Pathway Human Homo sapiens

Downregulation of SMAD2/3:SMAD4 transcriptional activity

R-HSA-2173795 in Reactome release 97: under Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer, with 31 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-2173795 (mouse), R-RNO-2173795 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-2173795.6
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2012-06-12
Last updated: 2022-06-09
Events inside: 27, counted from the record

Transcriptional activity of SMAD2/3:SMAD4 heterotrimer can be inhibited by formation of a complex with SKI or SKIL (SNO), where SKI or SKIL recruit NCOR and possibly other transcriptional repressors to SMAD-binding promoter elements (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Higher levels of phosphorylated SMAD2 and SMAD3, however, may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001) through recruitment of SMURF2 (Bonni et al. 2001) or RNF111 i.e. Arkadia (Levy et al. 2007) ubiquitin ligases to SKI/SKIL by SMAD2/3. Therefore,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.

SMAD4 can be monoubiquitinated by a nuclear ubiquitin ligase TRIM33 (Ecto, Ectodermin, Tif1-gamma). Monoubiquitination of SMAD4 disrupts SMAD2/3:SMAD4 heterotrimers and leads to SMAD4 translocation to the cytosol. In the cytosol, SMAD4 can be deubiquitinated by USP9X (FAM), reversing TRIM33-mediated negative regulation (Dupont et al. 2009).

Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 primes SMAD2/3:SMAD4 complex for ubiquitination by NEDD4L and SMURF ubiquitin ligases. NEDD4L ubiquitinates SMAD2/3 and targets SMAD2/3:SMAD4 heterotrimer for degradation (Gao et al. 2009). SMURF2 monoubiquitinates SMAD2/3, leading to disruption of SMAD2/3:SMAD4 complexes (Tang et al. 2011).

Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 complexes and inhibit SMAD-mediated transcription by recruitment of histone deacetylase HDAC1 to SMAD-binding promoter elements (Wotton et al. 1999, Melhuish et al. 2001).

PARP1 can attach poly ADP-ribosyl chains to SMAD3 and SMAD4 within SMAD2/3:SMAD4 heterotrimers. PARylated SMAD2/3:SMAD4 complexes are unable to bind SMAD-binding DNA elements (SBEs) (Lonn et al. 2010).

Phosphorylated SMAD2 and SMAD3 can be dephosphorylated by PPM1A protein phosphatase, leading to dissociation of SMAD2/3 complexes and translocation of unphosphorylated SMAD2/3 to the cytosol (Lin et al. 2006).

Literature Reactome attaches

Negative feedback regulation of TGF-beta signaling by the SnoN oncoproteinScience, 1999, vol. 286, p. 771-4PubMed 10531062
TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradationNat Cell Biol, 2001, vol. 3, p. 587-95PubMed 11389444
SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signalingProc Natl Acad Sci U S A, 1999, vol. 96, p. 12442-7PubMed 10535941
Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signalingMol Cell, 1999, vol. 4, p. 499-509PubMed 10549282
The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signalingGenes Dev, 1999, vol. 13, p. 2196-206PubMed 10485843
Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradationMol Cell Biol, 2007, vol. 27, p. 6068-83PubMed 17591695
FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination

Reactome's record lists 10 orthologous events, R-MMU-2173795 (Mus musculus), R-RNO-2173795 (Rattus norvegicus) among the species this site serves, and 8 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Downregulation of SMAD2/3:SMAD4 transcriptional activity". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-2173795 with StableID: R-HSA-2173795.6 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 31 genes in this human pathway; showing 1 to 31, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneATP1B4	AuthorityHGNC:808	Mapping file id23439 NCBI file	EvidenceTAS
GeneHDAC1	AuthorityHGNC:4852	Mapping file id3065 NCBI file	EvidenceTAS
GeneMAPK1	AuthorityHGNC:6871	Mapping file id5594 NCBI file	EvidenceTAS
GeneMAPK3	AuthorityHGNC:6877	Mapping file id5595 NCBI file	EvidenceTAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA, TAS
GeneNCOR2	AuthorityHGNC:7673	Mapping file id9612 NCBI file	EvidenceIEA, TAS
GeneNEDD4L	AuthorityHGNC:7728	Mapping file id23327 NCBI file	EvidenceTAS
GenePARP1	AuthorityHGNC:270	Mapping file id142 NCBI file	EvidenceTAS
GenePPM1A	AuthorityHGNC:9275	Mapping file id5494 NCBI file	EvidenceTAS
GeneRNF111	AuthorityHGNC:17384	Mapping file id54778 NCBI file	EvidenceIEA
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceIEA, TAS
GeneSERPINE1	AuthorityHGNC:8583	Mapping file idENSG00000106366 Ensembl file	EvidenceTAS
GeneSKI	AuthorityHGNC:10896	Mapping file id6497 NCBI file	EvidenceIEA, TAS
GeneSKIL	AuthorityHGNC:10897	Mapping file id6498 NCBI file	EvidenceIEA, TAS
GeneSMAD2	AuthorityHGNC:6768	Mapping file id4087 NCBI file	EvidenceIEA, TAS
GeneSMAD3	AuthorityHGNC:6769	Mapping file id4088 NCBI file	EvidenceIEA, TAS
GeneSMAD4	AuthorityHGNC:6770	Mapping file id4089 NCBI file	EvidenceIEA, TAS
GeneSMAD7	AuthorityHGNC:6773	Mapping file id4092 NCBI file	EvidenceTAS
GeneSMURF2	AuthorityHGNC:16809	Mapping file id64750 NCBI file	EvidenceIEA, TAS
GeneSNW1	AuthorityHGNC:16696	Mapping file id22938 NCBI file	EvidenceTAS
GeneSTAT1	AuthorityHGNC:11362	Mapping file id6772 NCBI file	EvidenceTAS
GeneTGIF1	AuthorityHGNC:11776	Mapping file id7050 NCBI file	EvidenceTAS
GeneTGIF2	AuthorityHGNC:15764	Mapping file id60436 NCBI file	EvidenceTAS
GeneTRIM33	AuthorityHGNC:16290	Mapping file id51592 NCBI file	EvidenceTAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceIEA, TAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceIEA, TAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceIEA, TAS
GeneUBE2D1	AuthorityHGNC:12474	Mapping file id7321 NCBI file	EvidenceTAS
GeneUBE2D3	AuthorityHGNC:12476	Mapping file id7323 NCBI file	EvidenceTAS
GeneUSP9X	AuthorityHGNC:12632	Mapping file id8239 NCBI file	EvidenceTAS
GeneWWTR1	AuthorityHGNC:24042	Mapping file id25937 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerR-HSA-217379351 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.