Mothers against decapentaplegic homolog 3 (Protein name
), SMAD3_HUMAN from NCBI database.
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General Annotation
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Gene name:
SMAD3(MADH3);
Protein name:
Mothers against decapentaplegic homolog 3(MAD homolog 3;Mad3;Mothers against DPP homolog 3;hMAD-3);
Alternative:
SMAD family member 3(SMAD 3;Smad3;hSMAD3);JV15-2;
Organism:
Human (Homo sapiens).
General Annotation
Sub Unit:
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 and WWP1. 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.
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.
Subcellular Location:
Cytoplasm
Nucleus
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.
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Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1);PHOSPHORYLATION
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Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3 AND 4)
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Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1)
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Cited for: IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX;INTERACTION WITH JUN AND FOS;DNA-BINDING;FUNCTION
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Cited for: INTERACTION WITH JUN IN THE SMAD3/SMAD4/JUN/FOS COMPLEX;DNA-BINDING;FUNCTION;MUTAGENESIS OF LYS-40; LYS-41; LYS-43; LYS-44 AND ARG-74
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Cited for: SUBUNIT;PHOSPHORYLATION;MUTAGENESIS OF 422-SER--SER-425
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Cited for: PHOSPHORYLATION AT THR-8; THR-179; SER-204; SER-208 AND SER-213;FUNCTION;MUTAGENESIS OF THR-8; THR-179; SER-204; SER-208 AND SER-213
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Cited for: TRANSCRIPTIONAL ACTIVATION DOMAIN;FUNCTION;PHOSPHORYLATION;SUBUNIT;INTERACTION WITH EP300
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Cited for: PHOSPHORYLATION AT THR-179; SER-204 AND SER-208;SUBCELLULAR LOCATION;FUNCTION;MUTAGENESIS OF THR-179; SER-204 AND SER-208
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Cited for: INTERACTION WITH PPM1A;DEPHOSPHORYLATION;FUNCTION;SUBCELLULAR LOCATION
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Cited for: IDENTIFICATION IN A COMPLEX WITH SMAD2 AND TRIM33;INTERACTION WITH SMAD2 AND TRIM33
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Cited for: IDENTIFICATION IN A COMPLEX WITH RAN AND XPO4;INTERACTION WITH XPO4;MUTAGENESIS OF 422-SER--SER-425
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Cited for: FUNCTION;SUBCELLULAR LOCATION;PHOSPHORYLATION BY PDPK1;INTERACTION WITH PDPK1
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Cited for: ACETYLATION AT LYS-378;FUNCTION;MUTAGENESIS OF LYS-333; LYS-341; LYS-378; LYS-409 AND 422-SER--SER-425
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Cited for: INTERACTION WITH CSNK1G2;UBIQUITINATION;PHOSPHORYLATION AT SER-418 BY CSNK1G2/CK1;MUTAGENESIS OF SER-418
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Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-416;IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]
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Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2;IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS];CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS]
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Cited for: INTERACTION WITH RANBP3;SUBCELLULAR LOCATION;FUNCTION
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Cited for: PHOSPHORYLATION AT THR-179; SER-204 AND SER-208;SUBCELLULAR LOCATION;FUNCTION;MUTAGENESIS OF THR-179; SER-204 AND SER-208
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Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]
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Cited for: UBIQUITINATION;DEUBIQUITINATION BY USP15;DNA-BINDING;INTERACTION WITH USP15;UBIQUITINATION AT LYS-33 AND LYS-81;MUTAGENESIS OF LYS-33; LYS-53 AND LYS-81
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Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2;IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]
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Cited for: X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF 220-425 IN COMPLEX WITH ZFYVE9
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Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1-144 IN COMPLEX WITH DNA;ZINC
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Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 228-424 IN COMPLEX WITH SMAD4;SUBUNIT