Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer (Homo sapiens)

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9, 11, 17, 18, 26...2171, 9, 26, 276, 21, 35282267, 148, 40111730, 36, 4216, 23, 24, 29, 31...2015436, 35118, 34, 4026, 386, 21, 359, 2725408, 4028384, 10, 12, 13, 33...2811225, 6, 18, 19, 39202226434340DegradationDegradationnucleoplasmDegradationcytosolCCNT1 RPS27A(1-76) UBC(153-228) UBC(305-380) UBC(77-152) UBC(77-152) SMAD4 RNF111 SMAD4 UBC(381-456) UBB(1-76) p-S423,S425-SMAD3 SERPINE1p-S465,S467-SMAD2 UBA52(1-76) p-S423,S425-SMAD3 HDAC1NAD+p-2S-SMAD2/3:SMAD4:SP1UBA52(1-76) NCOR1 PPM1A PARP1 UBC(609-684) UBC(305-380) UBC(609-684) SMAD4 UBC(381-456) RNF111 UBB(77-152) UBC(229-304) UBC(77-152) UBC(77-152) SMAD4 RPS27A(1-76) NCOR2 UbUBC(533-608) UBC(153-228) USP9X UBC(153-228) UBB(1-76) UBB(153-228) MYCSMAD4 RPS27A(1-76) UBA52(1-76) TGIF2 E2F4 TRIM33 MYC geneSMAD4 UBB(153-228) SMURF2 WWTR1UBC(457-532) RPS27A(1-76) p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR:RNF111/SMURF2WWTR1:p-2S-SMAD2/3:SMAD4SMAD7 SMAD2/3UBC(305-380) RBL1 UBC(77-152) p-T179,S423,S425-SMAD3 UBB(1-76) p-S423,S425-SMAD3 p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCORNCOR2 PPM1AUBC(381-456) RBL1:E2F4/5:DP1/2UbCDKN2BUBC(381-456) SMAD2 UBB(1-76) p-T179,S423,S425-SMAD3 UBC(1-76) SMAD4 UBC(533-608) SKI TGIF1 RNF111UBC(533-608) JUNB geneSMAD4 WWTR1 UBC(153-228) p-S423,S425-SMAD3 ADPUBA52(1-76) p-S465,S467-SMAD2 UBC(457-532) p-T179,S423,S425-SMAD3 p-S465,S467-SMAD2 p-S423,S425-SMAD3 UBA52(1-76) UBB(153-228) H2OSKI UBB(77-152) p-2S-SMAD2/3:SMAD4:MEN1p-S423,S425-SMAD3 p-2S-SMAD2/3:SMAD4UBC(1-76) p-T179,S423,S425-SMAD3 UBC(1-76) CCNC UBC(533-608) SKI p-T220,S465,S467-SMAD2 TRIM33UBC(305-380) UBB(1-76) TFDP2 TGIF1 SMURF2 UBC(381-456) UBC(305-380) SMURF2 UBC(609-684) p-2S-SMAD2/3UBC(533-608) p-T179,S423,S425-SMAD3 UBC(153-228) UBC(381-456) p-S423,S425-SMAD3 p-S465,S467-SMAD2 UBC(305-380) UBC(305-380) UBC(77-152) UBC(457-532) NCOR1 UBC(457-532) RNF111 WWTR1 UBC(1-76) SERPINE1 GeneUBB(1-76) UBC(153-228) UBC(457-532) UBC(533-608) UBB(1-76) ATP1B4:SNW1UBC(381-456) SMAD2/3p-2S-SMAD2/3:SMAD4:PPM1ASMAD4 SMAD4 RPS27A(1-76) NAMp-S423,S425-SMAD3 UBA52(1-76) SNW1UBC(533-608) p-S465,S467-SMAD2 CDK8 UBC(1-76) p-S423,S425-SMAD3 UBC(1-76) UBC(305-380) MEN1p-T-2S-SMAD2/3:SMAD4:NEDDL4UBB(77-152) UBC(609-684) PARP1SKI/SKILUBC(153-228) UbUbUBB(77-152) TFDP1 PAR-SMAD2/3:PAR-SMAD4p-S465,S467-SMAD2 TGIFRBL1 p-SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2UBC(1-76) UBB(77-152) UBB(77-152) UBA52(1-76) UBC(457-532) UBC(609-684) NCOR2 p-S465,S467-SMAD2 UbUBB(1-76) UBC(381-456) UBB(77-152) UBA52(1-76) SMAD4 SMAD4 UBC(77-152) SMAD3 UBB(77-152) p-T,2S-SMAD2/3:SMAD4E2F5 SMAD4 UBC(381-456) UBC(229-304) p-S465,S467-SMAD2 UBC(609-684) RPS27A(1-76) USP9XH2Op-S423,S425-SMAD3 UBC(457-532) RPS27A(1-76) UBC(229-304) SMAD4 SKIL UBC(229-304) SMAD4 SMAD7:RNF111SMAD3 p-T220,S465,S467-SMAD2 E2F5 UBC(77-152) UBB(153-228) UBC(609-684) p-S465,S467-SMAD2 UBC(381-456) Ub-SKI/Ub-SKILUBC(305-380) UBE2D3 UBB(153-228) UBC(457-532) UBA52(1-76) UBB(153-228) UBA52(1-76) p-S465,S467-SMAD2 JUNBCCNT2 p-T220,S465,S467-SMAD2 SMAD4SMAD7 geneUBC(77-152) MEN1 ATP1B4UBC(305-380) SMURF2p-S423,S425-SMAD3 UBC(77-152) UBC(381-456) p-2S-SMAD2/3:SMAD4p-T220,S465,S467-SMAD2 p-S423,S425-SMAD3 UBC(457-532) NEDD4L UBB(153-228) ATPUBE2D1 Ub-p-T-2S-SMAD2/3:SMAD4CDK9 Nuclear ubiquitinligaseUBB(77-152) p-SMAD2/3:SMAD4:TRIM33RPS27A(1-76) UBC(229-304) UBB(1-76) UBC(229-304) UBB(1-76) 2xADPRib-p-S423,S425-SMAD3 SMAD4 RNF111/SMURF2UBC(457-532) UBB(153-228) UBC(229-304) CDKN2B genep-2S-SMAD2/3RibC-SMAD4 UBC(229-304) UBA52(1-76) UBC(153-228) UBC(533-608) RPS27A(1-76) UBC(153-228) UBC(305-380) p-S423,S425-SMAD3 p-S423,S425-SMAD3 PiNCOR1 p-S465,S467-SMAD2 SKIL p-2S-SMAD2/3:SMAD4:TGIF:HDAC1SP1p-T220,S465,S467-SMAD2 UBC(609-684) UBA52(1-76) UBC(533-608) TGIF2 Ub-SMAD7UBC(1-76) CDK8:CCNC/ CDK9:CCNTUBC(609-684) UBC(457-532) UBB(77-152) CCNK WWTR1:p-2S-SMAD2/3:SMAD4UBB(153-228) NEDD4LUBB(153-228) RPS27A(1-76) UBB(77-152) Ub-p-T-2S-SMAD2/3UBC(533-608) UBC(229-304) HDAC1 Signaling byTGF-beta ReceptorComplexSMAD4Ub-SMAD4RPS27A(1-76) p-S465,S467-SMAD2 p-T-2S-SMAD2/3:SMAD4:SMURF2p-2S-SMAD2/3:SMAD4:PARP1UBC(1-76) SMAD4 SMAD4 UBC(609-684) UBC(229-304) E2F4 SKIL UBC(533-608) UBB(77-152) SMAD7SKI UBC(153-228) UBC(77-152) SMAD7 p-S465,S467-SMAD2 ATP1B4 UBC(77-152) UBC(305-380) UBC(609-684) UBC(1-76) UBB(153-228) SMAD2 UBC(1-76) TFDP2 RPS27A(1-76) UBB(1-76) UBC(153-228) NCOR1, NCOR2SNW1 p-S465,S467-SMAD2 UBC(609-684) p-S465,S467-SMAD2 Ub-SMAD4:USP9XUBC(381-456) UBC(1-76) Ub-SMAD4p-S423,S425-SMAD3 TFDP1 UBC(153-228) UBB(1-76) SMAD4 SKIL UBC(457-532) p-S465,S467-SMAD2 SP1 UBC(229-304) UBC(533-608) UBB(153-228) UBC(229-304) SMAD4 337


Description

In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2173793
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms

 

Bibliography

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  35. Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS.; ''Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation.''; PubMed Europe PMC
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History

View all...
CompareRevisionActionTimeUserComment
101403view11:29, 1 November 2018ReactomeTeamreactome version 66
100941view21:05, 31 October 2018ReactomeTeamreactome version 65
100478view19:39, 31 October 2018ReactomeTeamreactome version 64
100023view16:22, 31 October 2018ReactomeTeamreactome version 63
99576view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99198view12:43, 31 October 2018ReactomeTeamreactome version 62
93819view13:38, 16 August 2017ReactomeTeamreactome version 61
93365view11:21, 9 August 2017ReactomeTeamreactome version 61
88362view16:40, 1 August 2016FehrhartOntology Term : 'transcription factor mediated signaling pathway' added !
86449view09:18, 11 July 2016ReactomeTeamreactome version 56
83472view13:25, 18 November 2015ReactomeTeamVersion54
81537view13:04, 21 August 2015ReactomeTeamVersion53
77005view08:30, 17 July 2014ReactomeTeamFixed remaining interactions
76710view12:07, 16 July 2014ReactomeTeamFixed remaining interactions
76036view10:09, 11 June 2014ReactomeTeamRe-fixing comment source
75745view11:23, 10 June 2014ReactomeTeamReactome 48 Update
75095view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74742view08:49, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xADPRib-p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP1B4 ProteinQ9UN42 (Uniprot-TrEMBL)
ATP1B4:SNW1ComplexR-HSA-5252105 (Reactome)
ATP1B4ProteinQ9UN42 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CCNC ProteinP24863 (Uniprot-TrEMBL)
CCNK ProteinO75909 (Uniprot-TrEMBL)
CCNT1 ProteinO60563 (Uniprot-TrEMBL)
CCNT2 ProteinO60583 (Uniprot-TrEMBL)
CDK8 ProteinP49336 (Uniprot-TrEMBL)
CDK8:CCNC/ CDK9:CCNTComplexR-HSA-2176485 (Reactome)
CDK9 ProteinP50750 (Uniprot-TrEMBL)
CDKN2B geneGeneProductENSG00000147883 (Ensembl)
CDKN2BProteinP42772 (Uniprot-TrEMBL)
E2F4 ProteinQ16254 (Uniprot-TrEMBL)
E2F5 ProteinQ15329 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC1ProteinQ13547 (Uniprot-TrEMBL)
JUNB geneGeneProductENSG00000171223 (Ensembl)
JUNBProteinP17275 (Uniprot-TrEMBL)
MEN1 ProteinO00255 (Uniprot-TrEMBL)
MEN1ProteinO00255 (Uniprot-TrEMBL)
MYC geneGeneProductENSG00000136997 (Ensembl)
MYCProteinP01106 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR1, NCOR2ComplexR-HSA-349716 (Reactome)
NCOR2 ProteinQ9Y618 (Uniprot-TrEMBL)
NEDD4L ProteinQ96PU5 (Uniprot-TrEMBL)
NEDD4LProteinQ96PU5 (Uniprot-TrEMBL)
Nuclear ubiquitin ligaseComplexR-HSA-173530 (Reactome)
PAR-SMAD2/3:PAR-SMAD4ComplexR-HSA-2187328 (Reactome)
PARP1 ProteinP09874 (Uniprot-TrEMBL)
PARP1ProteinP09874 (Uniprot-TrEMBL)
PPM1A ProteinP35813 (Uniprot-TrEMBL)
PPM1AProteinP35813 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RBL1 ProteinP28749 (Uniprot-TrEMBL)
RBL1:E2F4/5:DP1/2ComplexR-HSA-2127252 (Reactome)
RNF111 ProteinQ6ZNA4 (Uniprot-TrEMBL)
RNF111/SMURF2ComplexR-HSA-2186743 (Reactome)
RNF111ProteinQ6ZNA4 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RibC-SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SERPINE1 GeneGeneProductENSG00000106366 (Ensembl)
SERPINE1ProteinP05121 (Uniprot-TrEMBL)
SKI ProteinP12755 (Uniprot-TrEMBL)
SKI/SKILComplexR-HSA-2186620 (Reactome)
SKIL ProteinP12757 (Uniprot-TrEMBL)
SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
SMAD2/3ComplexR-HSA-171172 (Reactome)
SMAD2/3ComplexR-HSA-2187387 (Reactome)
SMAD3 ProteinP84022 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
SMAD7 ProteinO15105 (Uniprot-TrEMBL)
SMAD7 geneGeneProductENSG00000101665 (Ensembl)
SMAD7:RNF111ComplexR-HSA-2186769 (Reactome)
SMAD7ProteinO15105 (Uniprot-TrEMBL)
SMURF2 ProteinQ9HAU4 (Uniprot-TrEMBL)
SMURF2ProteinQ9HAU4 (Uniprot-TrEMBL)
SNW1 ProteinQ13573 (Uniprot-TrEMBL)
SNW1ProteinQ13573 (Uniprot-TrEMBL)
SP1 ProteinP08047 (Uniprot-TrEMBL)
SP1ProteinP08047 (Uniprot-TrEMBL)
Signaling by

TGF-beta Receptor

Complex
PathwayR-HSA-170834 (Reactome) The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.
TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TGIF1 ProteinQ15583 (Uniprot-TrEMBL)
TGIF2 ProteinQ9GZN2 (Uniprot-TrEMBL)
TGIFComplexR-HSA-2186609 (Reactome)
TRIM33 ProteinQ9UPN9 (Uniprot-TrEMBL)
TRIM33ProteinQ9UPN9 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
USP9X ProteinQ93008 (Uniprot-TrEMBL)
USP9XProteinQ93008 (Uniprot-TrEMBL)
Ub-SKI/Ub-SKILComplexR-HSA-2186733 (Reactome)
Ub-SMAD4:USP9XComplexR-HSA-870520 (Reactome)
Ub-SMAD4ComplexR-HSA-870463 (Reactome)
Ub-SMAD4ComplexR-HSA-870482 (Reactome)
Ub-SMAD7ComplexR-HSA-2186778 (Reactome)
Ub-p-T-2S-SMAD2/3:SMAD4ComplexR-HSA-2176504 (Reactome)
Ub-p-T-2S-SMAD2/3ComplexR-HSA-2179273 (Reactome)
UbComplexR-HSA-113595 (Reactome)
UbComplexR-HSA-68524 (Reactome)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1:p-2S-SMAD2/3:SMAD4ComplexR-HSA-2031357 (Reactome)
WWTR1:p-2S-SMAD2/3:SMAD4ComplexR-HSA-2106580 (Reactome)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
p-2S-SMAD2/3:SMAD4:MEN1ComplexR-HSA-2186642 (Reactome)
p-2S-SMAD2/3:SMAD4:PARP1ComplexR-HSA-2187322 (Reactome)
p-2S-SMAD2/3:SMAD4:PPM1AComplexR-HSA-2187392 (Reactome)
p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR:RNF111/SMURF2ComplexR-HSA-2186744 (Reactome)
p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCORComplexR-HSA-177110 (Reactome)
p-2S-SMAD2/3:SMAD4:SP1ComplexR-HSA-2187302 (Reactome)
p-2S-SMAD2/3:SMAD4:TGIF:HDAC1ComplexR-HSA-2186606 (Reactome)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-171175 (Reactome)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-173511 (Reactome)
p-2S-SMAD2/3ComplexR-HSA-171182 (Reactome)
p-2S-SMAD2/3ComplexR-HSA-177105 (Reactome)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
p-SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2ComplexR-HSA-2127250 (Reactome)
p-SMAD2/3:SMAD4:TRIM33ComplexR-HSA-870446 (Reactome)
p-T,2S-SMAD2/3:SMAD4ComplexR-HSA-2176487 (Reactome)
p-T-2S-SMAD2/3:SMAD4:NEDDL4ComplexR-HSA-2176495 (Reactome)
p-T-2S-SMAD2/3:SMAD4:SMURF2ComplexR-HSA-2179277 (Reactome)
p-T179,S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-T220,S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-2176475 (Reactome)
ATP1B4:SNW1ArrowR-HSA-2106591 (Reactome)
ATP1B4:SNW1ArrowR-HSA-5252001 (Reactome)
ATP1B4R-HSA-5252001 (Reactome)
ATPR-HSA-2176475 (Reactome)
CDK8:CCNC/ CDK9:CCNTmim-catalysisR-HSA-2176475 (Reactome)
CDKN2B geneR-HSA-2187303 (Reactome)
CDKN2BArrowR-HSA-2187303 (Reactome)
H2OR-HSA-209055 (Reactome)
H2OR-HSA-870437 (Reactome)
HDAC1R-HSA-2186607 (Reactome)
JUNB geneR-HSA-2187293 (Reactome)
JUNBArrowR-HSA-2187293 (Reactome)
MEN1R-HSA-2186643 (Reactome)
MYC geneR-HSA-1484099 (Reactome)
MYCArrowR-HSA-1484099 (Reactome)
NAD+R-HSA-2187325 (Reactome)
NAMArrowR-HSA-2187325 (Reactome)
NCOR1, NCOR2ArrowR-HSA-2186747 (Reactome)
NCOR1, NCOR2R-HSA-173481 (Reactome)
NEDD4LArrowR-HSA-2176502 (Reactome)
NEDD4LR-HSA-2176491 (Reactome)
Nuclear ubiquitin ligasemim-catalysisR-HSA-173545 (Reactome)
PAR-SMAD2/3:PAR-SMAD4ArrowR-HSA-2187325 (Reactome)
PARP1ArrowR-HSA-2187325 (Reactome)
PARP1R-HSA-2187330 (Reactome)
PPM1AArrowR-HSA-209055 (Reactome)
PPM1AR-HSA-2187388 (Reactome)
PiArrowR-HSA-209055 (Reactome)
R-HSA-1484099 (Reactome) Complex formed by RBL1 (p107), E2F4/5, DP1/2 and a trimer of phosphorylated R-SMADs (SMAD2/3) and SMAD4 (Co-SMAD) cooperatively binds to TIE (TGF-beta inhibitory element) and E2F sites in the MYC promoter and promotes cell-cycle independent inhibition of MYC transcription in response to TGF-beta stimulation (Chen et al. 2002).
R-HSA-170847 (Reactome) The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.

ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).
R-HSA-173481 (Reactome) SKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex.
R-HSA-173488 (Reactome) The phosphorylated R-SMAD:CO-SMAD complex rapidly translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003) where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for I-SMADs. Thus, TGF-beta/SMAD signaling induces the expression of the negative regulators of the pathway (negative feedback loop).
R-HSA-173545 (Reactome) The nuclear R-SMAD:Co-SMAD complex recruits ubiquitin conjugating enzymes, such as UBE2D1 and UBE2D3, that ubiquitinate the complex and eventually lead to its proteasomal degradation. This provides an end point to the signaling pathway.
R-HSA-2031355 (Reactome) In the cytosol of human embryonic stem cells, WWTR1 (TAZ) binds heterotrimer composed of two R-SMADs (SMAD2 and/or SMAD3) and SMAD4. This interaction involves the C-terminus of WWTR1 (TAZ) and the MH1 domain of SMAD proteins.
R-HSA-209055 (Reactome) In the nucleus, protein type 2C phosphatase, PPM1A, dephosphorylates SMAD2 and SMAD3, resulting in dissociation of SMAD2/3:SMAD4 heterotrimeric complexes.
R-HSA-2106579 (Reactome) TGF-beta-dependent nuclear accumulation of SMAD2/3 and SMAD4 is mediated by WWTR1 (TAZ). WWTR1 does not affect phosphorylation of SMAD2/3 or the formation of SMAD2/3:SMAD4 trimers.
R-HSA-2106586 (Reactome) Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) in hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SERPINE1 gene in response to TGF-beta stimulation (Varelas et al. 2008). Binding of TGIF1 or TGIF2 to SMAD2/3:SMAD4 heterotrimer negatively regulates transcription of SERPINE1 (Wotton et al. 1999, Melhuish et al. 2001). SMAD7 can also bind PAI-1 promoter (and probably other TGF-beta-responsive promoters) and inhibit PAI-1 expression, probably by competing with SMAD2/3:SMAD4 binding (Zhang et al. 2007).
R-HSA-2106591 (Reactome) Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SMAD7 in human hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SMAD7 gene in response to TGF-beta stimulation (Varelas et al. 2008).
In fish, amphibian and avian species, ATP1B4 (aka X,K ATPase subunit beta m) functions as a subunit of Na/K ATPase, located in the plasma membrane. In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain containing protein 1 (SNW1 aka Ski interacting protein, SKIP), a transcriptional regulator. This ATP1B4:SNW1 complex is able to modulate TGF beta mediated transcription by increasing mRNA levels of SMAD7, an inhibitor of TGF beta signalling (Pestov et al. 2007).
R-HSA-2127257 (Reactome) In response to TGF-beta stimulation, a complex composed of SMAD2/3:SMAD4 heterotrimer and RBL1 (p107), E2F4/5 and DP1/2 can be detected in the nucleus. Formation of this complex was confirmed by both co-immunoprecipitation of the endogenous complex from the human keratinocyte cell line HaCat and by protein interaction studies using tagged recombinant proteins. It is possible that cells contain pre-assembled cytosolic complexes of SMAD2/3, RBL1 (p107) and E2F4/5, that translocate to the nucleus after TGF-beta stimulation, when phosphorylated SMAD2/3 recruit SMAD4. The MH2 domain of SMAD3 establishes independent contacts with the N-termini of E2F4 (or E2F5) and unphosphorylated RBL1 (p107). RBL2 (p130), RB1 and E2F1 do not interact with SMAD2/3 (Chen et al. 2002).
R-HSA-2176475 (Reactome) CDK8 in complex with cyclin C (CDK8:CCNC) and CDK9 in complex with cyclin T (CDK9:CCNT) are able to phosphorylate the linker region of SMAD2 and SMAD3. In SMAD3, CDK8/CDK9 preferentially targets threonine residue T179, although serine residues S208 and S213 can also be phosphorylated. In SMAD2, CDK8/9 preferentially targets threonine residue T220 (corresponds to T190 in the short isoform of SMAD2, SMAD2-2). Phosphorylation of serine residues that correspond to serines S208 and S213 of SMAD3 has not been examined. Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8/CDK9 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes SMAD2 and SMAD3 for ubiquitination and subsequent degradation (Alarcon et al. 2009).
R-HSA-2176491 (Reactome) Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 creates a docking site for E3-ubiquitin ligase NEDD4L.
R-HSA-2176502 (Reactome) NEDD4L ubiquitinates nuclear SMAD2 and SMAD3 phosphorylated at the linker region by CDK8 or CDK9, targeting SMAD2 and SMAD3 for degradation.
R-HSA-2176503 (Reactome) NEDD4L-mediated ubiquitination of SMAD2/3 triggers degradation and ends transcriptional activity of SMAD2/3:SMAD4 complex.
R-HSA-2179274 (Reactome) SMURF2 binds SMAD2/3:SMAD4 heterotrimer through ineraction with SMAD3. Phosphorylation of threonine T179 in the linker region of SMAD3 is critical for SMURF2 binding. SMURF2 also interacts with SMAD2 phosphorylated in the linker region.
R-HSA-2179276 (Reactome) SMURF2 monoubiquitinates SMAD3 on lysine residues in the MH2 domain. Lysines K333 and K378 are likely the major sites for monoubiquitination. Lysine K409 is also monoubiquitinated, and possibly lysine K341. Since lysines K333 and K378 are predicted to stabilize the interaction of SMAD3 with SMAD4, monoubiquitination of these lysine residues is expected to disrupt SMAD2/3:SMAD4 heterotrimer. SMURF2-mediated disruption of endogenous Smad2/3:Smad4 heterotrimers was demonstrated in mouse embryonic fibroblasts. SMURF2 also ubiquitinates SMAD2 phosphorylated in the linker region, but loss of Smurf2 has less impact on Smad2 ubiquitination than on Smad3 in vivo.
R-HSA-2186607 (Reactome) Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 heterotrimer through interaction with SMAD2 and/or SMAD3. TGIF1 and TGIF2 recruit hystone deacetylase HDAC1 to SMAD2/3:SMAD4 heterotrimer.
R-HSA-2186643 (Reactome) MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, binds SMAD2/3:SMAD4 heterotrimer through interaction with SMAD3. MEN1 likely acts as a trancriptional cofactor for SMAD2/3:SMAD4 and may be involved in transcriptional regulation of some SMAD2/3:SMAD4 target genes (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).
R-HSA-2186741 (Reactome) After phosphorylated SMAD2/3 accumulate in the nucleus in response to TGF-beta stimulation, E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007) and SMURF2 (Bonni et al. 2001) bind SKI/SKIL in complex with SMAD2/3:SMAD4 heterotrimer. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL (Levy et al. 2007). The role of SMURF2 was inferred from experiments involving human proteins only (Bonni et al. 2001).
R-HSA-2186747 (Reactome) E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007, Nagano et al. 2007) and SMURF2 (Bonni et al. 2001) ubiquitinate SKI/SKIL transcriptional repressors bound to activated SMAD2/3. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL. The role of SMURF2 was inferred from experiments involving human proteins only.
R-HSA-2186767 (Reactome) SKI/SKIL ubiquitinated by RNF111 (Levy et al. 2007, Nagano et al. 2007) or SMURF2 (Bonni et al. 2001) are degraded in a proteasome dependent way, enabling transcription of SMAD2/3:SMAD4 target genes.
R-HSA-2186771 (Reactome) E3 ubiquitin ligase RNF111 (Arkadia) binds SMAD7 in the nucleus (Koinuma et al. 2003).
R-HSA-2186780 (Reactome) After ubiquitination by RNF111 (Arkadia), ubiquitinated SMAD7 is degraded in a proteasome dependent way. Therefore, RNF111 has a positive effect on trancription initiated by TGF-beta signaling. However, TGF-beta signaling ultimately results in a decrease of RNF111 mRNA level, enabling negative-feedback regulation of TGF-beta signal by SMAD7.
RNF111 may fine tune the duration of cellular response to TGF-beta signal. Initially, RNF111 may enable signal propagation by inhibiting negative regulators of TGF-beta signaling, SKI/SKIL and SMAD7. Subsequent negative regulation of RNF111 expression by TGF-beta may allow the signaling cascade to be turned off (Koinuma et al. 2003).
R-HSA-2186785 (Reactome) RNF111 (Arkadia) polyubiquitinates SMAD7 (Koinuma et al. 2003). This was inferred from studies using recombinant mouse Smad7 and recombinant mouse Rnf111 expressed in human embryonic kidney cell line HEK293.
R-HSA-2187293 (Reactome) SMAD2/3:SMAD4 heterotrimer binds SMAD binding site in the promoter of JUNB transcription factor and in cooperation with AP-1 transcription factors, which bind to an adjacent promoter element, stimulates transcription of JUNB gene (Wong et al. 1999).
R-HSA-2187303 (Reactome) SMAD2/3:SMAD4:SP1 complex binds SP1 and SMAD promoter elements of CDKN2B (p15-INK4B) gene and stimulates transcription of CDKN2B. CDKN2B inhibits the action of cyclin-dependent kinases CDK4 and CDK6 and may be an effector of TGF-beta induced cell cycle arrest (Feng et al. 2000).
R-HSA-2187309 (Reactome) TGF-beta (TGFB1) stimulates formation of a complex of SP1 transcription factor and SMAD2/3:SMAD4 heterotrimer. SMAD2 and SMAD4 bind to SP1 directly, through their C- and N-terminus, respectively (Feng et al. 2000).
R-HSA-2187325 (Reactome) PARP1 ADP-ribosylates SMAD3 and SMAD4 in SMAD2/3:SMAD4 heterotrimer. ADP-ribosyl group is attached to glutamic acid residues E50 and E52 of SMAD3 and unknown amino acid residues of SMAD4. ADP-ribose monomer attached to SMAD3 and SMAD4 is subsequently extended to poly (ADP-ribosyl) chains (i.e. PAR chains) by PARP1, which is not shown here. ADP-ribosylation (PARylation) of SMAD3 and SMAD4 by PARP1 inhibits binding of SMAD2/3:SMAD4 heterotrimers to SMAD binding elements (SBEs) in promoters of SMAD-target genes.
R-HSA-2187330 (Reactome) PARP1 (poly [ADP-ribose] polymerase 1) binds SMAD2/3:SMAD4 heterotrimers associated with DNA SMAD-binding elements (SBEs).
R-HSA-2187388 (Reactome) PPM1A protein phosphatase binds phosphorylated SMAD2 and SMAD3 in the nucleus.
R-HSA-2187395 (Reactome) After dephosphorylation by PPM1A, SMAD2 and SMAD3 translocate to the cytosol.
R-HSA-5252001 (Reactome) In fish, amphibian and avian species, ATP1B4 (aka X,K-ATPase subunit beta-m) functions as a subunit of Na/K-ATPase, located in the plasma membrane. In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain-containing protein 1 (SNW1 aka Ski-interacting protein, SKIP), a transcriptional regulator. This ATP1B4:SNW1 complex is able to modulate TGF-beta-mediated transcription by increasing mRNA levels of SMAD7, an inhibitor of TGF-beta signalling (Pestov et al. 2007).
R-HSA-870437 (Reactome) USP9X (FAM) deubiquitinates SMAD4, thereby opposing the negative regulatory activity of TRIM33 (Ectodermin) (Dupont et al. 2009).
R-HSA-870449 (Reactome) TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) monoubiquitinates nuclear SMAD4 on lysine residue K519. This leads to disruption of heterotrimeric complexes composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3). TRIM33 inhibits SMAD activity without affecting steady state levels of SMAD4 (Dupont et al. 2009, Dupont et al. 2005).
R-HSA-870477 (Reactome) SMAD4 monoubiquitinated by TRIM33 translocates from the nucleus to the cytosol (Dupont et al. 2009, Dupont et al. 2005).
R-HSA-870479 (Reactome) In the cytosol, a ubiquitin hydrolase USP9X (FAM) binds to ubiquitinated SMAD4 (Dupont et al. 2009).
R-HSA-870538 (Reactome) E3 ubiquitin protein ligase TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) binds to the SMAD heterotrimer, composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3), in the nucleus (Dupont et al. 2009, Dupont et al. 2005, He et al. 2006).
RBL1:E2F4/5:DP1/2R-HSA-2127257 (Reactome)
RNF111/SMURF2ArrowR-HSA-2186747 (Reactome)
RNF111/SMURF2R-HSA-2186741 (Reactome)
RNF111ArrowR-HSA-2186785 (Reactome)
RNF111R-HSA-2186771 (Reactome)
SERPINE1 GeneR-HSA-2106586 (Reactome)
SERPINE1ArrowR-HSA-2106586 (Reactome)
SKI/SKILR-HSA-173481 (Reactome)
SMAD2/3ArrowR-HSA-209055 (Reactome)
SMAD2/3ArrowR-HSA-2187395 (Reactome)
SMAD2/3R-HSA-2187395 (Reactome)
SMAD4ArrowR-HSA-209055 (Reactome)
SMAD4ArrowR-HSA-2179276 (Reactome)
SMAD4ArrowR-HSA-870437 (Reactome)
SMAD4R-HSA-170847 (Reactome)
SMAD7 geneR-HSA-2106591 (Reactome)
SMAD7:RNF111ArrowR-HSA-2186771 (Reactome)
SMAD7:RNF111R-HSA-2186785 (Reactome)
SMAD7:RNF111mim-catalysisR-HSA-2186785 (Reactome)
SMAD7ArrowR-HSA-2106591 (Reactome)
SMAD7R-HSA-2186771 (Reactome)
SMAD7TBarR-HSA-2106586 (Reactome)
SMURF2ArrowR-HSA-2179276 (Reactome)
SMURF2R-HSA-2179274 (Reactome)
SNW1R-HSA-5252001 (Reactome)
SP1R-HSA-2187309 (Reactome)
TGIFR-HSA-2186607 (Reactome)
TRIM33Arrow