CPLM-010538

Genbank Nucleotide ID

Mothers against decapentaplegic homolog 3

Protein Synonyms/Alias

MAD homolog 3; Mad3; Mothers against DPP homolog 3; hMAD-3; JV15-2; SMAD family member 3; SMAD 3; Smad3; hSMAD3

Homo sapiens (Human)

Position	Peptide	Type	References
13	PFTPPIVKRLLGWKK	ubiquitination	[1, 2, 3]
19	VKRLLGWKKGEQNGQ	acetylation	[4]
20	KRLLGWKKGEQNGQE	acetylation	[4]
63	TTQNVNTKCITIPRS	ubiquitination	[1]
378	TIRMSFVKGWGAEYR	acetylation	[5, 6]

[1] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
[2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
[3] Integrated proteomic analysis of post-translational modifications by serial enrichment.
Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
[4] The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation.
Simonsson M, Kanduri M, Grönroos E, Heldin CH, Ericsson J.
J Biol Chem. 2006 Dec 29;281(52):39870-80. [PMID: 17074756]
[5] Smad3 is acetylated by p300/CBP to regulate its transactivation activity.
Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, Onozaki K, Hayashi H.
Oncogene. 2007 Jan 25;26(4):500-8. [PMID: 16862174]
[6] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]

Functional Description

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.

DOMAIN 10 136 MH1.
DOMAIN 232 425 MH2.
REGION 137 231 Linker.
REGION 271 324 Sufficient for interaction with XPO4.
METAL 64 64 Zinc.
METAL 109 109 Zinc.
METAL 121 121 Zinc.
METAL 126 126 Zinc.
MOD_RES 2 2 N-acetylserine.
MOD_RES 8 8 Phosphothreonine; by CDK2 and CDK4.
MOD_RES 179 179 Phosphothreonine; by CDK2, CDK4 and MAPK.
MOD_RES 204 204 Phosphoserine; by GSK3 and MAPK.
MOD_RES 208 208 Phosphoserine; by MAPK.
MOD_RES 213 213 Phosphoserine; by CDK2 and CDK4.
MOD_RES 378 378 N6-acetyllysine.
MOD_RES 416 416 Phosphoserine.
MOD_RES 418 418 Phosphoserine; by CK1.
MOD_RES 422 422 Phosphoserine; by TGFBR1 (By similarity).
MOD_RES 423 423 Phosphoserine; by TGFBR1 (By similarity).
MOD_RES 425 425 Phosphoserine; by TGFBR1 (By similarity).
CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly)
CROSSLNK 81 81 Glycyl lysine isopeptide (Lys-Gly)

3D-structure; Acetylation; Alternative splicing; Aortic aneurysm; Complete proteome; Cytoplasm; Disease mutation; DNA-binding; Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0005829; C:cytosol; TAS:Reactome.
GO:0005637; C:nuclear inner membrane; IDA:UniProtKB.
GO:0005886; C:plasma membrane; IEA:Compara.
GO:0043235; C:receptor complex; IMP:BHF-UCL.
GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
GO:0005667; C:transcription factor complex; IDA:UniProtKB.
GO:0031490; F:chromatin DNA binding; IEA:Compara.
GO:0000987; F:core promoter proximal region sequence-specific DNA binding; IDA:UniProtKB.
GO:0003690; F:double-stranded DNA binding; IEA:Compara.
GO:0003700; F:sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
GO:0030618; F:transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity; IDA:BHF-UCL.
GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
GO:0008270; F:zinc ion binding; IDA:UniProtKB.
GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:BHF-UCL.
GO:0007050; P:cell cycle arrest; IMP:BHF-UCL.
GO:0045216; P:cell-cell junction organization; IMP:BHF-UCL.
GO:0048589; P:developmental growth; IEA:Compara.
GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Compara.
GO:0048617; P:embryonic foregut morphogenesis; IEA:Compara.
GO:0009880; P:embryonic pattern specification; IEA:Compara.
GO:0007492; P:endoderm development; IEA:Compara.
GO:0019049; P:evasion or tolerance of host defenses by virus; IDA:BHF-UCL.
GO:0001947; P:heart looping; IEA:Compara.
GO:0006955; P:immune response; IMP:BHF-UCL.
GO:0002520; P:immune system development; IEA:Compara.
GO:0001701; P:in utero embryonic development; IEA:Compara.
GO:0006917; P:induction of apoptosis; IMP:BHF-UCL.
GO:0070306; P:lens fiber cell differentiation; IEA:Compara.
GO:0001889; P:liver development; IEA:Compara.
GO:0001707; P:mesoderm formation; IEA:Compara.
GO:0043066; P:negative regulation of apoptotic process; IEA:Compara.
GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
GO:0050728; P:negative regulation of inflammatory response; IEA:Compara.
GO:0045930; P:negative regulation of mitotic cell cycle; IMP:BHF-UCL.
GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Compara.
GO:0033689; P:negative regulation of osteoblast proliferation; IEA:Compara.
GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
GO:0001933; P:negative regulation of protein phosphorylation; IMP:BHF-UCL.
GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
GO:0061045; P:negative regulation of wound healing; IEA:Compara.
GO:0038092; P:nodal signaling pathway; IMP:BHF-UCL.
GO:0002076; P:osteoblast development; IEA:Compara.
GO:0048340; P:paraxial mesoderm morphogenesis; IEA:Compara.
GO:0060039; P:pericardium development; IEA:Compara.
GO:0010694; P:positive regulation of alkaline phosphatase activity; IEA:Compara.
GO:0030501; P:positive regulation of bone mineralization; IEA:Compara.
GO:0090263; P:positive regulation of canonical Wnt receptor signaling pathway; IMP:BHF-UCL.
GO:0035413; P:positive regulation of catenin import into nucleus; IMP:BHF-UCL.
GO:0030335; P:positive regulation of cell migration; IEA:Compara.
GO:0032332; P:positive regulation of chondrocyte differentiation; IEA:Compara.
GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IDA:BHF-UCL.
GO:0051894; P:positive regulation of focal adhesion assembly; IEA:Compara.
GO:1901313; P:positive regulation of gene expression involved in extracellular matrix organization; IMP:BHF-UCL.
GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Compara.
GO:0050927; P:positive regulation of positive chemotaxis; IEA:Compara.
GO:0051496; P:positive regulation of stress fiber assembly; IEA:Compara.
GO:0042993; P:positive regulation of transcription factor import into nucleus; IDA:BHF-UCL.
GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
GO:0032916; P:positive regulation of transforming growth factor beta3 production; IEA:Compara.
GO:0031053; P:primary miRNA processing; TAS:BHF-UCL.
GO:0050821; P:protein stabilization; IMP:BHF-UCL.
GO:0051098; P:regulation of binding; IEA:Compara.
GO:0050678; P:regulation of epithelial cell proliferation; IEA:Compara.
GO:0050776; P:regulation of immune response; IEA:Compara.
GO:0016202; P:regulation of striated muscle tissue development; IEA:Compara.
GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL.
GO:0001836; P:release of cytochrome c from mitochondria; IEA:Compara.
GO:0001666; P:response to hypoxia; IMP:BHF-UCL.
GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
GO:0001756; P:somitogenesis; IEA:Compara.
GO:0042110; P:T cell activation; IEA:Compara.
GO:0030878; P:thyroid gland development; IEA:Compara.
GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
GO:0060290; P:transdifferentiation; IEA:Compara.
GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
GO:0006810; P:transport; IDA:BHF-UCL.
GO:0001657; P:ureteric bud development; IEA:Compara.
GO:0042060; P:wound healing; TAS:BHF-UCL.

IPR013790; Dwarfin.
IPR003619; MAD_homology1_Dwarfin-type.
IPR013019; MAD_homology_MH1.
IPR017855; SMAD_dom-like.
IPR001132; SMAD_dom_Dwarfin-type.
IPR008984; SMAD_FHA_domain.

PF03165; MH1
PF03166; MH2

SM00523; DWA
SM00524; DWB

PS51075; MH1
PS51076; MH2