SMAD3
entrez
4088
canonical
uniprot
P84022
canonical
ensembl
ENSG00000166949
resolver
ensp
ENSP00000332973
resolver
ensp
ENSP00000401133
resolver
ensp
ENSP00000437757
resolver
ensp
ENSP00000445348
resolver
ensp
ENSP00000452767
resolver
ensp
ENSP00000453684
resolver
ensp
ENSP00000455540
resolver
ensp
ENSP00000519400
resolver
ensp
ENSP00000519401
resolver
enst
ENST00000560424
resolver
enst
ENST00000714109
resolver
genesymbol
SMAD3
resolver
genesymbol_syn
MADH3
resolver
hgnc
HGNC:6769
resolver
uniprot
A0AAQ5BHI7
resolver
uniprot
A8K4B6
resolver
uniprot
B7Z4Z5
resolver
uniprot
B7Z6M9
resolver
uniprot
B7Z9Q2
resolver
uniprot
F5H383
resolver
uniprot
H3BQ00
resolver
uniprot
O09064
resolver
uniprot
O09144
resolver
uniprot
O14510
resolver
uniprot
O35273
resolver
uniprot
Q92940
resolver
uniprot
Q93002
resolver
uniprot
Q9GKR4
resolver
uniprot
Q9P0T0
resolver
uniprot_entry
A0AAQ5BHI7_HUMAN
resolver
uniprot_entry
H3BQ00_HUMAN
resolver
uniprot_entry
Q9P0T0_HUMAN
resolver
uniprot_entry
SMAD3_HUMAN
resolver
uniprot_sec
A8K4B6
resolver
uniprot_sec
B7Z4Z5
resolver
uniprot_sec
B7Z6M9
resolver
uniprot_sec
B7Z9Q2
resolver
uniprot_sec
F5H383
resolver
uniprot_sec
O09064
resolver
uniprot_sec
O09144
resolver
uniprot_sec
O14510
resolver
uniprot_sec
O35273
resolver
uniprot_sec
Q92940
resolver
uniprot_sec
Q93002
resolver
uniprot_sec
Q9GKR4
resolver
amino_acid_sequence
MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKTGQLDELEKAITTQNVNTKCITIPRSLDGRLQVSHRKGLPHVIYCRLWRWPDLHSHHELRAMELCEFAFNMKKDEVCVNPYHYQRVETPVLPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETPPPGYLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYCEPAFWCSISYYELNQRVGETFHASQPSMTVDGFTDPSNSERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYIGGEVFAECLSDSAIFVQSPNCNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGFEAVYQLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLDKVLTQMGSPSIRCSSVS
uniprot
proteins
disease_involvement
DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease may be caused by variants affecting the gene represented in this entry.; DISEASE: Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]: An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and intellectual disability. {ECO:0000269|PubMed:21217753, ECO:0000269|PubMed:21778426}. Note=The disease is caused by variants affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource. {ECO:0000269|PubMed:21778426}.
uniprot
proteins
function
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. {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}.
uniprot
proteins
mass_dalton
48081
uniprot
proteins
mutagenesis
MUTAGEN 8; /note="T->V: Reduced phosphorylation, increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-179 and A-213."; /evidence="ECO:0000269|PubMed:15241418"; MUTAGEN 33; /note="K->R: Slightly decreased monoubiquitination."; /evidence="ECO:0000269|PubMed:21947082"; MUTAGEN 40; /note="K->A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-41; A-43 and A-44."; /evidence="ECO:0000269|PubMed:10995748"; MUTAGEN 41; /note="K->A: Greatly reduced interaction with DNA and JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-44 and A-43."; /evidence="ECO:0000269|PubMed:10995748"; MUTAGEN 43; /note="K->A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-41 and A-44."; /evidence="ECO:0000269|PubMed:10995748"; MUTAGEN 44; /note="K->A: Little effect on interaction with DNA or JUN. Abolishes interaction with JUN; when associated with A-40; A-41 and A-43."; /evidence="ECO:0000269|PubMed:10995748"; MUTAGEN 53; /note="K->R: Slightly decreased monoubiquitination."; /evidence="ECO:0000269|PubMed:21947082"; MUTAGEN 74; /note="R->D: Reduced interaction with JUN. Loss of transcriptional activity and cooperation with JUN."; /evidence="ECO:0000269|PubMed:10995748"; MUTAGEN 81; /note="K->R: Decreased monoubiquitination."; /evidence="ECO:0000269|PubMed:21947082"; MUTAGEN 179; /note="T->V: Reduced phosphorylation, increased transcriptional and increased antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and A-213."; /evidence="ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:19218245"; MUTAGEN 204; /note="S->A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208."; /evidence="ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:19218245"; MUTAGEN 208; /note="S->A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208."; /evidence="ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:19218245"; MUTAGEN 213; /note="S->A: Reduced phosphorylation. Increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and V-179."; /evidence="ECO:0000269|PubMed:15241418"; MUTAGEN 333; /note="K->R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-341; R-378 and R-409."; /evidence="ECO:0000269|PubMed:16862174"; MUTAGEN 341; /note="K->R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-378 and R-409."; /evidence="ECO:0000269|PubMed:16862174"; MUTAGEN 378; /note="K->Q: Increased transcriptional activity. No further increase in transcriptional activity with EP300."; /evidence="ECO:0000269|PubMed:16862174"; MUTAGEN 378; /note="K->R: Greatly reduced acetylation and 85% reduction in transcriptional activity. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-409."; /evidence="ECO:0000269|PubMed:16862174"; MUTAGEN 409; /note="K->R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-378."; /evidence="ECO:0000269|PubMed:16862174"; MUTAGEN 418; /note="S->A: Increased constitutive activity."; /evidence="ECO:0000269|PubMed:18794808"; MUTAGEN 418; /note="S->D: Decreased activity."; /evidence="ECO:0000269|PubMed:18794808"; MUTAGEN 422..425; /note="SSVS->AAVA: Does not abolish protein nuclear export. Abolishes almost completely acetylation."; /evidence="ECO:0000269|PubMed:11224571, ECO:0000269|PubMed:16449645, ECO:0000269|PubMed:16862174"; MUTAGEN 422..425; /note="SSVS->EEVE: Forms heterotrimers."; /evidence="ECO:0000269|PubMed:11224571, ECO:0000269|PubMed:16449645, ECO:0000269|PubMed:16862174"; MUTAGEN 422..425; /note="SSVS->RRVR: Diminishes cargo protein export."; /evidence="ECO:0000269|PubMed:11224571, ECO:0000269|PubMed:16449645, ECO:0000269|PubMed:16862174
uniprot
proteins
post_translational_modification
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. Phosphorylated by PDPK1. {ECO:0000269|PubMed:11224571, ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:15588252, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:18794808, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:39143229, ECO:0000269|PubMed:8774881, ECO:0000269|PubMed:9843571}.; PTM: Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta. {ECO:0000269|PubMed:16862174}.; PTM: Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling. {ECO:0000269|PubMed:25133494}.; PTM: Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). 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 (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385). {ECO:0000250|UniProtKB:Q8BUN5, ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:24613385}.
uniprot
proteins
protein_family
Dwarfin/SMAD family
uniprot
proteins
pubmed
10995748
uniprot
proteins
pubmed
11224571
uniprot
proteins
pubmed
11274402
uniprot
proteins
pubmed
11278756
uniprot
proteins
pubmed
11387212
uniprot
proteins
pubmed
11427533
uniprot
proteins
pubmed
12154125
uniprot
proteins
pubmed
12370310
uniprot
proteins
pubmed
12686552
uniprot
proteins
pubmed
14525983
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15051726
uniprot
proteins
pubmed
15241418
uniprot
proteins
pubmed
15350224
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15561701
uniprot
proteins
pubmed
15588252
uniprot
proteins
pubmed
15601644
uniprot
proteins
pubmed
15647271
uniprot
proteins
pubmed
15799969
uniprot
proteins
pubmed
15897867
uniprot
proteins
pubmed
16156666
uniprot
proteins
pubmed
16200078
uniprot
proteins
pubmed
16449645
uniprot
proteins
pubmed
16572171
uniprot
proteins
pubmed
16751101
uniprot
proteins
pubmed
16751102
uniprot
proteins
pubmed
16777850
uniprot
proteins
pubmed
16862174
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17099224
uniprot
proteins
pubmed
17292623
uniprot
proteins
pubmed
17327236
uniprot
proteins
pubmed
18055455
uniprot
proteins
pubmed
18568018
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18794808
uniprot
proteins
pubmed
19049980
uniprot
proteins
pubmed
19218245
uniprot
proteins
pubmed
19289081
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
20061380
uniprot
proteins
pubmed
20129061
uniprot
proteins
pubmed
20935647
uniprot
proteins
pubmed
21145499
uniprot
proteins
pubmed
21217753
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21778426
uniprot
proteins
pubmed
21947082
uniprot
proteins
pubmed
22781750
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24324267
uniprot
proteins
pubmed
24613385
uniprot
proteins
pubmed
24627487
uniprot
proteins
pubmed
25105025
uniprot
proteins
pubmed
25133494
uniprot
proteins
pubmed
29899023
uniprot
proteins
pubmed
39143229
uniprot
proteins
pubmed
8673135
uniprot
proteins
pubmed
8774881
uniprot
proteins
pubmed
9311995
uniprot
proteins
pubmed
9464505
uniprot
proteins
pubmed
9665135
uniprot
proteins
pubmed
9670020
uniprot
proteins
pubmed
9732876
uniprot
proteins
pubmed
9741623
uniprot
proteins
pubmed
9843571
uniprot
proteins
pubmed
9865696
uniprot
proteins
pubmed
9892009
uniprot
proteins
sequence_length
425
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {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:21145499, ECO:0000269|PubMed:22781750, ECO:0000269|PubMed:39143229}. 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:21145499, 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, 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 (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). 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 (By similarity). {ECO:0000250|UniProtKB:Q8BUN5, 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:0000269|PubMed:21145499}.
uniprot
proteins