
SMAD, Mothers Against DPP Homolog 3 (Drosophila)¹		Smad3³
HSPC193²		SMAD 3³
LDS1C²

External Ids:	HGNC: 6769¹	Entrez Gene: 4088²	Ensembl: ENSG00000166949⁷	OMIM: 603109⁵	UniProtKB: P84022³

Export aliases for SMAD3 gene to outside databases

Previous GC identifers: GC15P065075 GC15P065145 GC15P044193

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for SMAD3:

The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the

Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal

transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions as a

transcriptional modulator activated by transforming growth factor-beta and is thought to play a role in the regulation

of carcinogenesis. (provided by RefSeq, Apr 2009)

UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022

Function: Receptor-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 (By

similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ

which acts as a negative regulator

Gene Wiki entry for SMAD3 (Mothers against decapentaplegic homolog 3)

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section

RefSeq DNA sequence:

NC_000015.9 NC_018926.1 NT_010194.17

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the SMAD3 gene promoter:
Egr-3 C/EBPbeta Sp1 ATF-2 NF-AT GATA-1 C/EBPalpha N-Myc PPAR-alpha NF-AT1
Other transcription factors

SwitchGear Promoter luciferase reporter plasmids (see all 2): SMAD3 promoter sequence

Search SABiosciences Chromatin IP Primers for SMAD3

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat SMAD3

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 15q22.33 Ensembl cytogenetic band: 15q22.33 HGNC cytogenetic band: 15q21-q22

SMAD3 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
SMAD3 gene location

GeneLoc information about chromosome 15 GeneLoc Exon Structure

GeneLoc location for GC15P067358: view genomic region (about GC identifiers)

Start:	67,356,101 bp from pter	End:	67,487,533 bp from pter
Size:	131,433 bases	Orientation:	plus strand

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022 (See protein sequence)

Recommended Name: Mothers against decapentaplegic homolog 3

Size: 425 amino acids; 48081 Da

Subunit: Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a

heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and

one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Part of a complex

consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, HGS, WWP1 and

SNW1. Interacts (via MH2 domain) with CITED2 (via C-terminus) (By similarity). Interacts with NEDD4L; the interaction

requires TGF-beta stimulation (By similarity). Interacts (via the MH2 domain) with ZFYVE9. Interacts with HDAC1, VDR,

TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and TGFB1I1. Interacts with DACH1; the interaction

inhibits the TGF-beta signaling. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex

with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via the MH2 domain) with LEMD3; the

interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with

SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with

WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction

promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction

can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then

results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses

SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1

promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts (via an

N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for

DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction

dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export

and termination of TGF-beta signaling. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via

its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and

termination of the TGF-beta signaling. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts

with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts

with USP15

Subcellular location: Cytoplasm. Nucleus. Note=Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta

stimulation, migrates to the nucleus when complexed with SMAD4. Through the action of the phosphatase PPM1A, released

from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1. Co-localizes with LEMD3 at

the nucleus inner membrane. MAPK-mediated phosphorylation appears to have no effect on nuclear import. PDPK1 prevents

its nuclear translocation in response to TGF-beta

6/7 PDB 3D structures from and Proteopedia for SMAD3 (see all 7):

1MHD (3D)

1MJS (3D)

1MK2 (3D)

1OZJ (3D)

1U7F (3D)

2LAJ (3D)

Secondary accessions: A8K4B6 B7Z4Z5 B7Z6M9 B7Z9Q2 F5H383 O09064 O09144 O14510 O35273 Q92940 Q93002

Q9GKR4

Alternative splicing: 4 isoforms: P84022-1 P84022-2 P84022-3 P84022-4 (No experimental confirmation available)

Explore the universe of human proteins at neXtProt for SMAD3: NX_P84022

Post-translational modifications:

Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and

Ser-208 on EGF AND TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated

phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and

antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at

the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1.

TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and

transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker

region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with

SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1

promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated

TGF-beta responses. Phosphorylated by PDPK1¹

Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced

by TGF-beta¹

Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and

promotes activation of TGF-beta target genes¹

View modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_P84022

SMAD3 Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins (4 alternative transcripts):

NP_001138574.1 NP_001138575.1 NP_001138576.1 NP_005893.1

ENSEMBL proteins:

ENSP00000453082 ENSP00000332973 ENSP00000453788 ENSP00000455095 ENSP00000437757

ENSP00000458060 ENSP00000401133 ENSP00000453684 ENSP00000445348 ENSP00000454165

ENSP00000452767 ENSP00000455540 ENSP00000441856

Reactome Protein details: P84022
Human Recombinant Protein Products:

	Browse Purified and Recombinant Proteins at EMD Millipore
	Browse R&D Systems for human recombinant proteins
	Browse recombinant and purified proteins available from Enzo Life Sciences
	OriGene Purified Protein: SMAD3 OriGene Protein Over-expression Lysate (see all 2): SMAD3 OriGene Custom Protein Services for SMAD3
	GenScript Custom Purified and Recombinant Proteins Services for SMAD3
	Novus Biologicals SMAD3 Proteins Novus Biologicals SMAD3 Lysates
	Browse Sino Biological Recombinant Proteins
	ProSpec Recombinant Protein for SMAD3
	Uscn Proteins for SMAD3

Gene Ontology (GO): 5/10 cellular component terms (GO ID links to tree view) (see all 10): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005634	nucleus	IDA	9311995
GO:0005637	nuclear inner membrane	IDA	15647271
GO:0005654	nucleoplasm	TAS	--
GO:0005667	transcription factor complex	IDA	--
GO:0005737	cytoplasm	IDA	9311995

SMAD3 for ontologies About GeneDecksing

SMAD3 Antibody Products:

	EMD Millipore Mono- and Polyclonal Antibodies for the study of SMAD3
	R&D Systems Antibodies for SMAD3
	Cell Signaling Technology (CST) Antibodies for SMAD3
	OriGene Antibodies (see all 3): SMAD3 OriGene Custom Antibody Services for SMAD3
	GenScript Custom Superior Antibodies Services for SMAD3
	Novus Biologicals SMAD3 Antibodies
	Abcam antibodies for SMAD3
	Uscn Antibodies for SMAD3
	ThermoFisher Antibody for SMAD3

Assay Products for SMAD3:

	Browse Kits and Assays available from EMD Millipore
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	R&D Systems ELISAs for SMAD3 (see all)
	GenScript Custom Assay Services for SMAD3
	Cell Signaling Technology (CST) Sandwich ELISA Kits for SMAD3
	Browse Enzo Life Sciences for kits & assays
	Uscn ELISAs and CLIAs for SMAD3

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

SMAD3 for domains About GeneDecksing

5/6 InterPro domains/families (see all 6):

IPR013019 MAD_homology_MH1

IPR008984 SMAD_FHA_domain

IPR001132 SMAD_dom_Dwarfin-type

IPR017855 SMAD_dom-like

IPR013790 Dwarfin

Graphical View of Domain Structure for InterPro Entry P84022

ProtoNet protein and cluster: P84022

1 Blocks protein family: IPB001132 Dwarfin protein

UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022

Domain: The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding

Domain: The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation.

Sufficient for nuclear import

Domain: The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with

the MH2 domain

Similarity: Belongs to the dwarfin/SMAD family

Similarity: Contains 1 MH1 (MAD homology 1) domain

Similarity: Contains 1 MH2 (MAD homology 2) domain

(According to ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Function Summary: