BioPAX pathway converted from "Transcriptional regulation of white adipocyte differentiation" in the Reactome database.

Transcriptional regulation of white adipocyte differentiation

Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011). Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes. Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known. CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research. During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA. PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994). The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008). Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes. Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4 (SLC2A4)), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006). Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG.

Authored: May, B, 2009-05-15 01:13:47Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37

Expression of CEBPB in adipogenesis

Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors: 1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB. 2) Glucocorticoids activate expression of CEBPD. 3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB. The detailed mechanisms of activation are not yet known.

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 3858376

nucleoplasmGO0005654

ENSEMBL:ENSG00000172216 CEBPBCEBPBPP9092TCF5

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606ENSEMBLENSG00000172216

Reactome DB_ID: 381378

UniProt:P17676 CEBPB

CEBPB

CEBPBPP9092TCF5FUNCTION Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:1741402, PubMed:9374525, PubMed:12048245, PubMed:18647749). Plays also a significant role in adipogenesis, as well as in the gluconeogenic pathway, liver regeneration, and hematopoiesis. The consensus recognition site is 5'-T[TG]NNGNAA[TG]-3'. Its functional capacity is governed by protein interactions and post-translational protein modifications. During early embryogenesis, plays essential and redundant functions with CEBPA. Has a promitotic effect on many cell types such as hepatocytes and adipocytes but has an antiproliferative effect on T-cells by repressing MYC expression, facilitating differentiation along the T-helper 2 lineage. Binds to regulatory regions of several acute-phase and cytokines genes and plays a role in the regulation of acute-phase reaction and inflammation. Plays also a role in intracellular bacteria killing (By similarity). During adipogenesis, is rapidly expressed and, after activation by phosphorylation, induces CEBPA and PPARG, which turn on the series of adipocyte genes that give rise to the adipocyte phenotype. The delayed transactivation of the CEBPA and PPARG genes by CEBPB appears necessary to allow mitotic clonal expansion and thereby progression of terminal differentiation (PubMed:20829347). Essential for female reproduction because of a critical role in ovarian follicle development (By similarity). Restricts osteoclastogenesis: together with NFE2L1; represses expression of DSPP during odontoblast differentiation.FUNCTION Isoform 2: Essential for gene expression induction in activated macrophages. Plays a major role in immune responses such as CD4(+) T-cell response, granuloma formation and endotoxin shock. Not essential for intracellular bacteria killing.FUNCTION Isoform 3: Acts as a dominant negative through heterodimerization with isoform 2 (PubMed:11741938). Promotes osteoblast differentiation and osteoclastogenesis.SUBUNIT Binds DNA as a homodimer and as a heterodimer (PubMed:11018027, PubMed:11257229, PubMed:11792321). Interacts with ATF4. Binds DNA as a heterodimer with ATF4 (PubMed:11018027). Interacts with MYB; within the complex, MYB and CEBPB bind to different promoter regions (PubMed:11792321). Can form stable heterodimers with CEBPD (PubMed:1741402). Can form stable heterodimers with CEBPA and CEBPE (By similarity). Isoform 2 and isoform 3 also form heterodimers. Interacts with TRIM28 and PTGES2. Interacts with PRDM16. Interacts with CCDC85B. Forms a complex with THOC5. Interacts with ZNF638; this interaction increases transcriptional activation. Interacts with CIDEA and CIDEC; these interactions increase transcriptional activation of a subset of CEBPB downstream target genes (By similarity). Interacts with DDIT3/CHOP (PubMed:20829347). Interacts with EP300; recruits EP300 to chromatin. Interacts with RORA; the interaction disrupts interaction with EP300. Interacts (not methylated) with MED23, MED26, SMARCA2, SMARCB1 and SMARCC1 (PubMed:20111005). Interacts with KAT2A and KAT2B (By similarity). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with NFE2L1; the heterodimer represses expression of DSPP during odontoblast differentiation.TISSUE SPECIFICITY Expressed at low levels in the lung, kidney and spleen.INDUCTION By ER stress.DOMAIN the 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Methylated. Methylation at Arg-3 by CARM1 and at Lys-43 by EHMT2 inhibit transactivation activity. Methylation is probably inhibited by phosphorylation at Thr-235.PTM Sumoylated by polymeric chains of SUMO2 or SUMO3 (PubMed:12810706). Sumoylation at Lys-174 is required for inhibition of T-cells proliferation. In adipocytes, sumoylation at Lys-174 by PIAS1 leads to ubiquitination and subsequent proteasomal degradation. Desumoylated by SENP2, which abolishes ubiquitination and stabilizes protein levels.PTM Ubiquitinated, leading to proteasomal degradation.PTM Phosphorylated at Thr-235 by MAPK and CDK2, serves to prime phosphorylation at Thr-226 and Ser-231 by GSK3B and acquire DNA-binding as well as transactivation activities, required to induce adipogenesis. MAPK and CDK2 act sequentially to maintain Thr-235 in the primed phosphorylated state during mitotical cloning expansion and thereby progression of terminal differentiation. Phosphorylation at Thr-266 enhances transactivation activity. Phosphorylation at Ser-325 in response to calcium increases transactivation activity. Phosphorylated at Thr-235 by RPS6KA1 (PubMed:11684016).PTM O-glycosylated, glycosylation at Ser-227 and Ser-228 prevents phosphorylation on Thr-235, Ser-231 and Thr-226 and DNA binding activity which delays the adipocyte differentiation program.PTM Acetylated. Acetylation at Lys-43 is an important and dynamic regulatory event that contributes to its ability to transactivate target genes, including those associated with adipogenesis and adipocyte function. Deacetylation by HDAC1 represses its transactivation activity. Acetylated by KAT2A and KAT2B within a cluster of lysine residues between amino acids 129-133, this acetylation is strongly induced by glucocorticoid treatment and enhances transactivation activity.SIMILARITY Belongs to the bZIP family. C/EBP subfamily.

UniProtP17676

Chain Coordinates

EQUAL

345

EQUAL

Reactome Database ID Release 69381337Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381337ReactomeR-HSA-381337

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381337.417011499Pubmed2006Transcriptional control of adipocyte formationFarmer, SRCell Metab 4:263-73

ACTIVATION

As inferred from mouse, EGF2 (KROX20) together with KLF4 bind the promoter of the CEBPB gene and activate transcription.

Reactome Database ID Release 69977394Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977394ReactomeR-HSA-977394

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977394.116054051Pubmed2005Krox20 stimulates adipogenesis via C/EBPbeta-dependent and -independent mechanismsChen, ZTorrens, JIAnand, ASpiegelman, BMFriedman, JMCell Metab 1:93-106

Reactome DB_ID: 977385

UniProt:P11161 EGR2

EGR2

EGR2KROX20FUNCTION Sequence-specific DNA-binding transcription factor. Binds to two specific DNA sites located in the promoter region of HOXA4.FUNCTION E3 SUMO-protein ligase helping SUMO1 conjugation to its coregulators NAB1 and NAB2, whose sumoylation down-regulates EGR2 own transcriptional activity.PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with HCFC1. Interacts with WWP2. Interacts with UBC9.PTM Ubiquitinated by WWP2 leading to proteasomal degradation.SIMILARITY Belongs to the EGR C2H2-type zinc-finger protein family.

UniProtP11161

EQUAL

476

EQUAL

ACTIVATION

As inferred from mouse, KLF4 together with EGF2 (KROX20) bind the promoter of the CEBPB gene and activate transcription.

Reactome Database ID Release 69977399Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977399ReactomeR-HSA-977399

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977399.118396140Pubmed2008Transcriptional regulation of adipogenesis by KLF4Birsoy, KChen, ZFriedman, JCell Metab 7:339-47

Reactome DB_ID: 434463

UniProt:O43474 KLF4

KLF4

EZFKLF4GKLFFUNCTION Transcription factor; can act both as activator and as repressor. Binds the 5'-CACCC-3' core sequence. Binds to the promoter region of its own gene and can activate its own transcription. Regulates the expression of key transcription factors during embryonic development. Plays an important role in maintaining embryonic stem cells, and in preventing their differentiation. Required for establishing the barrier function of the skin and for postnatal maturation and maintenance of the ocular surface. Involved in the differentiation of epithelial cells and may also function in skeletal and kidney development. Contributes to the down-regulation of p53/TP53 transcription.SUBUNIT Interacts with POU5F1/OCT4 and SOX2 (By similarity). Interacts with MUC1 (via the C-terminal domain) (PubMed:17308127). Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a (PubMed:21746878). Interacts with ZNF296.DOMAIN the 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.BIOTECHNOLOGY POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors. When combined, these factors are sufficient to reprogram differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes.SIMILARITY Belongs to the krueppel C2H2-type zinc-finger protein family.

UniProtO43474

EQUAL

513

EQUAL

Expression of CEBPD

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 5640179

ENSEMBL:ENSG00000221869 CEBPDCEBPD

ENSEMBLENSG00000221869

Reactome DB_ID: 381280

UniProt:P49716 CEBPD

CEBPD

CEBPDFUNCTION Transcription activator that recognizes two different DNA motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers (PubMed:16397300). Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:1741402, PubMed:16397300). Transcriptional activator that enhances IL6 transcription alone and as heterodimer with CEBPB (PubMed:1741402).SUBUNIT Binds DNA as a homodimer and as a heterodimer (PubMed:1741402). Can form stable heterodimers with CEBPB (PubMed:1741402). Can form stable heterodimers with CEBPA and CEBPE. Interacts with SPI1/PU.1. Interacts with PRDM16.SIMILARITY Belongs to the bZIP family. C/EBP subfamily.

UniProtP49716

EQUAL

269

EQUAL

Reactome Database ID Release 69977392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977392ReactomeR-HSA-977392

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977392.1

Expression of KLF5

Increased expression of KLF5 occurs after activation of the transcription factors CEBPB and CEBPD during differentiation and activation of KLF5 depends on CEBPB and CEBPD. Both CEBPB and CEBPD bind the promoter of the KLF5 gene upstream of the site of transcription initiation and activate transcription of KLF5.

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 5640185

ENSEMBL:ENSG00000102554 KLF5KLF5BTEB2CKLFIKLF

ENSEMBLENSG00000102554

Reactome DB_ID: 381279

UniProt:Q13887 KLF5

KLF5

KLF5BTEB2CKLFIKLFFUNCTION Transcription factor that binds to GC box promoter elements. Activates the transcription of these genes.SUBUNIT Interacts with WWP1.TISSUE SPECIFICITY Expressed only in testis and placenta.PTM Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein.SIMILARITY Belongs to the krueppel C2H2-type zinc-finger protein family.

UniProtQ13887

EQUAL

457

EQUAL

Reactome Database ID Release 69381377Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381377ReactomeR-HSA-381377

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381377.3

ACTIVATION

Reactome Database ID Release 69390517Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390517ReactomeR-HSA-390517

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390517.116054042Pubmed2005Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiationOishi, YManabe, ITobe, KTsushima, KShindo, TFujiu, KNishimura, GMaemura, KYamauchi, TKubota, NSuzuki, RKitamura, TAkira, ShizuoKadowaki, TNagai, RCell Metab 1:27-39

Reactome DB_ID: 381280

EQUAL

269

EQUAL

ACTIVATION

Reactome Database ID Release 69390520Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390520ReactomeR-HSA-390520

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390520.1

Reactome DB_ID: 381378

EQUAL

345

EQUAL

Expression of EBF1

The gene encoding transcription factor EBF1 is transcribed to yield mRNA and the mRNA is translated to yield protein in pre-adipocytes and adipocytes. Transcription of EBF1 is enhanced by CEBPB and CEBPD, which bind the EBF1 promoter.

Authored: May, B, 2010-10-18Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-10-18

Reactome DB_ID: 5640209

ENSEMBL:ENSG00000164330 EBF1COE1EBF1EBF

ENSEMBLENSG00000164330

Reactome DB_ID: 158571

UniProt:Q9UH73 EBF1

EBF1

COE1EBF1EBFFUNCTION Transcriptional activator which recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3'.SUBUNIT Forms either a homodimer or a heterodimer with a related family member (By similarity). Interacts with ZNF423 and ZNF521, leading to prevent EBF1 to bind DNA and activate target genes.SIMILARITY Belongs to the COE family.

UniProtQ9UH73

EQUAL

591

EQUAL

Reactome Database ID Release 69977271Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977271ReactomeR-HSA-977271

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977271.3

ACTIVATION

As inferred from mouse, CEBPD binds the promoter of the EBF1 gene and activates transcription.

Reactome Database ID Release 69977295Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977295ReactomeR-HSA-977295

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977295.117060461Pubmed2007Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascadeJimenez, MAAkerblad, PSigvardsson, MRosen, EDMol Cell Biol 27:743-57

Reactome DB_ID: 381280

EQUAL

269

EQUAL

ACTIVATION

As inferred from mouse, CEBPB binds the promoter of the EBF1 gene and activates transcription.

Reactome Database ID Release 69977290Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977290ReactomeR-HSA-977290

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-977290.1

Reactome DB_ID: 381378

EQUAL

345

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Expression of PPARG

The transcription factors CEBPB, CEBPD, and KLF5 simultaneously bind the PPARG promoter and synergistically activate transcription of the PPARG gene. These three factors activate transcription after initial stimulation of adipocyte differentiation but then are replaced by CEBPA within 10 days. CEBPA and other factors may be responsible for long term maintenance of PPARG expression and the differentiated state. Pre-adipose tissue contains both the widely expressed PPARG isoform 1 mRNA and the more tissue-specific PPARG isoform 2. The PPARG isoform 2 mRNA is translated to yield PPARG isoform 2 protein, which has 505 amino acid residues (57 KDa) and is the longest of the 4 observed variants. Isoform 2 is specific to preadipose and adipose tissue (Mukherjee et al. 1997). Confusingly, the longest variant is called isoform 1 in some publications. In mouse, by 10 days after induction of adipocyte differentiation Cebpa, but neither Cebpb nor Cebpd, is detectable at the Pparg promoter. While adipocyte differentiation can proceed without Cebpa, adipocytes differentiated from Cebpa-knockout cells are insulin insensitive due to a defect in Glut4 (Slc2a4) vesicle trafficking. The adipogenesis regulatory factor (ADIRF, aka AFRO, APM2, C10orf116) promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA (Ni et al. 2013).

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 5640205

ENSEMBL:ENSG00000132170 PPARGPPARGNR1C3

ENSEMBLENSG00000132170

Reactome DB_ID: 446172

UniProt:P37231 PPARG

PPARG

PPARGNR1C3FUNCTION Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels.FUNCTION (Microbial infection) Upon treatment with M.tuberculosis or its lipoprotein LpqH, phosphorylation of MAPK p38 and IL-6 production are modulated, probably via this protein.ACTIVITY REGULATION PDPK1 activates its transcriptional activity independently of its kinase activity.SUBUNIT Interacts with FOXO1 (acetylated form) (By similarity). Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters. Interacts with NOCT. Interacts with ACTN4. Interacts (when in the liganded conformation) with GPS2.TISSUE SPECIFICITY Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary.INDUCTION (Microbial infection) Expression increases when incubated with M.tuberculosis or its lipoprotein LpqH; induction is TLR2-dependent (at protein level).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes.PTM Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity.POLYMORPHISM Genetic variations in PPARG define the body mass index quantitative trait locus 1 (BMIQ1) [MIM:606641]. The body max index (BMI) reflects the amount of fat, lean mass, and body build.POLYMORPHISM Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable-adjusted CIMT is explained by genetic factors.DISEASE Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.

UniProtP37231

EQUAL

505

EQUAL

Reactome Database ID Release 69381283Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381283ReactomeR-HSA-381283

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381283.423239344Pubmed2013A Novel pro-adipogenesis factor abundant in adipose tissues and over-expressed in obesity acts upstream of PPARγ and C/EBPαNi, YuhuiJi, ChenboWang, BQiu, JieWang, JiwuGuo, XirongJ. Bioenerg. Biomembr. 45:219-2811872672Pubmed2002Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonistsSewter, CPBlows, FVidal-Puig, AO'Rahilly, SDiabetes 51:718-239065481Pubmed1997Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonistsMukherjee, RJow, LCroston, GEPaterniti JR, JrJ Biol Chem 272:8071-6

ACTIVATION

Reactome Database ID Release 698936821Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8936821ReactomeR-HSA-8936821

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8936821.1

Reactome DB_ID: 8936822

UniProt:Q15847 ADIRF

ADIRF

C10orf116ADIRFAPM2AFROFUNCTION Plays a role in fat cell development; promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA at early stages of preadipocyte differentiation. Its overexpression confers resistance to the anticancer chemotherapeutic drug cisplatin.TISSUE SPECIFICITY Expressed in adipose tissue (at protein level). Highly expressed in omental and subcutaneous adipose tissues. Expressed in heart, cornea, liver, kidney and spleen.INDUCTION Up-regulated during pre-adipocyte differentiation. Up-regulated following DNA damage induced by UV irradiation.

UniProtQ15847

EQUAL

ACTIVATION

Reactome Database ID Release 69390511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390511ReactomeR-HSA-390511

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390511.1

Reactome DB_ID: 381279

EQUAL

457

EQUAL

ACTIVATION

Reactome Database ID Release 69390518Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390518ReactomeR-HSA-390518

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390518.111279134Pubmed2001A role for C/EBPbeta in regulating peroxisome proliferator-activated receptor gamma activity during adipogenesis in 3T3-L1 preadipocytesHamm, JKPark, BHFarmer, SRJ Biol Chem 276:18464-717557387Pubmed1995Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesisWu, ZXie, YBucher, NLFarmer, SRGenes Dev 9:2350-639405372Pubmed1997Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta geneTanaka, TYoshida, NKishimoto, TAkira, ShizuoEMBO J 16:7432-438754811Pubmed1996Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoidsWu, ZBucher, NLFarmer, SRMol Cell Biol 16:4128-3615110775Pubmed2004Sequential gene promoter interactions by C/EBPbeta, C/EBPalpha, and PPARgamma during adipogenesisTang, QQZhang, JWDaniel Lane, MBiochem Biophys Res Commun 318:213-8

Reactome DB_ID: 381378

EQUAL

345

EQUAL

ACTIVATION

As inferred from mouse, SREBP1A and SREBP2 bind to the PPARG1 and PPARG2 promoters and activate transcription.

Reactome Database ID Release 69934638Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=934638ReactomeR-HSA-934638

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-934638.110409739Pubmed1999Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolismFajas, LSchoonjans, KGelman, LKim, JBNajib, JMartin, GFruchart, JCBriggs, MSpiegelman, BMAuwerx, JMol Cell Biol 19:5495-503Converted from EntitySet in Reactome

Reactome DB_ID: 1655734

SREBF1A,2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySREBF2(1-484) [nucleoplasm]SREBF1-1(1-490) [nucleoplasm]

UniProtQ12772UniProtP36956-1

ACTIVATION

Reactome Database ID Release 69390512Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390512ReactomeR-HSA-390512

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390512.110862621Pubmed2000Modulation of the murine peroxisome proliferator-activated receptor gamma 2 promoter activity by CCAAT/enhancer-binding proteinsElberg, GGimble, JMTsai, SYJ Biol Chem 275:27815-22

Reactome DB_ID: 381280

EQUAL

269

EQUAL

INHIBITION

As inferred from mouse, TGF-beta inhibits expression of PPARG.

Reactome Database ID Release 69976214Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976214ReactomeR-HSA-976214

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976214.17694071Pubmed1993Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by antagonists of adipogenesisStephens, JMButts, MStone, RPekala, PHBernlohr, DAMol Cell Biochem 123:63-7110791980Pubmed2000Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiationChoy, LSkillington, JDerynck, RJ Cell Biol 149:667-82

Reactome DB_ID: 170838

extracellular regionGO0005576

UniProt:P01137 TGFB1

TGFB1

TGFB1TGFBFUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.FUNCTION Latency-associated peptide: Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix (PubMed:28117447). Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia (Probable). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447).FUNCTION Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292).SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Latency-associated peptide: Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (Probable). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Transforming growth factor beta-1: Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).DOMAIN Latency-associated peptide: The 'straitjacket' and 'arm' domains encircle the Transforming growth factor beta-1 (TGF-beta-1) monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104.DOMAIN Latency-associated peptide: The cell attachment site motif mediates binding to integrins (ITGAV:ITGB6 or ITGAV:ITGB8) (PubMed:28117447). The motif locates to a long loop in the arm domain called the bowtie tail (PubMed:28117447). Integrin-binding stabilizes an alternative conformation of the bowtie tail (PubMed:28117447). Activation by integrin requires force application by the actin cytoskeleton, which is resisted by the 'milieu molecules' (such as LTBP1, LRRC32/GARP and/or LRRC33/NRROS), resulting in distortion of the prodomain and release of the active TGF-beta-1 (PubMed:28117447).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.PTM Latency-associated peptide: N-glycosylated (PubMed:3162913, PubMed:2493139, PubMed:28117447). Deglycosylation leads to activation of Transforming growth factor beta-1 (TGF-beta-1); mechanisms triggering deglycosylation-driven activation of TGF-beta-1 are however unclear (PubMed:2493139).POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family.

UniProtP01137

279

EQUAL

390

EQUAL

INHIBITION

As inferred from mouse 3T3-L1 cells, Wnt-1 and Wnt-10b inhibit PPARG expression (Ross et al. 2000, Bennett et al. 2002) by activating COUP-TFII (NR2F2) which recruits the SMRT repressor complex to the PPARG gene (Okamura et al. 2009).

Reactome Database ID Release 69976231Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976231ReactomeR-HSA-976231

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976231.110937998Pubmed2000Inhibition of adipogenesis by Wnt signalingRoss, SEHemati, NLongo, KABennett, CNLucas, PCErickson, RLMacDougald, OAScience 289:950-319307559Pubmed2009COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesisOkamura, MKudo, HWakabayashi, KTanaka, TNonaka, AUchida, ATsutsumi, SSakakibara, INaito, MOsborne, TFHamakubo, TIto, SAburatani, HiroyukiYanagisawa, MKodama, TSakai, JProc Natl Acad Sci U S A 106:5819-2412055200Pubmed2002Regulation of Wnt signaling during adipogenesisBennett, CNRoss, SELongo, KABajnok, LHemati, NJohnson, KWHarrison, SDMacDougald, OAJ Biol Chem 277:30998-1004

Reactome DB_ID: 1183002

UniProt:P24468 NR2F2

NR2F2

NR2F2ARP1TFCOUP2FUNCTION Ligand-activated transcription factor. Activated by high concentrations of 9-cis-retinoic acid and all-trans-retinoic acid, but not by dexamethasone, cortisol or progesterone (in vitro). Regulation of the apolipoprotein A-I gene transcription. Binds to DNA site A.SUBUNIT Interacts with SQSTM1 (By similarity). Binds DNA as a dimer; homodimer or heterodimer with NR2F6. Interacts with NCOA1, NCOA2, NCOA3 and PPARGC1A. Interacts with ZFPM2.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily.

UniProtP24468

EQUAL

414

EQUAL

INHIBITION

As inferred from mouse, NF-kappaB inhibits expression of PPARG in pre-adipocytes (Chae and Kwak 2003). TNFalpha represses PPARG via NF-kappaB (Chae and Kwak 2003, Kurebayashi et al. 2001, Xing et al. 1997).

Reactome Database ID Release 69976211Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976211ReactomeR-HSA-976211

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976211.111456275Pubmed2001TNF-alpha inhibits 3T3-L1 adipocyte differentiation without downregulating the expression of C/EBPbeta and deltaKurebayashi, SSumitani, SKasayama, SJetten, AMHirose, TEndocr J 48:249-5314646597Pubmed2003NF-kappaB is involved in the TNF-alpha induced inhibition of the differentiation of 3T3-L1 cells by reducing PPARgamma expressionChae, GNKwak, SJExp Mol Med 35:431-79202217Pubmed1997TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expressionXing, HNorthrop, JPGrove, JRKilpatrick, KESu, JLRingold, GMEndocrinology 138:2776-83

Reactome DB_ID: 194047

NFKB1(1-433):RELA [nucleoplasm]

NFKB1(1-433):RELA

NF-kB complex

Reactome DB_ID: 177676

UniProt:Q04206 RELA

RELA

NFKB3RELAFUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds AES and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (By similarity). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.DOMAIN The transcriptional activation domain 3/TA3 does not participate to the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).PTM Ubiquitinated, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.PTM Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes.PTM Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.PTM Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.PTM S-nitrosylation of Cys-38 inactivates the enzyme activity.PTM Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.PTM Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.PTM Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).DISEASE A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141).

UniProtQ04206

EQUAL

551

EQUAL

Reactome DB_ID: 177655

UniProt:P19838 NFKB1

NFKB1

NFKB1FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-p50 complex. Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. Component of the NF-kappa-B p50-c-Rel complex. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Also interacts with MAP3K8. NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity. Interacts with DSIPI; this interaction prevents nuclear translocation and DNA-binding. Interacts with SPAG9 and UNC5CL. NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50. NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2. Interacts with GSK3B; the interaction prevents processing of p105 to p50. NFKB1/p50 interacts with NFKBIE. NFKB1/p50 interacts with NFKBIZ. Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1. Interacts with HIF1AN.INDUCTION By phorbol ester and TNF.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.DOMAIN Glycine-rich region (GRR) appears to be a critical element in the generation of p50.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.PTM Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.PTM Polyubiquitination seems to allow p105 processing.PTM S-nitrosylation of Cys-61 affects DNA binding.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.

UniProtP19838

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433

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Reactome Database ID Release 69194047Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194047ReactomeR-HSA-194047

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194047.2

ACTIVATION

As inferred from mouse homologs, ZNF467 (ZFP467) binds the promoter of the PPARG gene and recruits a histone deacetylase complex to activate transcription of PPARG.

Reactome Database ID Release 698940351Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8940351ReactomeR-HSA-8940351

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8940351.1

Reactome DB_ID: 8940332

UniProt:Q7Z7K2 ZNF467

ZNF467

ZNF467FUNCTION Transcription factor that promotes adipocyte differentiation and suppresses osteoblast differentiation in the bone marrow. Enhances the osteoclast-supporting ability of stromal cells. Binds with STAT3 the consensus sequence 5'-CTTCTGGGAAGA-3' of the acute phase response element (APRE). Transactivates several promoters including FOS, OSM and PPARG. Recruits a histone deacetylase complex.SUBUNIT Interacts with STAT3. Enhances STAT3 activity by keeping it in the nucleus.SIMILARITY Belongs to the krueppel C2H2-type zinc-finger protein family.

UniProtQ7Z7K2

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ACTIVATION

ZNF638 cooperates together with CEBPB and CEBPD at the promoter of the PPARG gene to activate transcription (inferred from mouse homologs).

Reactome Database ID Release 698939433Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8939433ReactomeR-HSA-8939433

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8939433.1

Reactome DB_ID: 8939429

UniProt:Q14966 ZNF638

ZNF638

ZFMLZNF638NP220FUNCTION Early regulator of adipogenesis that works as a transcription cofactor of CEBPs, controlling the expression of PPARG and probably of other proadipogenic genes, such as SREBF1 (By similarity). Binds to cytidine clusters in double-stranded DNA (PubMed:8647861). May also regulate alternative splicing of target genes during adipogenesis.SUBUNIT Interacts with FHL2 (PubMed:11813260). Interacts with CEBPA, CEBPD and CEBPG.DOMAIN The matrin-type zinc finger domain is required for localization to nuclear speckles.MISCELLANEOUS Isoform 5 is a tumor-associated antigen found in several cutaneous T-cell lymphoma (CTCL), and in particular in mycosis fungoides patients and in Sezary syndrome patients.

UniProtQ14966

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1978

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ACTIVATION

Reactome Database ID Release 69390516Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390516ReactomeR-HSA-390516

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390516.1

Reactome DB_ID: 158571

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ACTIVATION

Activation of PPARG transcription by CEPBA is inferred from mouse.

Reactome Database ID Release 69390514Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390514ReactomeR-HSA-390514

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390514.211782441Pubmed2002C/EBPalpha induces adipogenesis through PPARgamma: a unified pathwayRosen, EDHsu, CHWang, XSakai, SFreeman, MWGonzalez, FJSpiegelman, BMGenes Dev 16:22-6

Reactome DB_ID: 381289

UniProt:P49715 CEBPA

CEBPA

CEBPACEBPFUNCTION Transcription factor that coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, and cells of the lung and the placenta. Binds directly to the consensus DNA sequence 5'-T[TG]NNGNAA[TG]-3' acting as an activator on distinct target genes (PubMed:11242107). During early embryogenesis, plays essential and redundant functions with CEBPB. Essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP). Critical for the proper development of the liver and the lung (By similarity). Necessary for terminal adipocyte differentiation, is required for postnatal maintenance of systemic energy homeostasis and lipid storage (By similarity). To regulate these different processes at the proper moment and tissue, interplays with other transcription factors and modulators. Downregulates the expression of genes that maintain cells in an undifferentiated and proliferative state through E2F1 repression, which is critical for its ability to induce adipocyte and granulocyte terminal differentiation. Reciprocally E2F1 blocks adipocyte differentiation by binding to specific promoters and repressing CEBPA binding to its target gene promoters. Proliferation arrest also depends on a functional binding to SWI/SNF complex (PubMed:14660596). In liver, regulates gluconeogenesis and lipogenesis through different mechanisms. To regulate gluconeogenesis, functionally cooperates with FOXO1 binding to IRE-controlled promoters and regulating the expression of target genes such as PCK1 or G6PC. To modulate lipogenesis, interacts and transcriptionally synergizes with SREBF1 in promoter activation of specific lipogenic target genes such as ACAS2. In adipose tissue, seems to act as FOXO1 coactivator accessing to ADIPOQ promoter through FOXO1 binding sites.FUNCTION Isoform 3: Can act as dominant-negative. Binds DNA and have transctivation activity, even if much less efficiently than isoform 2. Does not inhibit cell proliferation (PubMed:14660596).FUNCTION Isoform 4: Directly and specifically enhances ribosomal DNA transcription interacting with RNA polymerase I-specific cofactors and inducing histone acetylation.SUBUNIT Binds DNA as a homodimer and as a heterodimer. Can form stable heterodimers with CEBPB, CEBPD, CEBPE and CEBPG (By similarity). Interacts with PRDM16 (By similarity). Interacts with UBN1 (PubMed:10725330). Interacts with ZNF638; this interaction increases transcriptional activation (By similarity). Interacts with the complex TFDP2:E2F1; the interaction prevents CEBPA binding to target gene promoters and represses its transcriptional activity (PubMed:20176812). Interacts with RB1 (PubMed:15107404). Interacts (when phosphorylated at SER-190) with CDK2, CDK4, E2F4 and SMARCA2 (PubMed:15107404). Interacts with SREBPF1 (By similarity). Interacts with FOXO1 (via the Fork-head domain); the interaction increases when FOXO1 is deacetylated (By similarity). Isoform 1 and isoform 4 interacts with TAF1A and UBTF (PubMed:20075868). Isoform 4 interacts with NPM1 (PubMed:20075868). Interacts (via recognition sequence) with TRIB1 (PubMed:20410507, PubMed:26455797).SUBUNIT (Microbial infection) Interacts with HBV protein X.DOMAIN The recognition sequence (54-72) is required for interaction with TRIB1.PTM Phosphorylation at Ser-190 is required for interaction with CDK2, CDK4 and SWI/SNF complex leading to cell cycle inhibition. Dephosphorylated at Ser-190 by protein phosphatase 2A (PP2A) through PI3K/AKT signaling pathway regulation (PubMed:15107404). Phosphorylation at Thr-226 and Thr-230 by GSK3 is constitutive in adipose tissue and lung. In liver, both Thr-226 and Thr-230 are phosphorylated only during feeding but not during fasting. Phosphorylation of the GSK3 consensus sites selectively decreases transactivation activity on IRE-controlled promoters.PTM Sumoylated, sumoylation blocks the inhibitory effect on cell proliferation by disrupting the interaction with SMARCA2.PTM Ubiquitinated by COP1 upon interaction with TRIB1.SIMILARITY Belongs to the bZIP family. C/EBP subfamily.

UniProtP49715

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Formation of PPARG:RXRA heterodimer (ARF6 complex)

PPARG binds the Retinoic acid X Receptor RXRA to form a heterodimer that has transcriptional acivation activity. The complex was initially called ARF6 when discovered. PPARG binds RXRA via the C-terminus and AF-2 regions of PPARG.

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 446172

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UniProt:P19793 RXRA

RXRA

RXRANR2B1FUNCTION Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.SUBUNIT Homodimer. Heterodimer with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity. Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity. Also heterodimerizes with PPARG. Interacts with NCOA3 and NCOA6 coactivators. Interacts with FAM120B (By similarity). Interacts with PELP1, SENP6, SFPQ, DNTTIP2 and RNF8. Interacts with PRMT2. Interacts with ASXL1 (By similarity). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2. Interacts in a ligand-dependent fashion with MED1 and NCOA1. Interacts with VDR.SUBUNIT (Microbial infection) Interacts (via the DNA binding domain) with HCV core protein; the interaction enhances the transcriptional activities of the RXRA/RARA and the RXRA/PPARA heterodimers.TISSUE SPECIFICITY Highly expressed in liver, also found in lung, kidney and heart.DOMAIN Composed of three domains: a modulating N-terminal domain (AF1 domain), a DNA-binding domain and a C-terminal ligand-binding domain (AF2 domain).PTM Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain. Constiutively phosphorylated on Ser-21 in the presence or absence of ligand. Under stress conditions, hyperphosphorylated by activated JNK on Ser-56, Ser-70, Thr-82 and Ser-260 (By similarity). Phosphorylated on Ser-27, in vitro, by PKA. This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA.PTM Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily.

UniProtP19793

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Reactome DB_ID: 381281

PPARG:RXRA Heterodimer [nucleoplasm]

PPARG:RXRA Heterodimer

ARF6 ComplexPeroxisome proliferator-activated receptor:retinoic acid receptor heterodimer

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Reactome Database ID Release 69381281Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381281ReactomeR-HSA-381281

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381281.1Reactome Database ID Release 69381262Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381262ReactomeR-HSA-381262

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381262.117980149Pubmed2008Effect of heterodimer partner RXRalpha on PPARgamma activation function-2 helix in solutionLu, JChen, MStanley, SELi, EBiochem Biophys Res Commun 365:42-619043829Pubmed2008Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNAChandra, VHuang, PHamuro, YRaghuram, SWang, YBurris, TPRastinejad, FNature 456:350-6

PPARG:RXRA heterodimer binds to PPARG corepressors

The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state.

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 442469

UniProt:Q9Y618 NCOR2

NCOR2

NCOR2CTG26FUNCTION Transcriptional corepressor (PubMed:20812024). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 4 have different affinities for different nuclear receptors. Involved in the regulation BCL6-dependent of the germinal center (GC) reactions, mainly through the control of the GC B-cells proliferation and survival. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid (TR) and the retinoid acid receptors (RAR) in the absence of ligand, and may stabilize their interaction with TFIIB. Interacts directly with RARA in the absence of ligand; the interaction represses RARA activity. Interacts (isoform SMRT) with HDAC10. Interacts with MINT. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:10944117, PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts with CBFA2T3 and ATXN1L. Interacts with RARB; the interaction is weak and does not repress RARB transactivational activity. Interacts with HDAC7 and C1D. Interacts with NR4A2; this interaction increases in the absence of PITX3. Interacts with BCL6 (via the BTB domain), required for BCL6 transcriptional repressor activity on a subset of target genes. Forms ternary complexes with BCOR and BCL6 on target gene promoters but, on enhancer elements, interacts with BCL6 and HDAC3 to repress proximal gene expression. May interact with DEAF1. Interacts with RXRA. Interacts with MECP2 (By similarity). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024).TISSUE SPECIFICITY Ubiquitous. High levels of expression are detected in lung, spleen and brain.INDUCTION Regulated during cell cycle progression.DOMAIN The N-terminal region contains repression functions that are divided into three independent repression domains (RD1, RD2 and RD3). The C-terminal region contains the nuclear receptor-interacting domains that are divided in two separate interaction domains (ID1 and ID2).DOMAIN The two interaction domains (ID) contain a conserved sequence referred to as the CORNR box. This motif is required and sufficient to permit binding to unligated TR and RARS. Sequences flanking the CORNR box determine nuclear hormone receptor specificity.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family.

UniProtQ9Y618

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Reactome DB_ID: 442464

UniProt:O15379 HDAC3

HDAC3

HDAC3FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner (By similarity). During the activation phase, promotes the accumulation of ubiquitinated ARNTL/BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and ARNTL/BMAL1.SUBUNIT Interacts with HDAC7 and HDAC9. Forms a heterologous complex at least with YY1. Interacts with DAXX, HDAC10 and DACH1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY. Interacts with BTBD14B. Interacts with GLIS2. Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation. Component of the Notch corepressor complex. Interacts with CBFA2T3 and NKAP. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with and deacetylates MAPK14. Interacts with ZMYND15. Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements. Interacts with INSM1 (PubMed:10655483, PubMed:10669754, PubMed:10860984, PubMed:10898795, PubMed:11006275, PubMed:11466315, PubMed:11533236, PubMed:11861901, PubMed:14525983, PubMed:14633989, PubMed:15297880, PubMed:15927959, PubMed:16569215, PubMed:18417529, PubMed:19409814, PubMed:23911289). Interacts with XBP1 isoform 1; the interaction occurs in endothelial cell (EC) under disturbed flow (PubMed:25190803). Interacts (via C-terminus) with CCAR2 (via N-terminus). Interacts with and deacetylates MEF2D. Interacts with BEND3. Interacts with NKAPL (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts weakly with CRY1; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with FBXL3 and ARNTL/BMAL1.TISSUE SPECIFICITY Widely expressed.INDUCTION Up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803).PTM Sumoylated in vitro.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily.

UniProtO15379

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Reactome DB_ID: 442501

UniProt:O75376 NCOR1

NCOR1

NCOR1KIAA1047FUNCTION Mediates transcriptional repression by certain nuclear receptors (PubMed:20812024). Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors. Participates in the transcriptional repressor activity produced by BCL6. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid receptor (TR) and the retinoid acid receptor (RAR) in the absence of ligand. Interacts directly with RARA; the interaction is facilitated with RARA trimethylation. Component of the N-Cor repressor complex, at least composed of CBFA2T3, HEXIM1, NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2. Interacts with ZBTB33; the interaction serves to recruit the N-CoR complex to promoter regions containing methylated CpG dinucleotides. Interacts with TRIM28 and KDM3A. Interacts (via the RD1 domain) with BAZ1A (via its N-terminal); the interaction corepresses a number of NCOR1-regulated genes. Interacts with BCL6, C1D, DACH1, HEXIM1, HDAC7, RORA, RORC, SAP30, SIAH2, SIN3A and SIN3B. May interact with DEAF1. Interacts with RXRA. Interacts with SETD5 (By similarity). Interacts with VDR (PubMed:28698609). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024).DOMAIN The N-terminal region contains three independent domains that are capable of mediating transcriptional repression (RD1, RD2 and RD3).DOMAIN The C-terminal region contains two separate nuclear receptor-interacting domains (ID1 and ID2), each of which contains a conserved sequence referred to as the CORNR box. This motif is necessary and sufficient for binding to unligated nuclear hormone receptors, while sequences flanking the CORNR box determine the precise nuclear hormone receptor specificity.PTM Ubiquitinated; mediated by SIAH2 and leading to its subsequent proteasomal degradation.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family.

UniProtO75376

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Reactome DB_ID: 381226

PPARG:RXRA:Corepressor Complex [nucleoplasm]

PPARG:RXRA:Corepressor Complex

Reactome DB_ID: 442469

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Reactome Database ID Release 69381226Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381226ReactomeR-HSA-381226

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381226.1Reactome Database ID Release 69381290Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381290ReactomeR-HSA-381290

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381290.18970730Pubmed1996Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiologyLemberger, TDesvergne, BWahli, WAnnu Rev Cell Dev Biol 12:335-63

PPARG:RXRA heterodimer binds to fatty acid-like ligands

PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996). FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010). Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010). The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL).

Authored: May, B, 2009-05-15 01:16:49Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37Edited: May, B, 2009-05-15 01:16:49

Reactome DB_ID: 442499

UniProt:Q9BYK8 HELZ2

HELZ2

HELZ2PRIC285KIAA1769FUNCTION Helicase that acts as a transcriptional coactivator for a number of nuclear receptors including PPARA, PPARG, THRA, THRB and RXRA.SUBUNIT Interacts with PPARA (via DNA-binding domain) and PPARG; the interaction stimulates the transcriptional activity of PPARA and PPARG. Interacts with THRAP3; the interaction is direct and HELZ2 and THRAP3 synergistically enhance the transcriptional activity of PPARG. It is probably part of the peroxisome proliferator activated receptor alpha interacting complex (PRIC).TISSUE SPECIFICITY Expressed in various tissues including heart, pancreas, skeletal muscle, colon, spleen, liver, kidney, lung, peripheral blood and placenta.DOMAIN Contains 5 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. These motifs are not required for interaction with PPARG.SIMILARITY Belongs to the DNA2/NAM7 helicase family.CAUTION PubMed:12189208 experiments have been carried out partly in rat and partly in human.

UniProtQ9BYK8

EQUAL

2649

EQUAL

Reactome DB_ID: 442481

UniProt:Q9UBK2 PPARGC1A

PPARGC1A

PGC1LEM6PGC1APPARGC1PPARGC1AFUNCTION Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. Required for oscillatory expression of clock genes, such as ARNTL/BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK.SUBUNIT Homooligomer. Interacts with MYBBP1A; inhibits MYBBP1A transcriptional activation (By similarity). Interacts with PRDM16, LPIN1 and PML (By similarity). Interacts (via LXXLL motif) with RORA and RORC (via AF-2 motif); activates RORA and RORC transcriptional activation (By similarity). Interacts with LRPPRC. Interacts with RNF34 (via RING-type zinc finger).TISSUE SPECIFICITY Heart, skeletal muscle, liver and kidney. Expressed at lower levels in brain and pancreas and at very low levels in the intestine and white adipose tissue. In skeletal muscle, levels were lower in obese than in lean subjects and fasting induced a 2-fold increase in levels in the skeletal muscle in obese subjects.INDUCTION Transcription is repressed by ZNF746 which binds to 'insulin response sequences' its promoter.PTM Phosphorylation by AMPK in skeletal muscle increases activation of its own promoter. Phosphorylated by CLK2.PTM Heavily acetylated by GCN5 and biologically inactive under conditions of high nutrients. Deacetylated by SIRT1 in low nutrients/high NAD conditions.PTM Ubiquitinated. Ubiquitination by RNF34 induces proteasomal degradation.

UniProtQ9UBK2

EQUAL

798

EQUAL

Reactome DB_ID: 2026090

FABP4:Ligands of PPARG [nucleoplasm]

FABP4:Ligands of PPARG

Reactome DB_ID: 2026072

UniProt:P15090 FABP4

FABP4

FABP4FUNCTION Lipid transport protein in adipocytes. Binds both long chain fatty acids and retinoic acid. Delivers long-chain fatty acids and retinoic acid to their cognate receptors in the nucleus.SUBUNIT Monomer (PubMed:15357969, PubMed:17077479). Homodimer. Interacts with PPARG.DOMAIN Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.SIMILARITY Belongs to the calycin superfamily. Fatty-acid binding protein (FABP) family.

UniProtP15090

EQUAL

132

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 381235

Ligands of PPARG [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity9S-HODE [nucleoplasm]13(S')-HODE [nucleoplasm]Actos [nucleoplasm]RGZ [nucleoplasm]

ChEBI34496ChEBI34154ChEBI8228ChEBI50122Reactome Database ID Release 692026090Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2026090ReactomeR-HSA-2026090

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2026090.1

Reactome DB_ID: 381325

UniProt:Q09472 EP300

EP300

P300EP300FUNCTION Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRMT1 or SIRT2 (PubMed:12929931, PubMed:16762839, PubMed:18722353). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degragation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA) or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation or propionylation, respectively (PubMed:25818647, PubMed:17267393). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (E)-but-2-enoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein.SUBUNIT Interacts with phosphorylated CREB1. Interacts with HIF1A; the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts (via N-terminus) with TFAP2A (via N-terminus); the interaction requires CITED2. Interacts (via CH1 domain) with CITED2 (via C-terminus). Interacts with CITED1 (unphosphorylated form preferentially and via C-terminus). Interacts with ESR1; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with DTX1, EID1, ELF3, FEN1, LEF1, NCOA1, NCOA6, NR3C1, PCAF, PELP1, PRDM6, SP1, SP3, SPIB, SRY, TCF7L2, TP53, DDX5, DDX17, SATB1, SRCAP, TTC5, JMY and TRERF1. The TAZ-type 1 domain interacts with HIF1A. Probably part of a complex with HIF1A and CREBBP. Part of a complex containing CARM1 and NCOA2/GRIP1. Interacts with ING4 and this interaction may be indirect. Interacts with ING5. Interacts with the C-terminal region of CITED4. Non-sumoylated EP300 preferentially interacts with SENP3. Interacts with SS18L1/CREST. Interacts with ALX1 (via homeobox domain). Interacts with NEUROD1; the interaction is inhibited by NR0B2. Interacts with TCF3. Interacts (via CREB-binding domain) with MYOCD (via C-terminus). Binds to HIPK2. Interacts with ROCK2 and PPARG. Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes. Interacts with IRF1 and this interaction enhances acetylation of p53/TP53 and stimulation of its activity. Interacts with FOXO1; the interaction acetylates FOXO1 and enhances its transcriptional activity. Interacts with ALKBH4 and DDIT3/CHOP. Interacts with KLF15. Interacts with CEBPB and RORA. Interacts with p30II. Interacts with NPAS2, ARNTL/BMAL1 and CLOCK. Interacts with SIRT2 isoform 1, isoform 2 and isoform 5. Interacts with MTA1. Interacts with HDAC4 and HDAC5 in the presence of TFAP2C (PubMed:10722728, PubMed:10823961, PubMed:11073989, PubMed:11073990, PubMed:11349124, PubMed:11430825, PubMed:11481323, PubMed:11518699, PubMed:11559821, PubMed:11564735, PubMed:11581164, PubMed:11581372, PubMed:11701890, PubMed:11744733, PubMed:11864910, PubMed:11959990, PubMed:11997499, PubMed:12446687, PubMed:12527917, PubMed:12586840, PubMed:12750254, PubMed:12778114, PubMed:12837748, PubMed:12929931, PubMed:14605447, PubMed:14645221, PubMed:14716005, PubMed:14752053, PubMed:15075319, PubMed:15186775, PubMed:15297880, PubMed:15509808, PubMed:15731352, PubMed:15890677, PubMed:16478997, PubMed:16574662, PubMed:16617102, PubMed:16864582, PubMed:17226766, PubMed:17872950, PubMed:18273021, PubMed:19217391, PubMed:19680224, PubMed:20081228, PubMed:23145062, PubMed:23999430, PubMed:24177535, PubMed:24413532, PubMed:8684459, PubMed:8917528, PubMed:9528808, PubMed:9590696, PubMed:9862959, PubMed:9887100). Interacts with TRIP4 (PubMed:25219498). Directly interacts with ZBTB49; this interaction leads to synergistic transactivation of CDKN1A (PubMed:25245946). Interacts with NR4A3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with ZBTB48/TZAP (PubMed:24382891). Interacts with STAT1; the interaction is enhanced upon IFN-gamma stimulation (PubMed:26479788). Interacts with HNRNPU (via C-terminus); this interaction enhances DNA-binding of HNRNPU to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with BCL11B (PubMed:27959755, PubMed:16809611). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Interacts with NUPR1; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction stimulates the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-protein complex.SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 proteins Tax, p30II and HBZ.DOMAIN The CRD1 domain (cell cycle regulatory domain 1) mediates transcriptional repression of a subset of p300 responsive genes; it can be de-repressed by CDKN1A/p21WAF1 at least at some promoters. It conatins sumoylation and acetylation sites and the same lysine residues may be targeted for the respective modifications. It is proposed that deacetylation by SIRT1 allows sumoylation leading to suppressed activity.PTM Acetylated on Lys at up to 17 positions by intermolecular autocatalysis. Deacetylated in the transcriptional repression domain (CRD1) by SIRT1, preferentially at Lys-1020. Deacetylated by SIRT2, preferentially at Lys-418, Lys-423, Lys-1542, Lys-1546, Lys-1549, Lys-1699, Lys-1704 and Lys-1707.PTM Citrullinated at Arg-2142 by PADI4, which impairs methylation by CARM1 and promotes interaction with NCOA2/GRIP1.PTM Methylated at Arg-580 and Arg-604 in the KIX domain by CARM1, which blocks association with CREB, inhibits CREB signaling and activates apoptotic response. Also methylated at Arg-2142 by CARM1, which impairs interaction with NCOA2/GRIP1.PTM Sumoylated; sumoylation in the transcriptional repression domain (CRD1) mediates transcriptional repression. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.PTM Probable target of ubiquitination by FBXO3, leading to rapid proteasome-dependent degradation.PTM Phosphorylated by HIPK2 in a RUNX1-dependent manner. This phosphorylation that activates EP300 happens when RUNX1 is associated with DNA and CBFB. Phosphorylated by ROCK2 and this enhances its activity. Phosphorylation at Ser-89 by AMPK reduces interaction with nuclear receptors, such as PPARG.DISEASE Defects in EP300 may play a role in epithelial cancer.DISEASE Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A.

UniProtQ09472

EQUAL

2414

EQUAL

Reactome DB_ID: 442496

UniProt:Q15788 NCOA1

NCOA1

NCOA1BHLHE74SRC1FUNCTION Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.SUBUNIT Interacts with the methyltransferase CARM1 (By similarity). Interacts with NCOA6 and NCOA2. Interacts with the FDL motif of STAT5A and STAT5B. Interacts with the LXXLL motif of STAT6. Interacts with STAT3 following IL-6 stimulation. Interacts with the basal transcription factor GTF2B. Interacts with the histone acetyltransferases EP300 and CREBBP. Interacts with PCAF, COPS5, NR3C1 and TTLL5/STAMP. Interacts with PSMB9. Interacts with UBE2L3; they functionally interact to regulate progesterone receptor transcriptional activity. Interacts with PRMT2 and DDX5. Interacts with ASXL1. Interacts with PRMT6. Interacts (via LXXLL 1, 2 and 3 motifs) with RORC (via AF-2 motif). Interacts in a ligand-dependent fashion with RXRA. Interacts with TRIP4. Interacts with NR4A3 (By similarity). Interacts with VDR.TISSUE SPECIFICITY Widely expressed.DOMAIN The C-terminal (1107-1441) part mediates the histone acetyltransferase (HAT) activity.DOMAIN Contains 7 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. LXXLL motifs 3, 4 and 5 are essential for the association with nuclear receptors. LXXLL motif 7, which is not present in isoform 2, increases the affinity for steroid receptors in vitro.PTM Sumoylated; sumoylation increases its interaction with PGR and prolongs its retention in the nucleus. It does not prevent its ubiquitination and does not exert a clear effect on the stability of the protein.PTM Ubiquitinated; leading to proteasome-mediated degradation. Ubiquitination and sumoylation take place at different sites.DISEASE A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.SIMILARITY Belongs to the SRC/p160 nuclear receptor coactivator family.

UniProtQ15788

EQUAL

1441

EQUAL

Reactome DB_ID: 381226

Reactome DB_ID: 376398

UniProt:Q15596 NCOA2

NCOA2

NCOA2TIF2SRC2BHLHE75FUNCTION Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Critical regulator of glucose metabolism regulation, acts as RORA coactivator to specifically modulate G6PC expression. Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3. Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK-ARNTL/BMAL1 heterodimer.SUBUNIT Present in a complex containing NCOA3, IKKA, IKKB, IKBKG and CREBBP. Interacts (via C-terminus) with CREBBP. Interacts with ESR1, HIF1A, NCOA1, APEX, NR3C1, NR3C2, CARM1, RARA, and RXRA. Present in a complex containing CARM1 and EP300/P300. Interacts with CASP8AP2 and TTLL5/STAMP. Interacts with PSMB9 and DDX5. Interacts (via LXXLL 1, 2 and 3 motifs) with RORA and RORC (via AF-2 motif). Interacts with RWDD3. Interacts with CLOCK and ARNTL/BMAL1 (By similarity). Interacts with NR4A3; potentiates the activity of the NR4A3 (By similarity). Interacts with NR1H3 (PubMed:19481530).DOMAIN Contains four Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors and are, at least in part, functionally redundant.DOMAIN The LLXXLXXXL motif is involved in transcriptional coactivation and CREBBP/CBP binding.DOMAIN Contains 2 C-terminal transcription activation domains (AD1 and AD2) that can function independently.DISEASE Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.SIMILARITY Belongs to the SRC/p160 nuclear receptor coactivator family.

UniProtQ15596

EQUAL

1464

EQUAL

Reactome DB_ID: 442488

UniProt:Q9Y6Q9 NCOA3

NCOA3

TRAM1NCOA3AIB1BHLHE42RAC3FUNCTION Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.ACTIVITY REGULATION Coactivator activity on nuclear receptors and NF-kappa-B pathways is enhanced by various hormones, and the TNF cytokine, respectively. TNF stimulation probably enhances phosphorylation, which in turn activates coactivator function. In contrast, acetylation by CREBBP apparently suppresses coactivation of target genes by disrupting its association with nuclear receptors. Binds to CSNK1D.SUBUNIT Interacts with CARM1 (By similarity). Present in a complex containing NCOA2, IKKA, IKKB, IKBKG and the histone acetyltransferase protein CREBBP. Interacts with CASP8AP2, NR3C1 and PCAF. Interacts with ATAD2 and this interaction is enhanced by estradiol. Found in a complex containing NCOA3, AR and MAK. Interacts with DDX5. Interacts with PSMB9. Interacts with NPAS2. Interacts with NR4A3 (By similarity). Interacts with ESRRB; mediates the interaction between ESRRB and RNA polymerase II complexes and allows NCOA3 corecruitment to ESRRB, KLF4, NANOG, and SOX2 enhancer regions to trigger ESRRB-dependent gene activation involved in self-renewal and pluripotency.TISSUE SPECIFICITY Widely expressed. High expression in heart, skeletal muscle, pancreas and placenta. Low expression in brain, and very low in lung, liver and kidney.DOMAIN Contains three Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. Motifs 1 and 2 are essential for the association with nuclear receptors, and constitute the RID domain (Receptor-interacting domain).PTM Acetylated by CREBBP. Acetylation occurs in the RID domain, and disrupts the interaction with nuclear receptors and regulates its function.PTM Methylated by CARM1.PTM Phosphorylated by IKK complex. Regulated its function. Phosphorylation at Ser-601 by CK1 promotes coactivator function.POLYMORPHISM The length of the poly-Gln region is polymorphic in the normal population.MISCELLANEOUS NCOA3 is frequently amplified or overexpressed in breast and ovarian cancers.SIMILARITY Belongs to the SRC/p160 nuclear receptor coactivator family.

UniProtQ9Y6Q9

EQUAL

1424

EQUAL

Reactome DB_ID: 556786

Mediator Complex (consensus) [nucleoplasm]

Mediator Complex (consensus)

Reactome DB_ID: 212331

UniProt:O75448 MED24

MED24

ARC100DRIP100MED24THRAP4TRAP100KIAA0130CRSP4FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with AR.TISSUE SPECIFICITY Ubiquitous. Abundant in skeletal muscle, heart and placenta.SIMILARITY Belongs to the Mediator complex subunit 24 family.

UniProtO75448

EQUAL

989

EQUAL

Reactome DB_ID: 212445

UniProt:Q15648 MED1

MED1

MED1TRAP220CRSP1CRSP200DRIP230PPARGBPPPARBPARC205RB18ATRIP2DRIP205PBPFUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors (PubMed:10406464, PubMed:11867769, PubMed:12037571, PubMed:12218053, PubMed:12556447, PubMed:14636573, PubMed:15340084, PubMed:15471764, PubMed:15989967, PubMed:16574658, PubMed:9653119). Acts as a coactivator for GATA1-mediated transcriptional activation during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781).SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. This subunit specifically interacts with a number of nuclear receptors in a ligand-dependent fashion including AR, ESR1, ESR2, PPARA, PPARG, RORA, RXRA, RXRG, THRA, THRB and VDR. Interacts with CTNNB1, GABPA, GLI3, PPARGC1A and TP53. Interacts with YWHAH. Interacts with CLOCK; this interaction requires the presence of THRAP3 (By similarity). Interacts with GATA1 and CCAR1. Interacts with NR4A3.TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylated by MAPK1 or MAPK3 during G2/M phase which may enhance protein stability and promote entry into the nucleolus.SIMILARITY Belongs to the Mediator complex subunit 1 family.

UniProtQ15648

EQUAL

1581

EQUAL

Reactome DB_ID: 556782

UniProt:Q9BWU1 CDK19

CDK19

CDK19KIAA1028CDC2L6CDK11SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtQ9BWU1

EQUAL

502

EQUAL

Reactome DB_ID: 212430

UniProt:O43513 MED7

MED7

ARC34CRSP9MED7FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.PTM Constitutively sumoylated.SIMILARITY Belongs to the Mediator complex subunit 7 family.

UniProtO43513

EQUAL

233

EQUAL

Reactome DB_ID: 556783

UniProt:O95402 MED26

MED26

ARC70MED26CRSP7FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated)(PubMed:20111005).SIMILARITY Belongs to the Mediator complex subunit 26 family.

UniProtO95402

EQUAL

600

EQUAL

Reactome DB_ID: 556802

UniProt:Q9Y2X0 MED16

MED16

DRIP92THRAP5MED16FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 16 family.CAUTION It is uncertain whether Met-1 or Met-13 is the initiator.

UniProtQ9Y2X0

EQUAL

877

EQUAL

Reactome DB_ID: 556784

UniProt:Q96G25 MED8

MED8

MED8FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. May play a role as a target recruitment subunit in E3 ubiquitin-protein ligase complexes and thus in ubiquitination and subsequent proteasomal degradation of target proteins.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. May be part of a multisubunit E3 ubiquitin-protein ligase complex with the elongin BC complex (ELOB and ELOC), CUL2 and RBX1.DOMAIN The elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].SIMILARITY Belongs to the Mediator complex subunit 8 family.

UniProtQ96G25

EQUAL

268

EQUAL

Reactome DB_ID: 212441

UniProt:O60244 MED14

MED14

CRSP2MED14RGR1CXorf4ARC150EXLM1DRIP150TRAP170FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with GATA1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with AR, ESR1, SREBF1 and STAT2.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 14 family.

UniProtO60244

EQUAL

1454

EQUAL

Reactome DB_ID: 212359

UniProt:O75586 MED6

MED6

ARC33MED6FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CTNNB1 and GLI3.SIMILARITY Belongs to the Mediator complex subunit 6 family.

UniProtO75586

EQUAL

246

EQUAL

Reactome DB_ID: 556804

UniProt:Q9NWA0 MED9

MED9

MED25MED9FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 9 family.

UniProtQ9NWA0

EQUAL

146

EQUAL

Reactome DB_ID: 556827

UniProt:Q96RN5 MED15

MED15

CTG7ATIG1TNRC7ARC105PCQAPMED15FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with SMAD2, SMAD3, SREBF1 and SREBF2. Interacts with WWTR1. Interacts with TRIM11.TISSUE SPECIFICITY Expressed in all tissues examined, including heart, brain, lung, spleen, thymus, pancreas, blood leukocyte and placenta. However, the level of expression varied, with highest expression in the placenta and peripheral blood and lowest in the pancreas and kidney.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).PTM Ubiquitinated by TRIM11, leading to proteasomal degradation.POLYMORPHISM The poly-Gln region from amino acids 235-262 of PCQAP is polymorphic. There are from 15 to 18 repeats in the Italian population.SIMILARITY Belongs to the Mediator complex subunit 15 family.

UniProtQ96RN5

EQUAL

788

EQUAL

Reactome DB_ID: 556821

UniProt:Q9NX70 MED29

MED29

IXLMED29FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Associates with the MED18/MED20 heteromer.TISSUE SPECIFICITY Widely expressed in embryo and adult.SIMILARITY Belongs to the Mediator complex subunit 29 family.

UniProtQ9NX70

EQUAL

200

EQUAL

Reactome DB_ID: 212429

UniProt:Q9Y3C7 MED31

MED31

SOH1MED31CGI-125FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 31 family.

UniProtQ9Y3C7

EQUAL

131

EQUAL

Reactome DB_ID: 556808

UniProt:Q9P086 MED11

MED11

MED11HSPC296FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 11 family.

UniProtQ9P086

EQUAL

117

EQUAL

Reactome DB_ID: 212398

UniProt:Q96HR3 MED30

MED30

MED30TRAP25THRAP6FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.TISSUE SPECIFICITY Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.SIMILARITY Belongs to the Mediator complex subunit 30 family.

UniProtQ96HR3

EQUAL

178

EQUAL

Reactome DB_ID: 212343

UniProt:Q93074 MED12

MED12

MED12ARC240TNRC11TRAP230HOPACAGH45KIAA0192FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Also interacts with CTNNB1 and GLI3.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 12 family.

UniProtQ93074

EQUAL

2177

EQUAL

Reactome DB_ID: 556797

UniProt:Q71F56 MED13L

MED13L

PROSIT240TRAP240LKIAA1025THRAP2MED13LFUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.TISSUE SPECIFICITY Highly expressed in brain (cerebellum), heart (aorta), skeletal muscle, kidney, placenta and peripheral blood leukocytes. Highly expressed in fetal brain.DISEASE A chromosomal aberration involving MED13L is found in a patient with transposition of the great arteries, dextro-looped and mental retardation. Translocation t(12;17)(q24.1;q21).SIMILARITY Belongs to the Mediator complex subunit 13 family.

UniProtQ71F56

EQUAL

2210

EQUAL

Reactome DB_ID: 556823

UniProt:Q9ULK4 MED23

MED23

MED23ARC130CRSP3KIAA1216SUR2DRIP130FUNCTION Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling.SUBUNIT Interacts with ELK1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated), CTNNB1, and GLI3. Interacts with the adenovirus E1A protein.SIMILARITY Belongs to the Mediator complex subunit 23 family.

UniProtQ9ULK4

EQUAL

1368

EQUAL

Reactome DB_ID: 212456

UniProt:Q13503 MED21

MED21

SRB7MED21SURB7FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with THRA in a ligand-dependent fashion.SIMILARITY Belongs to the Mediator complex subunit 21 family.

UniProtQ13503

EQUAL

144

EQUAL

Reactome DB_ID: 556761

UniProt:Q6P2C8 MED27

MED27

CRSP34CRSP8MED27FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 27 family.

UniProtQ6P2C8

EQUAL

311

EQUAL

Reactome DB_ID: 556819

UniProt:A0JLT2 MED19

MED19

MED19LCMR1FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 19 family.

UniProtA0JLT2

EQUAL

244

EQUAL

Reactome DB_ID: 556779

UniProt:Q15528 MED22

MED22

MED22SURF5FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 22 family.

UniProtQ15528

EQUAL

200

EQUAL

Reactome DB_ID: 6804546

UniProt:Q9H204 MED28

MED28

FKSG20EG1MED28FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. May be part of a complex containing NF2/merlin that participates in cellular signaling to the actin cytoskeleton downstream of tyrosine kinase signaling pathways.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Forms a ternary complex with NF2/merlin and GRB2. Binds to actin.TISSUE SPECIFICITY Widely expressed. Highly expressed in vascular tissues such as placenta, testis and liver.INDUCTION Up-regulated by endothelial cells when exposed to tumor conditional media.SIMILARITY Belongs to the Mediator complex subunit 28 family.

UniProtQ9H204

EQUAL

178

EQUAL

Reactome DB_ID: 212440

UniProt:P49336 CDK8

CDK8

CDK8FUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtP49336

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464

EQUAL

Reactome DB_ID: 212428

UniProt:Q9H944 MED20

MED20

MED20TRFPFUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 20 family.

UniProtQ9H944

EQUAL

212

EQUAL

Reactome DB_ID: 212410

UniProt:Q9BTT4 MED10

MED10

TRG20MED10TRG17L6FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 10 family.

UniProtQ9BTT4

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135

EQUAL

Reactome DB_ID: 212414

UniProt:Q71SY5 MED25

MED25

ARC92MED25ACID1PTOV2TCBAP0758FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for RARA/RXRA-mediated transcription.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CREBBP. Interacts with ESR1, GR, RARA, RXRA and THRB in a ligand-dependent fashion. Binds the Herpes simplex virus activator VP16.TISSUE SPECIFICITY Ubiquitously expressed. Highest levels in brain, heart, kidney, peripheral leukocytes, placenta, skeletal muscle and spleen.SIMILARITY Belongs to the Mediator complex subunit 25 family.

UniProtQ71SY5

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747

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Reactome DB_ID: 212391

UniProt:Q9UHV7 MED13

MED13

TRAP240MED13ARC250THRAP1KIAA0593FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 13 family.

UniProtQ9UHV7

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2174

EQUAL

Reactome DB_ID: 212418

UniProt:P24863 CCNC

CCNC

CCNCFUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II.TISSUE SPECIFICITY Highest levels in pancreas. High levels in heart, liver, skeletal muscle and kidney. Low levels in brain.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily.

UniProtP24863

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283

EQUAL

Reactome DB_ID: 556826

UniProt:Q9BUE0 MED18

MED18

MED18FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 18 family.

UniProtQ9BUE0

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208

EQUAL

Reactome DB_ID: 212401

UniProt:Q9NVC6 MED17

MED17

DRIP80ARC77DRIP77CRSP6TRAP80MED17FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with GATA1 and PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with STAT2.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 17 family.

UniProtQ9NVC6

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651

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Reactome DB_ID: 350263

UniProt:Q9NPJ6 MED4

MED4

DRIP36VDRIPMED4HSPC126ARC36FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 4 family.

UniProtQ9NPJ6

EQUAL

270

EQUAL

Reactome Database ID Release 69556786Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556786ReactomeR-HSA-556786

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556786.2

Reactome DB_ID: 8940294

UniProt:Q96EK7 FAM120B

FAM120B

FAM120BCCPGKIAA1838FUNCTION Functions as a transactivator of PPARG and ESR1. Functions in adipogenesis through PPARG activation.SUBUNIT Interacts with ESR1 and RXRA. Interacts with PPARG; in a ligand-independent manner.TISSUE SPECIFICITY Widely expressed.SIMILARITY Belongs to the constitutive coactivator of PPAR-gamma family.

UniProtQ96EK7

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910

EQUAL

Reactome DB_ID: 193545

UniProt:Q92793 CREBBP

CREBBP

CBPCREBBPFUNCTION Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers. Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).SUBUNIT Found in a complex containing NCOA2; NCOA3; IKKA; IKKB and IKBKG. Probably part of a complex with HIF1A and EP300. Interacts with GATA1; the interaction results in acetylation and enhancement of transcriptional activity of GATA1. Interacts with MAF AND ZCCHC12. Interacts with DAXX; the interaction is dependent on CBP sumoylation and results in suppression of the transcriptional activity via recruitment of HDAC2 to DAXX (By similarity). Interacts with phosphorylated CREB1. Interacts with CITED4 (C-terminal region). Interacts (via the TAZ-type 1 domain) with HIF1A. Interacts with SRCAP, CARM1, ELF3, MLLT7/FOXO4, N4BP2, NCOA1, NCOA3, NCOA6, PCAF, DDX5, DDX17, PELP1, PML, SMAD1, SMAD2, SMAD3, SPIB and TRERF1. Interacts with KLF1; the interaction results in acetylation of KLF1 and enhancement of its transcriptional activity. Interacts with MTDH. Interacts with NFATC4. Interacts with MAFG; the interaction acetylates MAFG in the basic region and stimulates NFE2 transcriptional activity through increasing its DNA-binding activity. Interacts with IRF2; the interaction acetylates IRF2 and regulates its activity on the H4 promoter. Interacts (via N-terminus) with SS18L1/CREST (via C-terminus). Interacts with MECOM. Interacts with CITED1 (via C-terminus). Interacts with FOXO1; the interaction acetylates FOXO1 and inhibits its transcriptional activity. Interacts with NPAS2, CLOCK and ARNTL/BMAL1. Interacts with ASF1A and ASF1B; this promotes histone acetylation. Interacts with acetylated TP53/p53 and with the acetylated histones H3 and H4. Interacts (via transactivation domain and C-terminus) with PCNA; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with DHX9 (via N-terminus); this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation (PubMed:9323138). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax, p30II and HBZ.SUBUNIT (Microbial infection) Interacts with human herpes virus 8/HHV-8 protein vIRF-1; this interaction inhibits CREBBP binding to IRF3.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.DOMAIN The KIX domain mediates binding to HIV-1 Tat.PTM Methylation of the KIX domain by CARM1 blocks association with CREB. This results in the blockade of CREB signaling, and in activation of apoptotic response.PTM Phosphorylated by CHUK/IKKA at Ser-1382 and Ser-1386; these phosphorylations promote cell growth by switching the binding preference of CREBBP from TP53 to NF-kappa-B.PTM Sumoylation negatively regulates transcriptional activity via the recruitment of DAAX.PTM Autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53.DISEASE Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription.DISEASE De novo missense mutations in the last part of exon 30 or beginning of exon 31 are associated with growth retardation, craniofacial dysmorphism and additional Rubinstein-Taybi-like features. No patients have broad thumbs. Patients have intellectual disability of variable severity, a marked speech delay, short stature and microcephaly. Main facial characteristics include short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella and long philtrum.

UniProtQ92793

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2442

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Reactome DB_ID: 8932115

UniProt:Q9Y2W1 THRAP3

THRAP3

BCLAF2THRAP3TRAP150FUNCTION Involved in pre-mRNA splicing. Remains associated with spliced mRNA after splicing which probably involves interactions with the exon junction complex (EJC). Can trigger mRNA decay which seems to be independent of nonsense-mediated decay involving premature stop codons (PTC) recognition. May be involved in nuclear mRNA decay. Involved in regulation of signal-induced alternative splicing. During splicing of PTPRC/CD45 is proposed to sequester phosphorylated SFPQ from PTPRC/CD45 pre-mRNA in resting T-cells. Involved in cyclin-D1/CCND1 mRNA stability probably by acting as component of the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in response to DNA damage. Is excluced from DNA damage sites in a manner that parallels transcription inhibition; the function may involve the SNARP complex. Initially thought to play a role in transcriptional coactivation through its association with the TRAP complex; however, it is not regarded as a stable Mediator complex subunit. Cooperatively with HELZ2, enhances the transcriptional activation mediated by PPARG, maybe through the stabilization of the PPARG binding to DNA in presence of ligand. May play a role in the terminal stage of adipocyte differentiation. Plays a role in the positive regulation of the circadian clock. Acts as a coactivator of the CLOCK-ARNTL/BMAL1 heterodimer and promotes its transcriptional activator activity and binding to circadian target genes (PubMed:24043798).SUBUNIT Associated with the large multiprotein complex TRAP (Mediator complex-like). Interacts with SFPQ; the interaction is dependent on SFPQ phosphorylation at 'Thr-687' and inhibits binding of SFPQ to an ESS1 exonic splicing silencer element-containing RNA. Interacts with NXF1. Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN. Associated with spliced mRNP complexes. Interacts with HELZ2 and PPARG. Interacts with CLOCK and ARNTL/BMAL1 (By similarity). Component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, KIAA1429, RBM15, BCLAF1 and THRAP3.TISSUE SPECIFICITY Ubiquitous.PTM ADP-ribosylation during genotoxic stress promotes accumulation in nuclear speckles.SIMILARITY Belongs to the BCLAF1/THRAP3 family.

UniProtQ9Y2W1

EQUAL

955

EQUAL

Reactome DB_ID: 442469

EQUAL

2525

EQUAL

Reactome DB_ID: 442464

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428

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Reactome DB_ID: 2026072

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132

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Reactome DB_ID: 442501

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2440

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Reactome DB_ID: 381367

PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]

PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex

Reactome DB_ID: 442499

EQUAL

2649

EQUAL

Reactome DB_ID: 442481

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798

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Reactome DB_ID: 381325

EQUAL

2414

EQUAL

Reactome DB_ID: 442496

EQUAL

1441

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Reactome DB_ID: 376398

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1464

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Reactome DB_ID: 442488

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1424

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Reactome DB_ID: 556786

Reactome DB_ID: 8940294

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910

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Reactome DB_ID: 193545

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2442

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Reactome DB_ID: 8932115

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955

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Reactome DB_ID: 2026078

Activated PPARG:RXRA [nucleoplasm]

Activated PPARG:RXRA

Reactome DB_ID: 2026077

PPARG:Fatty Acid Ligand [nucleoplasm]

PPARG:Fatty Acid Ligand

Reactome DB_ID: 446172

EQUAL

505

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 381235

Reactome Database ID Release 692026077Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2026077ReactomeR-HSA-2026077

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2026077.2

Reactome DB_ID: 381319

EQUAL

462

EQUAL

Reactome Database ID Release 692026078Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2026078ReactomeR-HSA-2026078

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2026078.1Reactome Database ID Release 69381367Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381367ReactomeR-HSA-381367

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381367.3Reactome Database ID Release 69381309Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381309ReactomeR-HSA-381309

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381309.419172745Pubmed2008Structural basis for the activation of PPARgamma by oxidized fatty acidsItoh, ToshimasaFairall, LouiseAmin, KushInaba, YukaSzanto, AttilaBalint, Balint LNagy, LaszloYamamoto, KeikoSchwabe, John W RNat. Struct. Mol. Biol. 15:924-318706692Pubmed1996A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugsLambe, KGTugwood, JDEur J Biochem 239:1-710075656Pubmed1999p300 interacts with the N- and C-terminal part of PPARgamma2 in a ligand-independent and -dependent manner, respectivelyGelman, LZhou, GFajas, LRaspé, EFruchart, JCAuwerx, JJ Biol Chem 274:7681-8

Expression of FABP4 (aP2)

The FABP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of FABP4 is activated during adipogenesis.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-03-23

Reactome DB_ID: 5640172

ENSEMBL:ENSG00000170323 FABP4FABP4

ENSEMBLENSG00000170323

Reactome DB_ID: 163428

lipid dropletGO0005811

EQUAL

132

EQUAL

Reactome Database ID Release 69560510Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560510ReactomeR-HSA-560510

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560510.419115207Pubmed2009A-FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cellsBoiteux, GLascombe, IRoche, EPlissonnier, MLClairotte, ABittard, HFauconnet, SInt J Cancer 124:1820-820101261Pubmed2010Human fetal mesenchymal stem cells differentiate into brown and white adipocytes: a role for ERRalpha in human UCP1 expressionMorganstein, DLWu, PMane, MRFisk, NMWhite, RParker, MGCell Res15273253Pubmed2004Human adipocyte fatty acid-binding protein (aP2) gene promoter-driven reporter assay discriminates nonlipogenic peroxisome proliferator-activated receptor gamma ligandsRival, YStennevin, APuech, LRouquette, ACathala, CLestienne, FDupont-Passelaigue, EPatoiseau, JFWurch, TJunquéro, DJ Pharmacol Exp Ther 311:467-7510425206Pubmed1999PPARgamma activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytesPelton, PDZhou, LDemarest, KTBurris, TPBiochem Biophys Res Commun 261:456-8

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of FABP4 (aP2). In mouse the Pparg:Rxra heterodimer directly binds the promoter of the Fabp4 gene (Grontveld et al. 2010, Ge et al. 2008, Lefterova et al. 2008)

Reactome Database ID Release 69390515Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390515ReactomeR-HSA-390515

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390515.120194623Pubmed2010MED14 tethers Mediator to the N-terminal domain of PPAR{gamma} and is required for full transcriptional activity and adipogenesisGrøntved, LMadsen, MSBoergesen, MRoeder, RGMandrup, SMol Cell Biol18981473Pubmed2008PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scaleLefterova, MIZhang, YSteger, DJSchupp, MSchug, JCristancho, AFeng, DZhuo, DStoeckert CJ, JrLiu, XSLazar, MAGenes Dev 22:2941-5223118933Pubmed2012PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mousePott, SebastianKamrani, Nima KBourque, GuillaumePettersson, SvenLiu, Edison TPLoS ONE 7:e4810218039840Pubmed2008Alternative mechanisms by which mediator subunit MED1/TRAP220 regulates peroxisome proliferator-activated receptor gamma-stimulated adipogenesis and target gene expressionGe, KCho, YWGuo, HHong, TBGuermah, MIto, MYu, HKalkum, MRoeder, RGMol Cell Biol 28:1081-91

Reactome DB_ID: 381367

ACTIVATION

As inferred from mouse, CyclinD3 interacts with PPARG and enhances transcription. Binding of the two factors was tested on the FABP4 (aP2) promoter.

Reactome Database ID Release 69935998Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=935998ReactomeR-HSA-935998

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-935998.116260612Pubmed2005Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor gammaSarruf, DAIankova, IAbella, AAssou, SMiard, SFajas, LMol Cell Biol 25:9985-95

Reactome DB_ID: 113835

UniProt:P30281 CCND3

CCND3

CCND3FUNCTION Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.SUBUNIT Interacts with the CDK4 and CDK6 protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Interacts with ATF5. Interacts with EIF3K. Component of the ternary complex cyclin D/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity. Can form similar complexes with either CDKN1A or CDKN2A.PTM Polyubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation.SIMILARITY Belongs to the cyclin family. Cyclin D subfamily.

UniProtP30281

EQUAL

292

EQUAL

ACTIVATION

As inferred from mouse, Cdk4 interacts with PPARG and enhances transcription. Binding of the two factors was tested on the FABP4 (aP2) promoter.

Reactome Database ID Release 69936001Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936001ReactomeR-HSA-936001

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-936001.116213226Pubmed2005Cdk4 promotes adipogenesis through PPARgamma activationAbella, ADubus, PMalumbres, MRane, SGKiyokawa, HSicard, AVignon, FLangin, DBarbacid, MFajas, LCell Metab 2:239-49

Reactome DB_ID: 113843

UniProt:P11802 CDK4

CDK4

CDK4FUNCTION Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.ACTIVITY REGULATION Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequent activation.SUBUNIT Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (PubMed:27353360).PTM Phosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T-loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtP11802

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303

EQUAL

Expression of Perilipin (PLIN)

The Perilipin (PLIN) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Perilipin is upregulated during adipogenesis.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-03-23

Reactome DB_ID: 5640178

ENSEMBL:ENSG00000166819 PLIN1PLINPERIPLIN1

ENSEMBLENSG00000166819

Reactome DB_ID: 163460

UniProt:O60240 PLIN1

PLIN1

PLINPERIPLIN1FUNCTION Modulator of adipocyte lipid metabolism. Coats lipid storage droplets to protect them from breakdown by hormone-sensitive lipase (HSL). Its absence may result in leanness. Plays a role in unilocular lipid droplet formation by activating CIDEC. Their interaction promotes lipid droplet enlargement and directional net neutral lipid transfer. May modulate lipolysis and triglyceride levels.SUBUNIT Interacts with ABHD5 (By similarity). Interacts with CIDEC.TISSUE SPECIFICITY Adipocytes.PTM Major cAMP-dependent protein kinase-substrate in adipocytes, also dephosphorylated by PP1. When phosphorylated, may be maximally sensitive to HSL and when unphosphorylated, may play a role in the inhibition of lipolysis, by acting as a barrier in lipid droplet.SIMILARITY Belongs to the perilipin family.

UniProtO60240

EQUAL

522

EQUAL

Reactome Database ID Release 69560493Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560493ReactomeR-HSA-560493

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560493.416380219Pubmed2006Identification of novel PPARgamma target genes in primary human adipocytesPerera, RJMarcusson, EGKoo, SKang, XKim, YWhite, NDean, NMGene 369:90-9

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the Perilipin (PLIN) gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Perilipin gene (Leftovera et al. 2008).

Reactome Database ID Release 69560522Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560522ReactomeR-HSA-560522

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560522.1

Reactome DB_ID: 381367

Expression of Phosphoenolpyruvate carboxykinase 1 (PEPCK-C)

The PEPCK-C gene is transcribed to yield mRNA and the mRNA is translated to yield protein.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-03-23

Reactome DB_ID: 5640206

ENSEMBL:ENSG00000124253 PCK1PEPCK1PCK1

ENSEMBLENSG00000124253

Reactome DB_ID: 70495

cytosolGO0005829

UniProt:P35558 PCK1

PCK1

PEPCK1PCK1FUNCTION Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle. At low glucose levels, it catalyzes the cataplerotic conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate.ACTIVITY REGULATION Enzyme activity is regulated by acetylation and glucose levels (PubMed:30193097, PubMed:20167786). The anaplerotic conversion of phosphoenolpyruvate to oxaloacetate is improved by PCK1 acetylation on Lys-91 (K91ac), Lys-473 (K473ac) and Lys-521 (K521ac) (By similarity). High glucose concentrations favor PCK1 anaplerotic activity by triggering acetylation on Lys-91 (K91ac). At low glucose levels, SIRT1-mediated deacetylation of Lys-91 promotes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PubMed:30193097).PATHWAY Carbohydrate biosynthesis; gluconeogenesis.SUBUNIT Monomer.TISSUE SPECIFICITY Major sites of expression are liver, kidney and adipocytes.INDUCTION Regulated by cAMP and insulin.PTM Acetylated. Lysine acetylation by p300/EP300 is increased on high glucose conditions (PubMed:20167786, PubMed:21726808, PubMed:30193097). Lysine acetylation promotes ubiquitination by UBR5 (PubMed:21726808). Acetylation is enhanced in the presence of BAG6. Deacetylated by SIRT2. Deacetylation of Lys-91 is carried out by SIRT1 and depends on PCK1 phosphorylation levels (PubMed:30193097).PTM Phosphorylated in a GSK3B-mediated pathway; phosphorylation affects the efficiency of SIRT1-mediated deacetylation, and regulates PCK1 ubiquitination and degradation.PTM Ubiquitination by UBR5 leads to proteasomal degradation.MISCELLANEOUS In eukaryotes there are two isozymes: a cytoplasmic one and a mitochondrial one.SIMILARITY Belongs to the phosphoenolpyruvate carboxykinase [GTP] family.

UniProtP35558

EQUAL

622

EQUAL

Reactome Database ID Release 69560472Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560472ReactomeR-HSA-560472

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560472.4

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the PEPCK-C gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Pepck-c gene (Leftovera et al. 2008).

Reactome Database ID Release 69560521Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560521ReactomeR-HSA-560521

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560521.1

Reactome DB_ID: 381367

Expression of ANGPTL4

Induction of Angiopoietin-related protein 4 (ANGPTL4) ExpressionThe ANGPTL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Reviewed: Kersten, S, 2009-06-08Edited: May, B, 2010-03-23

Reactome DB_ID: 5640194

ENSEMBL:ENSG00000167772 ANGPTL4

PP1158UNQ171/PRO197HFARPPSEC0166ANGPTL4ARP4PGAR

ENSEMBLENSG00000167772

Reactome DB_ID: 381271

UniProt:Q9BY76 ANGPTL4

ANGPTL4

PP1158UNQ171/PRO197HFARPPSEC0166ANGPTL4ARP4PGARFUNCTION Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). May also play a role in regulating glucose homeostasis and insulin sensitivity (Probable). Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage (PubMed:14583458, PubMed:17068295). Upon heterologous expression, inhibits the adhesion of endothelial cell to the extracellular matrix (ECM), and inhibits the reorganization of the actin cytoskeleton, formation of actin stress fibers and focal adhesions in endothelial cells that have adhered to ANGPTL4-containing ECM (in vitro) (PubMed:17068295). Depending on context, may modulate tumor-related angiogenesis.FUNCTION ANGPTL4 N-terminal chain: Mediates inactivation of the lipoprotein lipase LPL, and thereby plays an important role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). Has higher activity in LPL inactivation than the uncleaved protein (PubMed:19270337, PubMed:21398697).SUBUNIT Homooligomer; disulfide-linked via Cys residues in the N-terminal part of the protein (PubMed:19270337). The homooligomer undergoes proteolytic processing to release the ANGPTL4 C-terminal chain, which circulates as a monomer (PubMed:19270337). The homooligomer unprocessed form is able to interact with the extracellular matrix (PubMed:21398697).TISSUE SPECIFICITY Detected in blood plasma (at protein level) (PubMed:29899519). Detected in liver (PubMed:10698685). Detected in white fat tissue and placenta (PubMed:10866690). Expressed at high levels in the placenta, heart, liver, muscle, pancreas and lung but expressed poorly in the brain and kidney.INDUCTION Up-regulated when cells are exposed to severe hypoxia (in vitro).PTM N-glycosylated.PTM ANGPTL4 N-terminal chain: Forms disulfide-linked dimers and tetramers.PTM Cleaved into a smaller N-terminal chain and a larger chain that contains the fibrinogen C-terminal domain; both cleaved and uncleaved forms are detected in the extracellular space. The cleaved form is not present within the cell.POLYMORPHISM Genetic variations in ANGPTL4 are associated with low plasma triglyceride levels and define the plasma triglyceride level quantitative trait locus (TGQTL) [MIM:615881].

UniProtQ9BY76

EQUAL

406

EQUAL

Reactome Database ID Release 69560473Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560473ReactomeR-HSA-560473

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560473.419710929Pubmed2009Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and humanRakhshandehroo, MHooiveld, GMuller, MKersten, SanderPLoS One 4:e679619934321Pubmed2009Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesisTian, LZhou, JCasimiro, MCLiang, BOjeifo, JOWang, MHyslop, TWang, CPestell, RGCancer Res 69:9236-44

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the ANGPTL4 gene. The PPARG:RXRA heterodimer binds the promoter of the ANGPTL4 gene.

Reactome Database ID Release 69560539Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560539ReactomeR-HSA-560539

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560539.1

Reactome DB_ID: 381367

ACTIVATION

Reactome Database ID Release 691989823Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1989823ReactomeR-HSA-1989823

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1989823.326449539Pubmed2015The impact of PPARα activation on whole genome gene expression in human precision cut liver slicesJanssen, Aafke W FBetzel, BarkStoopen, GeertBerends, Frits JJanssen, Ignace MPeijnenburg, Ad AKersten, SanderBMC Genomics 16:76023811191Pubmed2013PPARα-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisonsKim, SKiyosawa, NBurgoon, L DChang, C CZacharewski, T RJ. Steroid Biochem. Mol. Biol. 138:236-47

Reactome DB_ID: 400154

PPARA:RXRA Coactivator complex [nucleoplasm]

PPARA:RXRA Coactivator complex

Reactome DB_ID: 422412

Activated PPARA:RXRA [nucleoplasm]

Activated PPARA:RXRA

Reactome DB_ID: 381319

EQUAL

462

EQUAL

Reactome DB_ID: 422413

PPARA:fatty acid (Activated PPARA) [nucleoplasm]

PPARA:fatty acid (Activated PPARA)

Converted from EntitySet in Reactome

Reactome DB_ID: 400149

Ligands of PPARA [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLINA [nucleoplasm]ALA [nucleoplasm]Palm [nucleoplasm]AA [nucleoplasm]EPA [nucleoplasm]

ChEBI17351ChEBI27432ChEBI15756ChEBI15843ChEBI28364

Reactome DB_ID: 400186

UniProt:Q07869 PPARA

PPARA

PPARNR1C1PPARAFUNCTION Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.SUBUNIT Heterodimer; with RXRA. This heterodimerization is required for DNA binding and transactivation activity. Interacts with NCOA3 coactivator. Interacts with CITED2; the interaction stimulates its transcriptional activity. Also interacts with PPARBP in vitro. Interacts with AKAP13, LPIN1, PRDM16 and coactivator NCOA6. Interacts with ASXL1 and ASXL2. Interacts with PER2. Interacts with SIRT1; the interaction seems to be modulated by NAD(+) levels (PubMed:24043310).TISSUE SPECIFICITY Skeletal muscle, liver, heart and kidney.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.

UniProtQ07869

EQUAL

468

EQUAL

Reactome Database ID Release 69422413Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=422413ReactomeR-HSA-422413

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-422413.1

Reactome DB_ID: 422139

Peroxisome Proliferator Receptor Element (PPRE) [nucleoplasm]

Peroxisome Proliferator Receptor Element (PPRE)

Reactome Database ID Release 69422412Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=422412ReactomeR-HSA-422412

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-422412.1

Reactome DB_ID: 351643

UniProt:Q9BZK7 TBL1XR1

TBL1XR1

TBLR1TBL1XR1IRA1FUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation.SUBUNIT Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2 (PubMed:11931768). Probable component of some E3 ubiquitin ligase complex. Interacts with histones H2B and H4 (PubMed:12628926). Interacts with MECP2; bridges interaction between MECP2 and NCOR1.TISSUE SPECIFICITY Widely expressed including the pituitary, hypothalamus, white and brown adipose tissue, muscle and liver.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family.

UniProtQ9BZK7

EQUAL

514

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 400216

Coactivators of PPARalpha [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHELZ2 [nucleoplasm]CHD9 [nucleoplasm]CARM1 [nucleoplasm]NCOA1 [nucleoplasm]NCOA2 [nucleoplasm]MED1 [nucleoplasm]TGS1 [nucleoplasm]NCOA6 [nucleoplasm]CREBBP [nucleoplasm]SMARCD3 [nucleoplasm]

UniProtQ3L8U1UniProtQ86X55UniProtQ96RS0UniProtQ14686UniProtQ6STE5

Reactome DB_ID: 351644

UniProt:O60907 TBL1X

TBL1X

TBL1TBL1XFUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272).SUBUNIT Homotetramer; dimer of dimers (PubMed:21240272). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:21240272). Interacts with GPS2 (when sumoylated); leading to protect GPS2 against degradation by the proteasome (PubMed:24943844). Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X (PubMed:11389839). Probably part of other corepressor complexes, that do not contain NCOR1 and NCOR2. Interacts with histones H2B, H3a and H4. Interacts with MECP2; recuits TBL1X to the heterochromatin foci.TISSUE SPECIFICITY Ubiquitous.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family.

UniProtO60907

EQUAL

577

EQUAL

Reactome Database ID Release 69400154Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400154ReactomeR-HSA-400154

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400154.1

Expression of Lipoprotein lipase (LPL)

The LPL gene is transcribed to yield mRNA and the mRNA is translated to yield protein.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-03-23

Reactome DB_ID: 5640177

ENSEMBL:ENSG00000175445 LPLLIPDLPL

ENSEMBLENSG00000175445

Reactome DB_ID: 174605

UniProt:P06858 LPL

LPL

LIPDLPLFUNCTION Key enzyme in triglyceride metabolism. Catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage (PubMed:8675619, PubMed:11342582, PubMed:27578112). Mediates margination of triglyceride-rich lipoprotein particles in capillaries (PubMed:24726386). Recruited to its site of action on the luminal surface of vascular endothelium by binding to GPIHBP1 and cell surface heparan sulfate proteoglycans (PubMed:11342582, PubMed:27811232).ACTIVITY REGULATION The apolipoprotein APOC2 acts as a coactivator of LPL activity (By similarity). Ca(2+) binding promotes protein stability and formation of the active homodimer (PubMed:16179346). Interaction with GPIHBP1 protects LPL against inactivation by ANGPTL4 (PubMed:27929370, PubMed:29899144).SUBUNIT Homodimer (PubMed:16179346, PubMed:26725083, PubMed:11893776) (Probable). Interacts with GPIHBP1 with 1:1 stoichiometry (PubMed:17997385, PubMed:27929370, PubMed:26725083, PubMed:27811232, PubMed:29899144, PubMed:30559189). Interacts with APOC2; the interaction activates LPL activity in the presence of lipids (By similarity). Interaction with heparan sulfate proteoglycans is required to protect LPL against loss of activity (PubMed:11342582). Associates with lipoprotein particles in blood plasma (PubMed:11342582, PubMed:11893776). Interacts with LMF1 and SEL1L; interaction with SEL1L is required to prevent aggregation of newly synthesized LPL in the endoplasmic reticulum (ER), and for normal export of LPL from the ER to the extracellular space (PubMed:25066055).TISSUE SPECIFICITY Detected in blood plasma (PubMed:2340307, PubMed:11893776, PubMed:12641539). Detected in milk (at protein level) (PubMed:2340307).PTM Tyrosine nitration after lipopolysaccharide (LPS) challenge down-regulates the lipase activity.SIMILARITY Belongs to the AB hydrolase superfamily. Lipase family.

UniProtP06858

EQUAL

475

EQUAL

Reactome Database ID Release 69560498Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560498ReactomeR-HSA-560498

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560498.4

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the LPL gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Lpl gene (Lefterova et al. 2008).

Reactome Database ID Release 69560526Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560526ReactomeR-HSA-560526

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560526.1

Reactome DB_ID: 381367

Expression of CEBPA

The CEBPA gene is transcribed to yield mRNA and the mRNA is translated to yield protein.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2010-03-23

Reactome DB_ID: 5640210

ENSEMBL:ENSG00000245848 CEBPACEBPACEBP

ENSEMBLENSG00000245848

Reactome DB_ID: 381289

EQUAL

358

EQUAL

Reactome Database ID Release 69560491Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560491ReactomeR-HSA-560491

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560491.3

INHIBITION

As inferred from mouse, TNF-alpha inhibits expression of CEBPA in pre-adipocytes.

Reactome Database ID Release 69976204Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976204ReactomeR-HSA-976204

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976204.1

Reactome DB_ID: 976821

UniProt:P01375 TNF

TNF

TNFSF2TNFATNFFUNCTION Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance.FUNCTION The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.SUBUNIT Homotrimer. Interacts with SPPL2B.PTM The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.PTM The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.PTM O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.POLYMORPHISM Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].POLYMORPHISM Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].SIMILARITY Belongs to the tumor necrosis factor family.

UniProtP01375

EQUAL

233

EQUAL

ACTIVATION

The activation of expression of CEBPA by EBF1 is inferred from mouse where Ebf1 directly binds one site in the Cebpa promoter and activates transcription of the Cebpa gene.

Reactome Database ID Release 69390510Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390510ReactomeR-HSA-390510

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390510.1

Reactome DB_ID: 158571

EQUAL

591

EQUAL

INHIBITION

As inferred from mouse 3T3-L1 cells, Wnt-1 and Wnt-10b inhibit expression of CEBPA through stabillization of beta-Catenin. Wnt-10b is probably the actual regulator in vivo.

Reactome Database ID Release 69976198Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976198ReactomeR-HSA-976198

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976198.1Converted from EntitySet in Reactome

Reactome DB_ID: 976184

WNT1,WNT10B [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityWNT1 [extracellular region]WNT10B [extracellular region]

UniProtP04628UniProtO00744

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the CEBPA gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Cebpa gene (Lefterova et al. 2008).

Reactome Database ID Release 69560533Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560533ReactomeR-HSA-560533

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560533.1

Reactome DB_ID: 381367

INHIBITION

As inferred from mouse, TGF-beta inhibits expression of CEPBA in preadipocytes.

Reactome Database ID Release 69976237Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=976237ReactomeR-HSA-976237

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-976237.1

Reactome DB_ID: 170838

279

EQUAL

390

EQUAL

Expression of CD36 (platelet glycoprotein IV, FAT)

Induction of Platelet glycoprotein IV (PAS IV, CD36, GPIV) Expression During AdipogenesisThe Platelet glycoprotein IV gene (CD36, PAS IV, GPIV) is transcribed to yield mRNA and the mRNA is translated to yield proteind.

Authored: May, B, 2010-03-23Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Reviewed: Kersten, S, 2009-06-08Edited: May, B, 2010-03-23

Reactome DB_ID: 5640184

ENSEMBL:ENSG00000135218 CD36GP3BGP4CD36

ENSEMBLENSG00000135218

Reactome DB_ID: 51645

plasma membraneGO0005886

UniProt:P16671 CD36

CD36

GP3BGP4CD36FUNCTION Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211).FUNCTION (Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling.SUBUNIT Interacts with THBS1 and THBS2; the interactions mediate the THBS antiangiogenic activity (PubMed:1371676). Upon interaction with a ligand, such as oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42, rapidly forms a complex with TLR4 and TLR6; the complex is internalized and triggers an inflammatory signal. Through its C-terminus, interacts with PTK2, PXN and LYN, but not with SRC. LYN kinase activity is required for facilitating TLR4:TLR6 heterodimerization and signal initiation (PubMed:1371676, PubMed:20037584). Upon interaction with ligands such as diacylated lipopeptides, interacts with the TLR2:TLR6 heterodimer (PubMed:16880211). Interacts with CD9, CD81, FCER1G, ITGB2 and/or ITGB2; forming a membrane heteromeric complex required for the internalization of CD36 and its ligands.SUBUNIT (Microbial infection) Binds to Plasmodium falciparum EMP1.PTM N-glycosylated and O-glycosylated with a ratio of 2:1.PTM Ubiquitinated at Lys-469 and Lys-472. Ubiquitination is induced by fatty acids such as oleic acid and leads to degradation by the proteasome (PubMed:21610069, PubMed:18353783). Ubiquitination and degradation are inhibited by insulin which blocks the effect of fatty acids (PubMed:18353783).POLYMORPHISM Genetic variations in CD36 are involved in susceptibility to malaria and influence the severity and outcome of malaria infection [MIM:611162].SIMILARITY Belongs to the CD36 family.

UniProtP16671

S-palmitoyl-L-cysteine at 3

EQUAL

S-palmitoyl-L-cysteine [MOD:00115]

S-palmitoyl-L-cysteine at 464

464

EQUAL

S-palmitoyl-L-cysteine at 466

466

EQUAL

S-palmitoyl-L-cysteine at 7

EQUAL

472

EQUAL

Reactome Database ID Release 69560517Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560517ReactomeR-HSA-560517

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560517.4

ACTIVATION

Reactome Database ID Release 691989789Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1989789ReactomeR-HSA-1989789

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1989789.320110263Pubmed2010Profiling of promoter occupancy by PPAR{alpha} in human hepatoma cells via ChIP-chip analysisvan der Meer, DLDegenhardt, TVaisanen, Sde Groot, PJHeinaniemi, Mde Vries, SCMuller, MCarlberg, CKersten, SanderNucleic Acids Res17084382Pubmed2006Cholesteryl ester hydroperoxides increase macrophage CD36 gene expression via PPARalphaJedidi, ICouturier, MThérond, PGardès-Albert, MLegrand, ABarouki, RBonnefont-Rousselot, DAggerbeck, MBiochem Biophys Res Commun 351:733-8

Reactome DB_ID: 400154

ACTIVATION

The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the Platelet glycoprotein IV (CD36, PAS IV, GPIV) gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Platelet glycoprotein IV gene (Lefterova et al. 2008).

Reactome Database ID Release 69560540Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=560540ReactomeR-HSA-560540

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-560540.1

Reactome DB_ID: 381367

Expression of Leptin

The Ob gene encoding leptin is transcribed to yield mRNA and translated to yield protein. Expression of leptin is positively regulated by C/EBPalpha (CEBPA, Miller et al. 1996, Melzner et al. 2002) and negatively regulated by PPARG in adipocytes (De Vos et al. 1996).

Authored: May, B, 2011-02-08Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2011-02-08

Reactome DB_ID: 5640196

ENSEMBL:ENSG00000174697 LEPOBSOBLEP

ENSEMBLENSG00000174697

Reactome DB_ID: 400490

UniProt:P41159 LEP

LEP

OBSOBLEPFUNCTION Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:17344214, PubMed:15899045, PubMed:19688109). In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:8589726, PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689).SUBUNIT Interacts with SIGLEC6.TISSUE SPECIFICITY Adipose tissue is the main source of leptin. It is also produced by other peripheral tissues such as the skeletal muscle (PubMed:7789654, PubMed:16052473, PubMed:12448771). Expressed by intercalated and striated tracts of submandibular and parotid salivary gland intralobular ducts (PubMed:12448771). Detected by fundic epithelium of the gastric mucosa (PubMed:10896907). Secreted into blood and gastric juice (PubMed:10896907).INDUCTION Induced by secretin.SIMILARITY Belongs to the leptin family.

UniProtP41159

EQUAL

167

EQUAL

Reactome Database ID Release 691183003Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183003ReactomeR-HSA-1183003

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183003.48643605Pubmed1996The adipocyte specific transcription factor C/EBPalpha modulates human ob gene expressionMiller, SGDe Vos, PGuerre-Millo, MWong, KHermann, TStaels, BBriggs, MRAuwerx, JProc Natl Acad Sci U S A 93:5507-1112213831Pubmed2002Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoterMelzner, IScott, VDorsch, KFischer, PWabitsch, MBruderlein, SilkeHasel, CMoller, PeterJ Biol Chem 277:45420-78770873Pubmed1996Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gammaDe Vos, PLefebvre, AMMiller, SGGuerre-Millo, MWong, KSaladin, RHamann, LGStaels, BBriggs, MRAuwerx, JJ Clin Invest 98:1004-9

ACTIVATION

C/EBPalpha (CEBPA) binds the promoter of the Ob gene encoding leptin and activates transcription.

Reactome Database ID Release 691183091Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183091ReactomeR-HSA-1183091

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183091.1

Reactome DB_ID: 381289

EQUAL

358

EQUAL

INHIBITION

PPARG together with an agonist, the thiazolidinedione BRL49653, repress expression of the Ob (leptin) gene.

Reactome Database ID Release 691183067Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183067ReactomeR-HSA-1183067

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183067.1

Reactome DB_ID: 381367

Expression of Adiponectin

The Adiponectin gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Adiponectin is upregulated during adipogenesis by C/EBPalpha (CEBPA), PPARG, and CEBPB (Segawa et al. 2009, Qiao et al. 2005, Iwaki et al. 2003, Kita et al. 2005).

Authored: May, B, 2011-02-08Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2011-02-08

Reactome DB_ID: 5640188

ENSEMBL:ENSG00000181092 ADIPOQADIPOQACRP30GBP28APM1ACDC

ENSEMBLENSG00000181092

Reactome DB_ID: 1183052

UniProt:Q15848 ADIPOQ

ADIPOQ

ADIPOQACRP30GBP28APM1ACDCFUNCTION Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities. Stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose utilization and fatty-acid combustion. Antagonizes TNF-alpha by negatively regulating its expression in various tissues such as liver and macrophages, and also by counteracting its effects. Inhibits endothelial NF-kappa-B signaling through a cAMP-dependent pathway. May play a role in cell growth, angiogenesis and tissue remodeling by binding and sequestering various growth factors with distinct binding affinities, depending on the type of complex, LMW, MMW or HMW.SUBUNIT Homomultimer. Forms trimers, hexamers and 12- to 18-mers. The trimers (low molecular weight complexes / LMW) are assembled via non-covalent interactions of the collagen-like domains in a triple helix and hydrophobic interactions within the globular C1q domain. Several trimers can associate to form disulfide-linked hexamers (middle molecular weight complexes / MMW) and larger complexes (higher molecular weight / HMW). The HMW-complex assembly is also modulated by the degree of lysine hydroxylation and glycosylation. LMW, MMW and HMW complexes bind to HBEGF, MMW and HMW complexes bind to PDGFB, and HMW complex binds to FGF2. Interacts with CTRP9 via the C1q domain (heterotrimeric complex).TISSUE SPECIFICITY Synthesized exclusively by adipocytes and secreted into plasma.DOMAIN The C1q domain is commonly called the globular domain.PTM HMW complexes are more extensively glycosylated than smaller oligomers. Hydroxylation and glycosylation of the lysine residues within the collagen-like domain of adiponectin seem to be critically involved in regulating the formation and/or secretion of HMW complexes and consequently contribute to the insulin-sensitizing activity of adiponectin in hepatocytes.PTM O-glycosylated. Not N-glycosylated. O-linked glycans on hydroxylysines consist of Glc-Gal disaccharides bound to the oxygen atom of post-translationally added hydroxyl groups. Sialylated to varying degrees depending on tissue. Thr-22 appears to be the major site of sialylation. Higher sialylation found in SGBS adipocytes than in HEK fibroblasts. Sialylation is not required neither for heterodimerization nor for secretion. Not sialylated on the glycosylated hydroxylysines. Desialylated forms are rapidly cleared from the circulation.POLYMORPHISM Genetic variations in ADIPOQ influence the variance in adiponectin serum levels and define the adiponectin serum levels quantitative trait locus 1 (ADIPQTL1) [MIM:612556].PHARMACEUTICAL Adiponectin might be used in the treatment of diabetes type 2 and insulin resistance.MISCELLANEOUS Variants Arg-84 and Ser-90 show impaired formation of HMW complexes whereas variants Cys-112 and Thr-164 show impaired secretion of adiponectin in any form.MISCELLANEOUS HMW-complex blood contents are higher in females than in males, are increased in males by castration and decreased again upon subsequent testosterone treatment, which blocks HMW-complex secretion (By similarity). In type 2 diabetic patients, both the ratios of HMW to total adiponectin and the degree of adiponectin glycosylation are significantly decreased as compared with healthy controls.CAUTION The expected hydroxylation of Lys-33 was not identified, probably due to poor representation of the N-terminal peptide in mass fingerprinting.

UniProtQ15848

EQUAL

244

EQUAL

Reactome Database ID Release 691183058Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183058ReactomeR-HSA-1183058

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183058.415850785Pubmed2005Identification of the promoter region required for human adiponectin gene transcription: Association with CCAAT/enhancer binding protein-beta and tumor necrosis factor-alphaKita, AYamasaki, HKuwahara, HMoriuchi, AFukushima, KKobayashi, MFukushima, TTakahashi, RAbiru, NUotani, SKawasaki, EEguchi, KBiochem Biophys Res Commun 331:484-9012829629Pubmed2003Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptorsIwaki, MMatsuda, MMaeda, NFunahashi, TMatsuzawa, YMakishima, MShimomura, IDiabetes 52:1655-6318931025Pubmed2009Identification of a novel distal enhancer in human adiponectin geneSegawa, KMatsuda, MFukuhara, AMorita, KOkuno, YKomuro, RShimomura, IJ Endocrinol 200:107-1615919796Pubmed2005C/EBPalpha regulates human adiponectin gene transcription through an intronic enhancerQiao, LMaclean, PSSchaack, JOrlicky, DJDarimont, CPagliassotti, MFriedman, JEShao, JiminDiabetes 54:1744-54

ACTIVATION

The PPARG:RXRA heterodimer activated by a thiazolidinedione agonist binds the promoter of the Adiponectin gene and activates transcription.

Reactome Database ID Release 691183084Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183084ReactomeR-HSA-1183084

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183084.1

Reactome DB_ID: 381367

ACTIVATION

C/EBPalpha (CEBPA) binds the promoter of the Adiponectin gene and activates transcription.

Reactome Database ID Release 691183063Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183063ReactomeR-HSA-1183063

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183063.1

Reactome DB_ID: 381289

EQUAL

358

EQUAL

ACTIVATION

C/EBPbeta (CEBPB) binds the promoter of the Adiponectin gene and activates transcription.

Reactome Database ID Release 691183080Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183080ReactomeR-HSA-1183080

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183080.1

Reactome DB_ID: 381378

EQUAL

345

EQUAL

Expression of GLUT4

The GLUT4 (SLC2A4) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.

Authored: May, B, 2011-02-08Reviewed: D'Eustachio, P, 2009-05-26 22:09:50Reviewed: Sethi, JK, 2011-02-09Edited: May, B, 2011-02-08

Reactome DB_ID: 5640175

ENSEMBL:ENSG00000181856 SLC2A4SLC2A4GLUT4

ENSEMBLENSG00000181856

Reactome DB_ID: 70384

GLUT4 / SLC2A4 tetramer [plasma membrane]

GLUT4 / SLC2A4 tetramer

Reactome DB_ID: 70383

UniProt:P14672 SLC2A4

SLC2A4

SLC2A4GLUT4FUNCTION Insulin-regulated facilitative glucose transporter.SUBUNIT Interacts with NDUFA9 (By similarity). Binds to DAXX (PubMed:11842083). Interacts via its N-terminus with SRFBP1 (PubMed:16647043). Interacts with TRARG1; the interaction is required for proper SLC2A4 reacycling after insulin stimulation.TISSUE SPECIFICITY Skeletal and cardiac muscles; brown and white fat.DOMAIN The dileucine internalization motif is critical for intracellular sequestration.PTM Sumoylated.MISCELLANEOUS Insulin-stimulated phosphorylation of TBC1D4 is required for GLUT4 translocation.SIMILARITY Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily.

UniProtP14672

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Reactome Database ID Release 6970384Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70384ReactomeR-HSA-70384

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70384.2Reactome Database ID Release 691183032Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183032ReactomeR-HSA-1183032

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183032.48325954Pubmed1993Insulin-responsive human adipocytes express two glucose transporter isoforms and target them to different vesiclesPilch, PFWilkinson, WGarvey, WTCiaraldi, TPHueckstaedt, TPOlefsky, JMJ Clin Endocrinol Metab 77:286-9

INHIBITION

As inferred from mouse cells, PPARG:RXRA in the absence of fatty acid ligand binds the promoter of the GLUT4 (SLC2A4) gene and represses expression. After activation of PPARG:RXRA by fatty acid ligand the repression is relieved.

Reactome Database ID Release 691183062Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183062ReactomeR-HSA-1183062

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183062.112777391Pubmed2003Peroxisome proliferator-activated receptor-gamma represses GLUT4 promoter activity in primary adipocytes, and rosiglitazone alleviates this effectArmoni, MKritz, NHarel, CBar-Yoseph, FChen, HQuon, MJKarnieli, EJ Biol Chem 278:30614-23

Reactome DB_ID: 381226

ACTIVATION

As inferred from mouse cells, C/EBPalpha (CEBPA) binds the promoter of the GLUT4 (SLC2A4) gene and activates transcription.

Reactome Database ID Release 691183065Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1183065ReactomeR-HSA-1183065

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1183065.116754198Pubmed2006GLUT4 repression in response to oxidative stress is associated with reciprocal alterations in C/EBP alpha and delta isoforms in 3T3-L1 adipocytesPessler-Cohen, DPekala, PHKovsan, JBloch-Damti, ARudich, ABashan, NArch Physiol Biochem 112:3-1218408001Pubmed2008Phosphorylation of CCAAT/enhancer-binding protein alpha regulates GLUT4 expression and glucose transport in adipocytesCha, HCOak, NRKang, STran, TAKobayashi, SChiang, SHTenen, DGMacDougald, OAJ Biol Chem 283:18002-112404278Pubmed1990Mouse insulin-responsive glucose transporter gene: characterization of the gene and trans-activation by the CCAAT/enhancer binding proteinKaestner, KHChristy, RJLane, MDProc Natl Acad Sci U S A 87:251-5

Reactome DB_ID: 381289

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Reactome Database ID Release 69381340Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381340ReactomeR-HSA-381340

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381340.217139329Pubmed2006Adipocyte differentiation from the inside outRosen, EDMacDougald, OANat Rev Mol Cell Biol 7:885-967531665Pubmed1995Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteinsYeh, WCCao, ZClasson, MMcKnight, SLGenes Dev 9:168-8120054179Pubmed2008Human SGBS cells - a unique tool for studies of human fat cell biologyFischer-Posovszky, PNewell, FSWabitsch, MTornqvist, HEObes Facts 1:184-910603305Pubmed1999Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiationLane, MDTang, QQJiang, MSBiochem Biophys Res Commun 266:677-8315860371Pubmed2005PPARs: therapeutic targets for metabolic diseaseBerger, JPAkiyama, TEMeinke, PTTrends Pharmacol Sci 26:244-517838715Pubmed1994Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alphaTontonoz, PGraves, RABudavari, AIErdjument-Bromage, HLui, MHu, ETempst, PSpiegelman, BMNucleic Acids Res 22:5628-3421082419Pubmed2011The generation and the manipulation of human multipotent adipose-derived stem cellsWdziekonski, BMohsen-Kanson, TVillageois, PDani, CMethods Mol Biol 702:419-2717956727Pubmed2007Developmental origin of fat: tracking obesity to its sourceGesta, STseng, YHKahn, CRCell 131:242-561840554Pubmed1991Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cellsCao, ZUmek, RMMcKnight, SLGenes Dev 5:1538-5217475546Pubmed2007PPARgamma in human and mouse physiologyHeikkinen, SAuwerx, JArgmann, CABiochim Biophys Acta 1771:999-101318518822Pubmed2008Fat and beyond: the diverse biology of PPARgammaTontonoz, PSpiegelman, BMAnnu Rev Biochem 77:289-312