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Details on Person UniProt:Q8BUN5 Smad3
| Class:Id | ReferenceGeneProduct:64622 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Sat February 7 2015;chain:2-425 added on Sat February 7 2015;initiator methionine:1 for 64622 removed on Fri Nov 03 2023;initiator methionine: for 64622 added on Fri Nov 03 2023;initiator methionine: for 64622 removed on Fri Aug 15 2025;initiator methionine:1 for 64622 added on Fri Aug 15 2025 |
| _displayName | UniProt:Q8BUN5 Smad3 |
| _timestamp | 2026-02-20 22:49:16 |
| chain | initiator methionine:1 chain:2-425 |
| checksum | 46DF5E8B371321AC |
| comment | 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. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity).SUBUNIT Monomer; in the absence of TGF-beta (By similarity). Homooligomer; in the presence of TGF-beta (By similarity). 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 (PubMed:21145499). Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3 (PubMed:15496141). Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta (By similarity). Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4 (By similarity). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta (By similarity). Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4; the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1 (By similarity). Interacts with NEDD9; the interaction promotes NEDD9 ubiquitination and proteasomal degradation (By similarity). 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 (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity). 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 (By similarity). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (PubMed:17341133). 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 (By similarity). Interacts (via 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 (By similarity). 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 (By similarity). 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 (By similarity). Interacts with TGFBR1 (By similarity). Interacts with TGFB1I1 (PubMed:14755691). Interacts with PRDM16 (PubMed:17467076). Interacts with SNW1 (By similarity). Interacts (via MH2 domain) with ZFYVE9 (PubMed:15356634). Interacts with HDAC1 (By similarity). Interacts with TGIF2 (By similarity). Interacts with SKOR1 (By similarity). Interacts with SKOR2 (By similarity). Interacts with DACH1; the interaction inhibits the TGF-beta signaling (By similarity). Interacts with RBPMS (By similarity). Interacts (via MH2 domain) with MECOM (By similarity). Interacts with WWTR1 (via its coiled-coil domain) (By similarity). Interacts with SKI; the interaction represses SMAD3 transcriptional activity (By similarity). Interacts with MEN1 (By similarity). Interacts with IL1F7 (By similarity). Interaction with CSNK1G2 (By similarity). Interacts with PDPK1 (via PH domain) (By similarity). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (By similarity). Interacts with USP15 (By similarity). Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (By similarity). Interacts with PMEPA1 (By similarity). Interacts with ZNF451 (By similarity). Interacts with ZFHX3 (By similarity). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-112') (PubMed:21145499). Interacts with MAGI2/ARIP1 (PubMed:10681527). Interacts (via MH2 domain) with CITED2 (via C-terminus) (By similarity). Interacts with HGS (PubMed:11094085). Interacts with WWP1 (PubMed:15221015). Interacts with TTRAP (PubMed:18039968). Interacts with FOXL2 (PubMed:19106105). Interacts with PML (PubMed:15356634). Interacts with NEDD4L; the interaction requires TGF-beta stimulation (PubMed:15496141). Interacts with ZC3H3 (PubMed:16115198). Interacts with TGIF. Interacts with CREBBP. Interacts with ATF2. Interacts with NEDD9; the interaction is inhibited by oxidation of NEDD9 (By similarity). Interacts with MTMR4; negatively regulates TGF-beta signaling through SMAD3 dephosphorylation and retention in endosomes (By similarity).INTERACTION Cytoplasmic and nuclear in the absence of TGF-beta (PubMed:21145499). On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4 (PubMed:21145499). Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 (By similarity). Co-localizes with LEMD3 at the nucleus inner membrane (By similarity). MAPK-mediated phosphorylation appears to have no effect on nuclear import. PDPK1 prevents its nuclear translocation in response to TGF-beta (By similarity). Localized mainly to the nucleus in the early stages of embryo development with expression becoming evident in the cytoplasm of the inner cell mass at the blastocyst stage (PubMed:21145499).TISSUE SPECIFICITY Highly expressed in the brain and ovary. Detected in the pyramidal cells of the hippocampus, granule cells of the dentate gyrus, granular cells of the cerebral cortex and the granulosa cells of the ovary.DOMAIN The MH1 domain is required for DNA binding (By similarity). 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 (By similarity).DOMAIN The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.PTM 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 (By similarity). Phosphorylated by PDPK1 (By similarity).PTM Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.PTM Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (By similarity). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (PubMed:17341133). Undergoes STUB1-mediated ubiquitination and degradation (By similarity).PTM Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.DISRUPTION PHENOTYPE SMAD3 null mice exhibit inhibition of proliferation of mammary gland epithelial cells. Fibrobasts are only partially growth inhibited. Defects in osteoblast differentiation are observed. Animals are osteopenic with less cortical and cancellous bone. Facture healing is accelerated. Decreased bone mineral density (BMD) reflects the inability of osteoblasts to balance osteoclast activity. Wound healing is accelerated to about two and a half times that of normal animals. Wound areas are significantly reduced with less quantities of granulation tissue. There is reduced local infiltration of moncytes and keratinocytes show altered patterns of growth and migration. Accelerated wound healing is observed on castration of null male mice, while null female mice exhibited delayed healing following ovariectomy.SIMILARITY Belongs to the dwarfin/SMAD family. |
| description | recommendedName: fullName evidence="28"SMAD family member 3 shortName evidence="27"SMAD 3 alternativeName: Mothers against decapentaplegic homolog 3 shortName: MAD homolog 3 shortName: Mad3 shortName: Mothers against DPP homolog 3 shortName: mMad3 |
| geneName | Smad3 Madh3 |
| identifier | Q8BUN5 |
| isSequenceChanged | FALSE |
| keyword | Acetylation ADP-ribosylation Cytoplasm Isopeptide bond Metal-binding Nucleus Phosphoprotein Reference proteome Transcription Transcription regulation Ubl conjugation Zinc |
| modified | [InstanceEdit:84067] Schmidt, EE, 2003-12-18 04:29:09 [InstanceEdit:143527] Schmidt, EE, 2004-11-12 07:45:10 [InstanceEdit:217385] Schmidt, EE, 2008-03-27 06:23:53 [InstanceEdit:354386] Schmidt, EE, 2008-06-18 04:45:12 [InstanceEdit:384350] Kanapin, AA, 2008-11-26 14:00:39 [InstanceEdit:392885] Kanapin, AA, 2009-03-09 12:07:18 [InstanceEdit:400710] Schmidt, EE, 2009-03-25 05:33:35 [InstanceEdit:423310] Kanapin, AA [InstanceEdit:435478] Kanapin, AA [InstanceEdit:435871] Kanapin, AA [InstanceEdit:447347] Kanapin, AA [InstanceEdit:525883] Kanapin, AA [InstanceEdit:613449] Kanapin, AA [InstanceEdit:797602] Kanapin, AA [InstanceEdit:937368] Yung, CK [InstanceEdit:1042053] Yung, CK [InstanceEdit:1220657] Yung, CK [InstanceEdit:1300696] Yung, CK [InstanceEdit:1301627] Yung, CK [InstanceEdit:1551960] Weiser, JD [InstanceEdit:1995863] Weiser, JD [InstanceEdit:2132304] Weiser, JD [InstanceEdit:2265580] Weiser, JD [InstanceEdit:3132113] Weiser, JD [InstanceEdit:5083144] Weiser, JD [InstanceEdit:5433710] Weiser, JD [InstanceEdit:5618415] Weiser, JD [InstanceEdit:5634237] Weiser, JD [InstanceEdit:5673015] Weiser, JD [InstanceEdit:8934940] Weiser, JD [InstanceEdit:9037114] Weiser, JD [InstanceEdit:9607352] Weiser, JD [InstanceEdit:9637257] Weiser, JD [InstanceEdit:9657908] Weiser, JD [InstanceEdit:9676415] Weiser, JD [InstanceEdit:9715482] Weiser, JD [InstanceEdit:9796772] Weiser, Joel [InstanceEdit:9819394] Weiser, Joel [InstanceEdit:9834092] Weiser, Joel [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | Smad3 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| secondaryIdentifier | SMAD3_MOUSE O09064 O09144 O14510 O35273 Q8BX84 Q92940 Q93002 Q9GKR4 |
| sequenceLength | 425 |
| species | [Species:48892] Mus musculus |
| (referenceEntity) | [EntityWithAccessionedSequence:1225907] p-S423,425-Smad3 [nucleoplasm] [Mus musculus] [EntityWithAccessionedSequence:4005959] monoSUMO1-Smad3 [nucleoplasm] [Mus musculus] [EntityWithAccessionedSequence:4006003] Smad3 [nucleoplasm] [Mus musculus] [EntityWithAccessionedSequence:9605416] p-S423,425-Smad3 [cytosol] [Mus musculus] |
| (referenceSequence) | [ModifiedResidue:1225885] O-phospho-L-serine at 423 [ModifiedResidue:1225910] O-phospho-L-serine at 425 [GroupModifiedResidue:4005979] sumoylated lysine (monoSUMO1 [nucleoplasm]) at unknown position |
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No pathways have been reviewed or authored by UniProt:Q8BUN5 Smad3 (64622)
