BioPAX pathway converted from "Transcriptional regulation of pluripotent stem cells" in the Reactome database.Transcriptional regulation of pluripotent stem cellsPluripotent stem cells are undifferentiated cells posessing an abbreviated cell cycle (reviewed in Stein et al. 2012), a characteristic profile of gene expression (Rao et al. 2004, Kim et al. 2006, Player et al. 2006, Wang et al 2006 using mouse, International Stem Cell Initiative 2007, Assou et al. 2007, Assou et al. 2009, Ding et al. 2012 using mouse), and the ability to self-renew and generate all cell types of the body except extraembryonic lineages (Marti et al. 2013, reviewed in Romeo et al. 2012). They are a major cell type in the inner cell mass of the early embryo in vivo, and cells with the same properties, induced pluripotent stem cells, can be generated in vitro from differentiated adult cells by overexpression of a set of transcription factor genes (Takahashi and Yamanaka 2006, Takahashi et al. 2007, Yu et al. 2007, Jaenisch and Young 2008, Stein et al. 2012, reviewed in Dejosez and Zwaka 2012).<br>Pluripotency is maintained by a self-reinforcing loop of transcription factors (Boyer et al. 2005, Rao et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007, Sun et al. 2008, Assou et al. 2009, reviewed in Kashyap et al. 2009, reviewed in Dejosez and Zwaka 2012). In vivo, initiation of pluripotency may depend on maternal factors transmitted through the oocyte (Assou et al. 2009) and on DNA demethylation in the zygote (recently reviewed in Seisenberger et al. 2013) and hypoxia experienced by the blastocyst in the reproductive tract before implantation (Forristal et al. 2010, reviewed in Mohyeldin et al. 2010). In vitro, induced pluripotency may initiate with demethylation and activation of the promoters of POU5F1 (OCT4) and NANOG (Bhutani et al. 2010). Hypoxia also significantly enhances conversion to pluripotent stem cells (Yoshida et al. 2009). POU5F1 and NANOG, together with SOX2, encode central factors in pluripotency and activate their own transcription (Boyer et al 2005, Babaie et al. 2007, Yu et al. 2007, Takahashi et al. 2007). The autoactivation loop maintains expression of POU5F1, NANOG, and SOX2 at high levels in stem cells and, in turn, complexes containing various combinations of these factors (Remenyi et al. 2003, Lam et al. 2012) activate the expression of a group of genes whose products are associated with rapid cell proliferation and repress the expression of a group of genes whose products are associated with cell differentiation (Boyer et al. 2005, Matoba et al. 2006, Babaie et al. 2007, Chavez et al. 2009, Forristal et al. 2010, Guenther 2011).<br>Comparisons between human and mouse embryonic stem cells must be made with caution and for this reason inferences from mouse have been used sparingly in this module. Human ESCs more closely resemble mouse epiblast stem cells in having inactivated X chromosomes, flattened morphology, and intolerance to passaging as single cells (Hanna et al. 2010). Molecularly, human ESCs differ from mouse ESCs in being maintained by FGF and Activin/Nodal/TGFbeta signaling rather than by LIF and canonical Wnt signaling (Greber et al. 2010, reviewed in Katoh 2011). In human ESCs POU5F1 binds and directly activates the FGF2 gene, however Pou5f1 does not activate Fgf2 in mouse ESCs (reviewed in De Los Angeles et al. 2012). Differences in expression patterns of KLF2, KLF4, KLF5, ESRRB, FOXD3, SOCS3, LIN28, NODAL were observed between human and mouse ESCs (Cai et al. 2010) as were differences in expression of EOMES, ARNT and several other genes (Ginis et al.2004).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12LEFT-TO-RIGHTExpression of EPAS1 (HIF2A)The EPAS1 (HIF2A) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EPAS1 is expressed in most adult tissues, but not in peripheral blood leukocytes (Tian et al. 1997). Normoxia causes constitutive oxygen-dependient hydroxylation of EPAS1 on asparagine and proline residues, resulting in degradation of EPAS1 via ubiquitinylation. Hypoxia therefore inhibits degradation of EPAS1 and also causes an increase in EPAS1 expression via HIF3A in embryonic stem cells, which experience hypoxic conditions in the reproductive tract prior to implantation (Forristal et al. 2010).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12EPAS1 geneReactome DB_ID: 2888960nucleoplasmGENE ONTOLOGYGO:0005654ENSEMBL:ENSG00000116016 EPAS1 (HIF2A)EPAS1 (HIF2A)EPAS1BHLHE73HIF2AMOP2PASD2Homo sapiensNCBI Taxonomy9606ENSEMBLENSG00000116016Reactome Database ID Release 752888960Database 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=2888960ReactomeR-HSA-28889601Reactome 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-2888960.1Reactomehttp://www.reactome.orgEPAS1HIF2AEndothelial PAS domain-containing protein 1EPAS1_HUMANReactome DB_ID: 452560UniProt:Q99814 EPAS1EPAS1BHLHE73HIF2AMOP2PASD2FUNCTION Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity).SUBUNIT Interacts with HIF3A (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:16181639). Interacts with CREBBP (By similarity). Interacts with EGLN1. Interacts with VHL (PubMed:19208626).TISSUE SPECIFICITY Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.PTM In normoxia, is probably hydroxylated on Pro-405 and Pro-531 by EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity).PTM In normoxia, is hydroxylated on Asn-847 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.PTM Phosphorylated on multiple sites in the CTAD.PTM The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.UniProtQ998141EQUAL870EQUALReactome Database ID Release 75452560Database 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=452560ReactomeR-HSA-4525601Reactome 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-452560.1Reactome Database ID Release 75480301Database 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=480301ReactomeR-HSA-4803015Reactome 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-480301.519755485Pubmed2010Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensionsForristal, CEWright, KLHanley, NAOreffo, ROHoughton, FDReproduction 139:85-979000051Pubmed1997Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cellsTian, HMcKnight, SLRussell, David WGenes Dev 11:72-82ACTIVATIONHypoxia causes an increase in the level of HIF3A which in turn enhances expression of EPAS1 (HIF2A). The mechanism is unknown.Reactome Database ID Release 75480943Database 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=480943ReactomeR-HSA-4809431Reactome 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-480943.1HIF3AHypoxia-inducible factor 3 alphaHIF3A_HUMANReactome DB_ID: 453015UniProt:Q9Y2N7 HIF3AHIF3ABHLHE17MOP7PASD7FUNCTION Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity).SUBUNIT Isoform 2 interacts (via ODD domain) with VHL (via beta domain) (PubMed:12538644). Isoform 4 interacts with HIF1A; the interaction inhibits the binding of HIF1A to hypoxia-responsive element (HRE) and HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with ARNT; the interaction occurs in a HIF1A- and DNA-binding-independent manner and does not induce HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with EPAS1 (PubMed:17998805). Interacts with BAD, BCL2L2 and MCL1 (By similarity).TISSUE SPECIFICITY Expressed in vascular cells (at protein level) (PubMed:21069422). Expressed in kidney (PubMed:11573933, PubMed:19694616). Expressed in lung epithelial cells (PubMed:16775626). Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta) (PubMed:21069422). Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney (PubMed:12538644). Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells (PubMed:16126907). Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues (PubMed:16126907). Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines (PubMed:20416395). Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas (PubMed:20416395). Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen (PubMed:20416395). Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney (PubMed:20416395).INDUCTION Up-regulated by hypoxia (at protein level) (PubMed:16775626). Induced by hypoxia (PubMed:16775626). Isoform 2, isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a HIF1A- and EPAS1/HIF2A-dependent manner (PubMed:19694616, PubMed:20416395, PubMed:21069422). Isoform 4 is down-regulated by hypoxia and up-regulated upon restoring normoxia in embryonic kidney cells (PubMed:16126907).PTM In normoxia, hydroxylated on Pro-492 in the oxygen-dependent degradation domain (ODD) by prolyl hydroxylase(s) (PHD). The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation.PTM Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.UniProtQ9Y2N71EQUAL669EQUALReactome Database ID Release 75453015Database 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=453015ReactomeR-HSA-4530151Reactome 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-453015.1LEFT-TO-RIGHTTranscription of POU5F1 (OCT4)The POU5F1 (OCT4) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Rao et al. 2004, Richards et al. 2004, Cauffman et al. 2005, Tai et al. 2005, Gerrard et al. 2005, Li et al. 2006, Adewumi et al. 2007,Assou etal. 2007). POU5F1 mRNA and protein are found in the cytoplasm of oocytes and cleavage-stage embryos (Cauffman et al. 2005). POU5F1 protein becomes nuclear during compaction, and protein and mRNA are present in inner cell mass and trophectoderm (Cauffman et al. 2005). Transcripts are also detectable in some differentiated tissues (Cauffman et al. 2005). POU5F1 is expressed in adult stem cells and cancers (Tai et al. 2005). POU5F1, SOX2, NANOG, SALL4, and SF-1(NR5A1) bind the promoter of the POU5F1 gene and enhance transcription (Matin et al. 2004, Chew et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Greber et al. 2007, Wang et al. 2007, Yang et al. 2010, Chia et al. 2010). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA. SALL4 binds the promoter of the POU5F1 gene and activates transcription of POU5F1 (Yang et al. 2010). POU5F1 activates SALL4 expression thus forming a self-reinforcing loop. Activation-induced cytidine deaminase (AID) binds the methylated promoter of the POU5F1 gene, demethylates it, and enhances expression of POU5F1 (Bhutani et al. 2009). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to enhance expression of POU5F1 (Forristal et al. 2010). LIN28 binds the POU5F1 mRNA and increases translation (Qiu et al. 2009).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12OCT4 genePOU5F1 geneReactome DB_ID: 2888984ENSEMBL:ENSG00000204531 POU5F1 (OCT4)POU5F1 (OCT4)POU5F1OCT3OCT4OTF3ENSEMBLENSG00000204531Reactome Database ID Release 752888984Database 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=2888984ReactomeR-HSA-28889841Reactome 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-2888984.1OCT4POU5F1 mRNAReactome DB_ID: 500358cytosolGENE ONTOLOGYGO:0005829ENSEMBL:ENST00000259915 POU5F1OCT4/POU5F1 transcriptPOU5F1OCT4ENSEMBLENST00000259915Reactome Database ID Release 75500358Database 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=500358ReactomeR-HSA-5003581Reactome 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-500358.1Reactome Database ID Release 75452392Database 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=452392ReactomeR-HSA-4523924Reactome 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-452392.420505821Pubmed2010A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cellsYang, JGao, CChai, LMa, YPLoS One 5:e1076614688391Pubmed2004The transcriptome profile of human embryonic stem cells as defined by SAGERichards, MTan, SPTan, JHChan, WKBongso, AStem Cells 22:51-6417068183Pubmed2007Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cellsBabaie, YHerwig, RGreber, BBrink, TCWruck, WGroth, DLehrach, HBurdon, TAdjaye, JStem Cells 25:500-1017628018Pubmed2007Zfp206 is a transcription factor that controls pluripotency of embryonic stem cellsWang, ZXKueh, JLTeh, CHRossbach, MLim, LLi, PWong, KYLufkin, TRobson, PStanton, LWStem Cells 25:2173-8215625129Pubmed2005Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotencyGerrard, LZhao, DClark, AJCui, WStem Cells 23:124-3316153702Pubmed2005Core transcriptional regulatory circuitry in human embryonic stem cellsBoyer, LALee, TICole, MFJohnstone, SELevine, SSZucker, JPGuenther, MGKumar, RMMurray, HLJenner, RGGifford, DKMelton, DAJaenisch, RYoung, RACell 122:947-5617204602Pubmed2007A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlasAssou, SLe Carrour, TTondeur, SStröm, SGabelle, AMarty, SNadal, LPantesco, VRéme, THugnot, JPGasca, SHovatta, OHamamah, SKlein, BDe Vos, JStem Cells 25:961-7316978057Pubmed2006Characterization and gene expression profiling of five new human embryonic stem cell lines derived in TaiwanLi, SSLiu, YHTseng, CNChung, TLLee, TYSingh, SStem Cells Dev 15:532-5519966271Pubmed2009Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cellsQiu, CMa, YWang, JPeng, SHuang, YNucleic Acids Res 38:1240-815342930Pubmed2004Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cellsMatin, MMWalsh, JRGokhale, PJDraper, JSBahrami, ARMorton, IMoore, HDAndrews, PWStem Cells 22:659-6815695770Pubmed2005Oct-4 mRNA and protein expression during human preimplantation developmentCauffman, GVan de Velde, HLiebaers, IVan Steirteghem, AMol Hum Reprod 11:173-8118029452Pubmed2007Induced pluripotent stem cell lines derived from human somatic cellsYu, JVodyanik, MASmuga-Otto, KAntosiewicz-Bourget, JFrane, JLTian, SNie, JJonsdottir, GARuotti, VStewart, RSlukvin, IIThomson, JAScience 318:1917-2017572666Pubmed2007Characterization of human embryonic stem cell lines by the International Stem Cell InitiativeInternational Stem Cell, InitiativeAdewumi, OAflatoonian, BAhrlund-Richter, LAmit, MAndrews, PWBeighton, GBello, PABenvenisty, NBerry, LSBevan, SBlum, BBrooking, JChen, KGChoo, ABChurchill, GACorbel, MDamjanov, IDraper, JSDvorak, PEmanuelsson, KFleck, RAFord, AGertow, KGertsenstein, MGokhale, PJHamilton, RSHampl, AHealy, LEHovatta, OHyllner, JImreh, MPItskovitz-Eldor, JJackson, JJohnson, JLJones, MKee, KKing, BLKnowles, BBLako, MLebrin, FMallon, BSManning, DMayshar, YMcKay, RDMichalska, AEMikkola, MMileikovsky, MMinger, SLMoore, HDMummery, CLNagy, ANakatsuji, NO'Brien, CMOh, SKOlsson, COtonkoski, TPark, KYPassier, RPatel, HPatel, MPedersen, RPera, MFPiekarczyk, MSPera, RAReubinoff, BERobins, AJRossant, JRugg-Gunn, PSchulz, TCSemb, HSherrer, ESSiemen, HStacey, GNStojkovic, MSuemori, HSzatkiewicz, JTuretsky, TTuuri, Tvan den Brink, SVintersten, KVuoristo, SWard, DWeaver, TAYoung, LAZhang, WNat Biotechnol 25:803-1620027182Pubmed2009Reprogramming towards pluripotency requires AID-dependent DNA demethylationBhutani, NBrady, JJDamian, MSacco, ACorbel, SYBlau, Helen MNature 463:1042-104715513931Pubmed2005Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesisTai, MHChang, CCKiupel, MWebster, JDOlson, LKTrosko, JECarcinogenesis 26:495-50220953172Pubmed2010A genome-wide RNAi screen reveals determinants of human embryonic stem cell identityChia, NYChan, YSFeng, BLu, XOrlov, YLMoreau, DKumar, PYang, LJiang, JLau, MSHuss, MSoh, BSKraus, PLi, PLufkin, TLim, BClarke, NDBard, FNg, HHNature 468:316-2015493035Pubmed2004Comparative transcriptional profiling of two human embryonic stem cell linesRao, RRCalhoun, JDQin, XRekaya, RClark, JKStice, SLBiotechnol Bioeng 88:273-8615988017Pubmed2005Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cellsChew, JLLoh, YHZhang, WChen, XTam, WLYeap, LSLi, PAng, YSLim, BRobson, PNg, HHMol Cell Biol 25:6031-4617506876Pubmed2007Silencing of core transcription factors in human EC cells highlights the importance of autocrine FGF signaling for self-renewalGreber, BorisLehrach, HansAdjaye, JamesBMC Dev. Biol. 7:46ACTIVATIONSteroidogenic factor 1 (SF-1/NR5A1) binds three sites in the promoter of OCT4/POU5F1 and enhances expression of OCT4 (POU5F1).Reactome Database ID Release 75453022Database 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=453022ReactomeR-HSA-4530221Reactome 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-453022.1NR5A1NR5A1 (SF1)Steroidogenic factor 1STF1_HUMANReactome DB_ID: 452955UniProt:Q13285 NR5A1NR5A1AD4BPFTZF1SF1FUNCTION Transcriptional activator. Essential for sexual differentiation and formation of the primary steroidogenic tissues (PubMed:27378692). Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1 (PubMed:27378692). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation.SUBUNIT Binds DNA as a monomer. Interacts with NR0B2 and PPARGC1A (By similarity). Part of a complex consisting of SFPQ, NONO and NR5A1. Interacts with NCOA2. Interacts with DGKQ and CDK7. Binds to and activated by HIPK3.TISSUE SPECIFICITY High expressed in the adrenal cortex, the ovary, the testis, and the spleen (PubMed:9177385).PTM Acetylation stimulates the transcriptional activity.PTM Sumoylation reduces CDK7-mediated phosphorylation on Ser-203.PTM Phosphorylated on Ser-203 by CDK7. This phosphorylation promotes transcriptional activity.SIMILARITY Belongs to the nuclear hormone receptor family. NR5 subfamily.UniProtQ132851EQUAL461EQUALReactome Database ID Release 75452955Database 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=452955ReactomeR-HSA-4529551Reactome 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-452955.1ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11activeUnit: #Protein12activeUnit: #Protein4activeUnit: #Complex2activeUnit: #Protein7activeUnit: #Protein5Reactome Database ID Release 755638452Database 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=5638452ReactomeR-HSA-56384521Reactome 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-5638452.1OCT4:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:OCT4 genePOU5F1:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:POU5F1 geneReactome DB_ID: 1112611ZNF206ZSCAN10Zinc finger and SCAN domain-containing protein 10ZSC10_HUMANZFP206Reactome DB_ID: 480774UniProt:Q96SZ4 ZSCAN10ZSCAN10ZNF206FUNCTION Embryonic stem (ES) cell-specific transcription factor required to maintain ES cell pluripotency. Can both activate and /or repress expression of target genes, depending on the context. Specifically binds the 5'-[GA]CGCNNGCG[CT]-3' DNA consensus sequence. Regulates expression of POU5F1/OCT4, ZSCAN4 and ALYREF/THOC4.SUBUNIT Interacts with POU5F1/OCT4 and SOX2.PTM Methylated at Gln-428 by N6AMT1.UniProtQ96SZ41EQUAL725EQUALReactome Database ID Release 75480774Database 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=480774ReactomeR-HSA-4807741Reactome 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-480774.11FOXP1FOXP1-ESForkhead box protein P1FOXP1_HUMANReactome DB_ID: 8939362UniProt:Q9H334-8 FOXP1FOXP1HSPC215FUNCTION Transcriptional repressor (PubMed:18347093, PubMed:26647308). Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential (By similarity). Plays an important role in the specification and differentiation of lung epithelium. Acts cooperatively with FOXP4 to regulate lung secretory epithelial cell fate and regeneration by restricting the goblet cell lineage program; the function may involve regulation of AGR2. Essential transcriptional regulator of B-cell development. Involved in regulation of cardiac muscle cell proliferation. Involved in the columnar organization of spinal motor neurons. Promotes the formation of the lateral motor neuron column (LMC) and the preganglionic motor column (PGC) and is required for respective appropriate motor axon projections. The segment-appropriate generation of spinal chord motor columns requires cooperation with other Hox proteins. Can regulate PITX3 promoter activity; may promote midbrain identity in embryonic stem cell-derived dopamine neurons by regulating PITX3. Negatively regulates the differentiation of T follicular helper cells T(FH)s. Involved in maintenance of hair follicle stem cell quiescence; the function probably involves regulation of FGF18 (By similarity). Represses transcription of various pro-apoptotic genes and cooperates with NF-kappa B-signaling in promoting B-cell expansion by inhibition of caspase-dependent apoptosis (PubMed:25267198). Binds to CSF1R promoter elements and is involved in regulation of monocyte differentiation and macrophage functions; repression of CSF1R in monocytes seems to involve NCOR2 as corepressor (PubMed:15286807, PubMed:18799727, PubMed:18347093). Involved in endothelial cell proliferation, tube formation and migration indicative for a role in angiogenesis; the role in neovascularization seems to implicate suppression of SEMA5B (PubMed:24023716). Can negatively regulate androgen receptor signaling (PubMed:18640093). Acts as a transcriptional activator of the FBXL7 promoter; this activity is regulated by AURKA (PubMed:28218735).SUBUNIT Forms homodimers and heterodimers with FOXP2 and FOXP4 (PubMed:25027557). Dimerization is required for DNA-binding. Self-associates (PubMed:26647308). Interacts with CTBP1 (By similarity). Interacts with NCOR2 and AR (PubMed:18347093, PubMed:18640093). Interacts with FOXP2 (PubMed:26647308). Interacts with TBR1 (PubMed:30250039). Interacts with AURKA; this interaction facilitates the phosphorylation of FOXP1, which suppresses the expression of FBXL7 (PubMed:28218735).TISSUE SPECIFICITY Isoform 8 is specifically expressed in embryonic stem cells.INDUCTION By androgen in an isoform-specific manner; expression of isoform 4 is greatly induced.DOMAIN The leucine-zipper is required for dimerization and transcriptional repression.DISEASE A chromosomal aberration involving FOXP1 is found in acute lymphoblastic leukemia. Translocation t(9;3)(p13;p14.1) with PAX5.UniProt IsoformQ9H334-81EQUAL693EQUALReactome Database ID Release 758939362Database 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=8939362ReactomeR-HSA-89393621Reactome 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-8939362.11NANOGHomeobox protein NANOGNANOG_HUMANReactome DB_ID: 452586UniProt:Q9H9S0 NANOGNANOGFUNCTION Transcription regulator involved in inner cell mass and embryonic stem (ES) cells proliferation and self-renewal. Imposes pluripotency on ES cells and prevents their differentiation towards extraembryonic endoderm and trophectoderm lineages. Blocks bone morphogenetic protein-induced mesoderm differentiation of ES cells by physically interacting with SMAD1 and interfering with the recruitment of coactivators to the active SMAD transcriptional complexes. Acts as a transcriptional activator or repressor. Binds optimally to the DNA consensus sequence 5'-TAAT[GT][GT]-3' or 5'-[CG][GA][CG]C[GC]ATTAN[GC]-3'. Binds to the POU5F1/OCT4 promoter (PubMed:25825768). Able to autorepress its expression in differentiating (ES) cells: binds to its own promoter following interaction with ZNF281/ZFP281, leading to recruitment of the NuRD complex and subsequent repression of expression. When overexpressed, promotes cells to enter into S phase and proliferation.SUBUNIT Interacts with SMAD1 and SALL4. Interacts with ZNF281/ZFP281 (By similarity). Interacts with PCGF1 (PubMed:26687479). Interacts with ESRRB; reciprocally modulates their transcriptional activities (By similarity).TISSUE SPECIFICITY Expressed in testicular carcinoma and derived germ cell tumors (at protein level). Expressed in fetal gonads, ovary and testis. Also expressed in ovary teratocarcinoma cell line and testicular embryonic carcinoma. Not expressed in many somatic organs and oocytes.DEVELOPMENTAL STAGE Expressed in embryonic stem (ES) and carcinoma (EC) cells. Expressed in inner cell mass (ICM) of the blastocyst and gonocytes between 14 and 19 weeks of gestation (at protein level). Not expressed in oocytes, unfertilized oocytes, 2-16 cell embryos and early morula (at protein level). Expressed in embryonic stem cells (ES). Expression decreases with ES differentiation.MISCELLANEOUS Exists an other tandem duplicated non-processed pseudogene (NANOGP1) and 10 other NANOG-related nucleotide sequences located on different chromosomes, all of which are processed pseudogenes lacking introns (NANOGP2 to NANOGP11); except NANOGP8 which is a retrogene.SIMILARITY Belongs to the Nanog homeobox family.UniProtQ9H9S01EQUAL305EQUALReactome Database ID Release 75452586Database 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=452586ReactomeR-HSA-4525861Reactome 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-452586.11SALL4Sal-like protein 4SALL4_HUMANReactome DB_ID: 452644UniProt:Q9UJQ4 SALL4SALL4ZNF797FUNCTION Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.SUBUNIT Interacts with NANOG (By similarity). Interacts with POU5F1/OCT4. Interacts with BEND3.TISSUE SPECIFICITY Expressed in testis. Constitutively expressed in acute myeloid leukemia (AML).PTM Isoform SALL4B exists primarily as a ubiquitinated form.PTM Sumoylation with both SUMO1 and SUMO2 regulates the stability, subcellular localization, transcriptional activity, and may reduce interaction with POU5F1/OCT4.SIMILARITY Belongs to the sal C2H2-type zinc-finger protein family.UniProtQ9UJQ41EQUAL1053EQUALReactome Database ID Release 75452644Database 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=452644ReactomeR-HSA-4526441Reactome 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-452644.11SMAD4:p-SMAD2:p-SMAD2SMAD4:Phospho SMAD2:Phospho SMAD2Reactome DB_ID: 206827SMAD4Co-SMADMothers against decapentaplegic homolog 4Reactome DB_ID: 177103UniProt:Q13485 SMAD4SMAD4DPC4MADH4FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Found in a complex with SMAD1 and YY1 (By similarity). Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3 (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtQ134851EQUAL552EQUALReactome Database ID Release 75177103Database 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=177103ReactomeR-HSA-1771031Reactome 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-177103.11p-2S-SMAD2p-S465,S467-SMAD2Reactome DB_ID: 3009185UniProt:Q15796 SMAD2SMAD2MADH2MADR2FUNCTION Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; the absence of TGF-beta. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4. Interacts with AIP1, HGS, PML and WWP1 (By similarity). Interacts with NEDD4L in response to TGF-beta (By similarity). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta. Interacts with ACVR1B, SMAD3 and TRIM33. Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with FOXH1, homeobox protein TGIF, PEBP2-alpha subunit, CREB-binding protein (CBP), EP300, SKI and SNW1. Interacts with SNON; when phosphorylated at Ser-465/467. Interacts with SKOR1 and SKOR2. Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3. Interacts with RBPMS. Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C. Interacts with ZNF580. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif). Interacts with ZFHX3. Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity).TISSUE SPECIFICITY Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta.PTM Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1.PTM In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity).PTM Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtQ15796465EQUALO-phospho-L-serineMODMOD:00046467EQUAL2EQUAL467EQUALReactome Database ID Release 753009185Database 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=3009185ReactomeR-HSA-30091851Reactome 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-3009185.12Reactome Database ID Release 75206827Database 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=206827ReactomeR-HSA-2068272Reactome 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-206827.2ComplexPortalCPX-3208additional informationMIMI:03611OCT3POU5F1OCT4 (POU5F1)POU domain, class 5, transcription factor 1PO5F1_HUMANOCT4Reactome DB_ID: 452472UniProt:Q01860 POU5F1POU5F1OCT3OCT4OTF3FUNCTION Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3'). Forms a trimeric complex with SOX2 or SOX15 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. Critical for early embryogenesis and for embryonic stem cell pluripotency.SUBUNIT Interacts with PKM. Interacts with WWP2. Interacts with UBE2I and ZSCAN10 (By similarity). Interacts with PCGF1 (PubMed:26687479). Interacts with ESRRB; recruits ESRRB near the POU5F1-SOX2 element in the NANOG proximal promoter; the interaction is DNA independent (By similarity). Interacts with ZNF322 (By similarity). Interacts with MAPK8 and MAPK9; the interaction allows MAPK8 and MAPK9 to phosphorylate POU5F1 on Ser-355 (By similarity). Interacts (when phosphorylated on Ser-355) with FBXW8 (By similarity). Interacts with FBXW4 (By similarity). Interacts with SOX2 and SOX15; binds synergistically with either SOX2 or SOX15 to DNA (By similarity).TISSUE SPECIFICITY Expressed in developing brain. Highest levels found in specific cell layers of the cortex, the olfactory bulb, the hippocampus and the cerebellum. Low levels of expression in adult tissues.DEVELOPMENTAL STAGE Highly expressed in undifferentiated embryonic stem cells and expression decreases gradually after embryoid body (EB) formation.INDUCTION Transcriptional activity is positively regulated by PKM.DOMAIN The POU-specific domain mediates interaction with PKM.PTM Sumoylation enhances the protein stability, DNA binding and transactivation activity. Sumoylation is required for enhanced YES1 expression.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination by WWP2 leading to proteasomal degradation.PTM ERK1/2-mediated phosphorylation at Ser-111 promotes nuclear exclusion and proteasomal degradation. Phosphorylation at Thr-235 and Ser-236 decrease DNA-binding and alters ability to activate transcription.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.MISCELLANEOUS Several pseudogenes of POU5F1 have been described on chromosomes 1, 3, 8, 10 and 12. 2 of them, localized in chromosomes 8 and 10, are transcribed in cancer tissues but not in normal ones and may be involved in the regulation of POU5F1 gene activity in carcinogenesis.SIMILARITY Belongs to the POU transcription factor family. Class-5 subfamily.UniProtQ018601EQUAL360EQUALReactome Database ID Release 75452472Database 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=452472ReactomeR-HSA-4524721Reactome 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-452472.11SOX2Transcription factor SOX-2SOX2_HUMANReactome DB_ID: 452271UniProt:P48431 SOX2SOX2FUNCTION Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206 (By similarity). Binds to the proximal enhancer region of NANOG (By similarity). Critical for early embryogenesis and for embryonic stem cell pluripotency (PubMed:18035408). Downstream SRRT target that mediates the promotion of neural stem cell self-renewal (By similarity). Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation (By similarity). May function as a switch in neuronal development (By similarity).SUBUNIT Interacts with ZSCAN10 (By similarity). Interacts with SOX3 and FGFR1 (By similarity). Interacts with GLIS1 (PubMed:21654807). Interacts with POU5F1; binds synergistically with POU5F1 to DNA (By similarity).PTM Sumoylation inhibits binding on DNA and negatively regulates the FGF4 transactivation.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.UniProtP484311EQUAL317EQUALReactome Database ID Release 75452271Database 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=452271ReactomeR-HSA-4522711Reactome 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-452271.11PRDM14PR domain zinc finger protein 14PRD14_HUMANReactome DB_ID: 1112608UniProt:Q9GZV8 PRDM14PRDM14FUNCTION Transcription factor that has both positive and negative roles on transcription. Required for the maintenance of embryonic stem cell identity and the reacquisition of pluripotency in somatic cells. May play an essential role in germ cell development at 2 levels: the reacquisition of potential pluripotency, including SOX2 up-regulation, and successful epigenetic reprogramming, characterized by EHMT1 repression. Its association with CBFA2T2 is required for the functions in pluripotency and germ cell formation (By similarity). Directly up-regulates the expression of pluripotency gene POU5F1 through its proximal enhancer. Binds to the DNA consensus sequence 5'-GGTC[TC]CTAA-3'.SUBUNIT Interacts with CBFA2T2.TISSUE SPECIFICITY Expressed in embryonic stem cells. Tends to be overexpressed in breast cancer (at protein level).DOMAIN The first 5 zinc fingers, but not the last one, are required for DNA-binding and transcriptional activity.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily.UniProtQ9GZV81EQUAL571EQUALReactome Database ID Release 751112608Database 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=1112608ReactomeR-HSA-11126081Reactome 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-1112608.111Reactome Database ID Release 751112611Database 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=1112611ReactomeR-HSA-11126112Reactome 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-1112611.2ACTIVATIONEPAS1 (HIF2A) enhances expression of OCT4 (POU5F1) by an unknown mechanism. Expression of EPAS1 is activated by hypoxia via HIF3A.Reactome Database ID Release 75480862Database 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=480862ReactomeR-HSA-4808621Reactome 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-480862.1LEFT-TO-RIGHTLIN28 binds POU5F1 (OCT4) mRNALIN28 binds the R2 region of the POU5F1 (OCT4) mRNA and increases translation of a luciferase reporter mRNA containing the binding site (Qiu et al. 2009, Lei et al. 2012). Reduction of LIN28 levels in embryonic stem cells causes a reduction in POU5F1 protein (Qiu et al. 2009).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12LIN28LIN28ALin-28 homolog ALN28A_HUMANReactome DB_ID: 500391UniProt:Q9H9Z2 LIN28ALIN28ACSDD1LIN28ZCCHC1FUNCTION RNA-binding protein that inhibits processing of pre-let-7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism (PubMed:21247876). Seems to recognize a common structural G-quartet (G4) feature in its miRNA and mRNA targets (Probable). 'Translational enhancer' that drives specific mRNAs to polysomes and increases the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in mRNA stabilization. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression. Suppressor of microRNA (miRNA) biogenesis, including that of let-7, miR107, miR-143 and miR-200c. Specifically binds the miRNA precursors (pre-miRNAs), recognizing an 5'-GGAG-3' motif found in pre-miRNA terminal loop, and recruits TUT4 AND tut7 uridylyltransferaseS. This results in the terminal uridylation of target pre-miRNAs. Uridylated pre-miRNAs fail to be processed by Dicer and undergo degradation. The repression of let-7 expression is required for normal development and contributes to maintain the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells (PubMed:18951094, PubMed:19703396, PubMed:22118463, PubMed:22898984). Localized to the periendoplasmic reticulum area, binds to a large number of spliced mRNAs and inhibits the translation of mRNAs destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Binds to and enhances the translation of mRNAs for several metabolic enzymes, such as PFKP, PDHA1 or SDHA, increasing glycolysis and oxidative phosphorylation. Which, with the let-7 repression may enhance tissue repair in adult tissue (By similarity).SUBUNIT Monomer (By similarity). During skeletal muscle differentiation, associated with translation initiation complexes in the polysomal compartment (PubMed:21247876). Directly interacts with EIF3S2 (By similarity). Interacts with NCL in an RNA-dependent manner (By similarity). Interacts (via C-terminus) with DHX9 (via N- and C-terminus); this interaction occurs in a RNA-independent manner (PubMed:21247876). Interacts with TUT4 in the presence of pre-let-7 RNA (PubMed:19703396, PubMed:22118463).TISSUE SPECIFICITY Expressed in embryonic stem cells, placenta and testis. Tends to be up-regulated in HER2-overexpressing breast tumors.DEVELOPMENTAL STAGE Expressed in fetal liver. Expression decreases during differentiation of ES cells or upon induction of neuronal differentiation by retinoic acid.INDUCTION Can be negatively regulated by the interaction of microRNAs miR-125a and miR-125b with at least two miRNA responsive elements (miREs) in the 3'-UTR of this gene. These interactions may reduce both translation efficiency and mRNA abundance. Negatively regulated by retinoic acid.DOMAIN The CSD domain is required for function in muscle differentiation.DOMAIN The CCHC zinc fingers interact with the GGAG motif at the 3' end of let-7 miRNAs precursors, more generally they bind the 5'-NGNNG-3' consensus motif with micromolar affinity. The CSD domain recognizes the loop at the 5' end. The flexible linker allows accommodating variable sequences and lengths among let-7 family members.MISCELLANEOUS Overexpressed in primary tumors (overall frequency approximately 15%), overexpression being linked to repression of let-7 family miRNAs and derepression of let-7 targets. Facilitates cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types.MISCELLANEOUS Reactivation of LIN28A expression enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics. Improves hair regrowth by promoting anagen in hair follicle and accelerates regrowth of cartilage, bone and mesenchyme after ear and digit injuries.SIMILARITY Belongs to the lin-28 family.UniProtQ9H9Z22EQUAL209EQUALReactome Database ID Release 75500391Database 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=500391ReactomeR-HSA-5003911Reactome 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-500391.1LIN28:OCT4 mRNALIN28:POU5F1 mRNAReactome DB_ID: 50037311Reactome Database ID Release 75500373Database 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=500373ReactomeR-HSA-5003731Reactome 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-500373.1Reactome Database ID Release 75500366Database 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=500366ReactomeR-HSA-5003661Reactome 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-500366.122210884Pubmed2012Determinants of mRNA recognition and translation regulation by Lin28Lei, Xin-XiangXu, JMa, WeiQiao, ChongNewman, Martin AHammond, Scott MHuang, YingqunNucleic Acids Res. 40:3574-84LEFT-TO-RIGHTTranslation of OCT4 mRNAThe POU5F1 (OCT4) mRNA is translated to yield protein. LIN28 bound to the mRNA appears to enhance translation (Qiu et al. 2009, Lei et al. 2012).Authored: May, B, 2012-12-29Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2012-12-29Reactome Database ID Release 752889036Database 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=2889036ReactomeR-HSA-28890364Reactome 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-2889036.4ACTIVATIONLIN28 binds the R2 region of OCT4 (POU5F1) mRNA and increases translation.activeUnit: #Protein13Reactome Database ID Release 75500402Database 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=500402ReactomeR-HSA-5004022Reactome 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-500402.2LEFT-TO-RIGHTExpression of SOX2The SOX2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Rao et al. 2004, Richards et al. 2004). SOX2 protein is expressed in the cytoplasm of oocytes and day-2 cleavage-stage embryos and in the nuclei of all cells of the inner cell mass of blastocysts (Cauffman et al. 2009). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SOX2 gene and enhance transcription (Chew et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Assou et al. 2007, Greber et al. 2007). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA (Boyer et al. 2005). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to activate expression of SOX2 (Forristal et al. 2010).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12SOX2 geneReactome DB_ID: 2888991ENSEMBL:ENSG00000181449 SOX2SOX2ENSEMBLENSG00000181449Reactome Database ID Release 752888991Database 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=2888991ReactomeR-HSA-28889911Reactome 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-2888991.1Reactome Database ID Release 75452894Database 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=452894ReactomeR-HSA-4528945Reactome 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-452894.518824471Pubmed2009Markers that define stemness in ESC are unable to identify the totipotent cells in human preimplantation embryosCauffman, GDe Rycke, MSermon, KLiebaers, IVan de Velde, HHum Reprod 24:63-7018035408Pubmed2007Induction of pluripotent stem cells from adult human fibroblasts by defined factorsTakahashi, KTanabe, KOhnuki, MNarita, MIchisaka, TTomoda, KYamanaka, SCell 131:861-72ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638454Database 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=5638454ReactomeR-HSA-56384541Reactome 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-5638454.1OCT4:SOX2:NANOG:SOX2 genePOU5F1:SOX2:NANOG:SOX2 geneReactome DB_ID: 4805721111Reactome Database ID Release 75480572Database 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=480572ReactomeR-HSA-4805721Reactome 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-480572.1ACTIVATIONEPAS1 (HIF2A) enhances expression of SOX2 by an unknown mechanism. Expression of EPAS1 is activated by hypoxia via HIF3A.Reactome Database ID Release 75480853Database 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=480853ReactomeR-HSA-4808531Reactome 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-480853.1LEFT-TO-RIGHTExpression of NANOGThe NANOG gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chambers et al. 2003, Hart et al. 2004, Hatano et al. 2005, Hyslop et al. 2005, Li et al. 2006). NANOG protein is not detected in oocytes or early cleavage-stage embryos, but is seen later in some but not all nuclei of the inner cell mass of blastocysts (Cauffman et al. 2009). KLF4, PBX1, POU5F1 (OCT4), SOX2, NANOG, and SMAD2 bind the promoter of the NANOG gene and enhance transcription (Boyer et al. 2005, Rodda et al. 2005, Kuroda et al. 2005, Babaie et al. 2007, Assou et al. 2007, Greber et al. 2007, Vallier et al. 2009, Brown et al. 2011). Activation-induced cytidine deaminase (AID) binds the methylated NANOG promoter and demethylates it (Bhutani et al. 2009). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to enhance expression of NANOG (Forristal et al. 2010). In mouse Nanog negatively regulates its own expression and this may account for the heterogeneous expression observed in cells of the inner cell mass (Fidalgo et al. 2012, Navarro et al. 2012). In human embryonic stem cells NANOG has been observed to be expressed monoallelically in the early pre-implantation embryo then expression becomes biallelic (Miyanari and Torres-Padilla 2012), however this is controversial because expreiments in mouse embryonic stem cells have shown biallelic expression (Faddah et al. 2013, Filipczyk et al. 2013). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA. In mice KLF4 interacts with POU5F1 and SOX2.Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12NANOG geneReactome DB_ID: 2888972ENSEMBL:ENSG00000111704 NANOGNANOGENSEMBLENSG00000111704Reactome Database ID Release 752888972Database 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=2888972ReactomeR-HSA-28889721Reactome 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-2888972.1Reactome Database ID Release 75452838Database 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=452838ReactomeR-HSA-4528385Reactome 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-452838.523827708Pubmed2013Single-cell analysis reveals that expression of nanog is biallelic and equally variable as that of other pluripotency factors in mouse ESCsFaddah, Dina AWang, HaoyiCheng, Albert WuKatz, YardenBuganim, YosefJaenisch, RudolfCell Stem Cell 13:23-915582778Pubmed2005Pluripotential competence of cells associated with Nanog activityHatano, SYTada, MKimura, HYamaguchi, SKono, TNakano, TSuemori, HNakatsuji, NTada, TMech Dev 122:67-7922327294Pubmed2012Control of ground-state pluripotency by allelic regulation of NanogMiyanari, YusukeTorres-Padilla, Maria-ElenaNature 483:470-323827706Pubmed2013Biallelic expression of nanog protein in mouse embryonic stem cellsFilipczyk, AdamGkatzis, KonstantinosFu, JunHoppe, Philipp SLickert, HeikoAnastassiadis, KonstantinosSchroeder, TimmCell Stem Cell 13:12-319688839Pubmed2009Signaling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cellsVallier, LudovicTouboul, ThomasBrown, StephanieCho, CandyBilican, BiladaAlexander, MorganCedervall, JessicaChandran, SiddharthanAhrlund-Richter, LarsWeber, AnnePedersen, Roger AStem Cells 27:2655-6621630377Pubmed2011Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitorsBrown, StephanieTeo, AdrianPauklin, SiimHannan, NicholasCho, Candy H-HLim, BingVardy, LeahDunn, N RayTrotter, MatthewPedersen, RogerVallier, LudovicStem Cells 29:1176-8515983365Pubmed2005Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineagesHyslop, LStojkovic, MArmstrong, LWalter, TStojkovic, PPrzyborski, SHerbert, MMurdoch, AStrachan, TLako, MStem Cells 23:1035-4312787505Pubmed2003Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cellsChambers, IColby, DRobertson, MNichols, JLee, STweedie, SSmith, ACell 113:643-5515860457Pubmed2005Transcriptional regulation of nanog by OCT4 and SOX2Rodda, DJChew, JLLim, LHLoh, YHWang, BNg, HHRobson, PJ Biol Chem 280:24731-723178592Pubmed2012OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cellsNavarro, PabloFestuccia, NicolaColby, DouglasGagliardi, AlessiaMullin, Nicholas PZhang, WenshengKarwacki-Neisius, ViolettaOsorno, RodrigoKelly, DavidRobertson, MoragChambers, IanEMBO J. 31:4547-6215108323Pubmed2004Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and humanHart, AHHartley, LIbrahim, MRobb, LDev Dyn 230:187-9819604364Pubmed2009In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approachChavez, LBais, ASVingron, MLehrach, HAdjaye, JHerwig, RBMC Genomics 10:31422988117Pubmed2012Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogrammingFidalgo, MiguelFaiola, FrancescoPereira, Carlos-FilipeDing, JunjunSaunders, ArvenGingold, JulianSchaniel, ChristophLemischka, Ihor RSilva, José C RWang, JianlongProc. Natl. Acad. Sci. U.S.A. 109:16202-715743839Pubmed2005Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expressionKuroda, TTada, MKubota, HKimura, HHatano, SYSuemori, HNakatsuji, NTada, TMol Cell Biol 25:2475-85ACTIVATIONactiveUnit: #Protein14activeUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein15activeUnit: #Protein11activeUnit: #Complex2activeUnit: #Protein5Reactome Database ID Release 755638456Database 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=5638456ReactomeR-HSA-56384561Reactome 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-5638456.1OCT4:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG genePOU5F1:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG geneReactome DB_ID: 480463KLF4Krueppel-like factor 4KLF4_HUMANReactome DB_ID: 434463UniProt:O43474 KLF4KLF4EZFGKLFFUNCTION 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 (By similarity). Interacts with GLIS1 (PubMed:21654807).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.UniProtO434741EQUAL513EQUALReactome Database ID Release 75434463Database 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=434463ReactomeR-HSA-4344631Reactome 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-434463.11111111PBX1Pre-B-cell leukemia transcription factor 1PBX1_HUMANReactome DB_ID: 453045UniProt:P40424 PBX1PBX1PRLFUNCTION Binds the sequence 5'-ATCAATCAA-3'. Acts as a transcriptional activator of PF4 in complex with MEIS1. Converted into a potent transcriptional activator by the (1;19) translocation. May have a role in steroidogenesis and, subsequently, sexual development and differentiation. Isoform PBX1b as part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Probably in complex with MEIS2, is involved in transcriptional regulation by KLF4. Acts as a transcriptional activator of NKX2-5 and a transcriptional repressor of CDKN2B. Together with NKX2-5, it is required for spleen development through a mechanism that involves CDKN2B repression (By similarity).SUBUNIT Forms a heterodimer with MEIS1 which binds DNA including a cAMP-responsive sequence in CYP17. Also forms heterotrimers with MEIS1 and a number of HOX proteins including HOXA9, HOXD4, HOXD9 and HOXD10. Interacts with PBXIP1 and TLX1. Isoform PBX1a interacts with MEIS2 isoform 4, SP1, SP3 and KLF4. Isoform PBX1b is part of a PDX1:PBX1b:MEIS2b complex; PBX1b recruits Meis2B to the complex. Interacts with FOXC1 (PubMed:15684392). Interacts with MN1 (PubMed:31839203).TISSUE SPECIFICITY Expressed in the kidney. Expressed in the endothelial cells of the glomeruli and interstitium (at protein level) (PubMed:28270404). Expressed in all tissues except in cells of the B and T lineage. Expressed strongly in kidney and brain (PubMed:28270404).DISEASE A chromosomal aberration involving PBX1 is a cause of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with TCF3. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family.SIMILARITY Belongs to the TALE/PBX homeobox family.UniProtP404241EQUAL430EQUALReactome Database ID Release 75453045Database 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=453045ReactomeR-HSA-4530451Reactome 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-453045.11Reactome Database ID Release 75480463Database 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=480463ReactomeR-HSA-4804632Reactome 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-480463.2ACTIVATIONEPAS1 (HIF2A) enhances expression of NANOG by an unknown mechanism. Expression of EPAS1 is activated by hypoxia via HIF3A.Reactome Database ID Release 75480898Database 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=480898ReactomeR-HSA-4808981Reactome 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-480898.1ACTIVATIONZIC3 enhances expression of NANOG (Lim et al. 2007, Lim et al. 2010). In mouse Zic3 binds the Nanog promoter (Lim et al. 2010).Reactome Database ID Release 752975869Database 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=2975869ReactomeR-HSA-29758691Reactome 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-2975869.1ZIC3Zinc finger protein ZIC 3ZIC3_HUMANReactome DB_ID: 480800UniProt:O60481 ZIC3ZIC3ZNF203FUNCTION Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.SUBUNIT Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity (By similarity). Interacts with KPNA1 and KPNA6. Interacts (via C2H2-type domains 3, 4 and 5) with GLI3; the interaction enhances its transcriptional activity.DOMAIN The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation.SIMILARITY Belongs to the GLI C2H2-type zinc-finger protein family.UniProtO604811EQUAL467EQUALReactome Database ID Release 75480800Database 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=480800ReactomeR-HSA-4808001Reactome 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-480800.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the SOX2 promoterFormation of OCT4:SOX2:NANOG Complex at SOX2 PromoterPOU5F1 (OCT4), SOX2, and NANOG bind distinct sites in the promoter of the SOX2 gene (Boyer et al. 2005, Jin et al. 2007, Lister et al. 2009, Jung et al. 2010). The set of target genes of POU5F1, SOX2, and NANOG includes POU5F1, SOX2, and NANOG themselves, thus their expression is a component of an autoregulatory loop (Boyer et al. 2005, Chew et al. 2005, Rodda et al. 2005, Babaie et al. 2007, Jung et al. 2010, Goke et al. 2011).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12Reactome Database ID Release 75480685Database 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=480685ReactomeR-HSA-4806851Reactome 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-480685.120505756Pubmed2010A data integration approach to mapping OCT4 gene regulatory networks operative in embryonic stem cells and embryonal carcinoma cellsJung, MPeterson, HChavez, LKahlem, PLehrach, HVilo, JAdjaye, JPLoS One 5:e1070922215994Pubmed2011Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic developmentGöke, JonathanJung, MarcBehrens, SarahChavez, LukasO'Keeffe, SeanTimmermann, BerndLehrach, HansAdjaye, JamesVingron, MartinPLoS Comput. Biol. 7:e100230417567999Pubmed2007Identification of an OCT4 and SRY regulatory module using integrated computational and experimental genomics approachesJin, Victor XO'Geen, HenrietteIyengar, SushmaGreen, RolandFarnham, Peggy JGenome Res. 17:807-1719829295Pubmed2009Human DNA methylomes at base resolution show widespread epigenomic differencesLister, RyanPelizzola, MattiaDowen, Robert HHawkins, R DavidHon, GaryTonti-Filippini, JulianNery, Joseph RLee, LeonardYe, ZhenNgo, Que-MinhEdsall, LeeAntosiewicz-Bourget, JessicaStewart, RonRuotti, VictorMillar, AHThomson, JARen, BingEcker, Joseph RNature 462:315-22LEFT-TO-RIGHTFormation of OCT4:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:FOXP1-ES Complex at OCT4 PromoterPOU5F1 (OCT4), SOX2, NANOG, ZSCAN10, PRDM14, SMAD2, FOXP1-ES bind the POU5F1 (OCT4) promoterPOU5F1 (OCT4), SOX2, and NANOG bind distinct sites in the promoter of the POU5F1 gene (Boyer et al. 2005, Chew et al. 2005, Rodda et al. 2005, Jin et al. 2007, Lister et al. 2009, Jung et al. 2010, Goke et al. 2011). The set of target genes of POU5F1, SOX2, and NANOG includes POU5F1, SOX2, and NANOG themselves, thus their expression is a component of an autoregulatory loop . Activin/Nodal signaling also regulates POU5F1 transcription via SMAD2 and SMAD3 (Brown et al. 2011). PRDM14 binds the POU5F1 promoter and regulates transcription (Chia et al. 2010).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12Reactome Database ID Release 751112609Database 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=1112609ReactomeR-HSA-11126092Reactome 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-1112609.221924763Pubmed2011An alternative splicing switch regulates embryonic stem cell pluripotency and reprogrammingGabut, MathieuSamavarchi-Tehrani, PWang, XinchenSlobodeniuc, ValentinaO'Hanlon, DaveSung, Hoon-KiAlvarez, ManuelTalukder, ShaheynoorPan, QunMazzoni, Esteban ONedelec, StephaneWichterle, HynekWoltjen, KnutHughes, Timothy RZandstra, Peter WNagy, AndrasWrana, JLBlencowe, Benjamin JCell 147:132-46LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG, KLF4, PBX1, SMAD2 bind the NANOG promoterFormation of OCT4:SOX2:NANOG:KLF4:PBX1:SMAD2 Complex at NANOG PromoterKLF4, PBX1, POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the NANOG gene and enhance expression of NANOG (Rodda et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Jin et al. 2007, Chan et al. 2009, Vallier et al. 2009, Jung et al. 2011). In mouse Nanog has been shown to repress its own expression (Fidalgo et al. 2012, Navarro et al. 2012). ZIC3, a NANOG target, also positively regulates NANOG expression, possibly by binding the NANOG promoter and activating transcription (Lim et al. 2007). Activin/Nodal signaling regulates NANOG via SMAD2 and SMAD3 (Brown et al. 2011)Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12Reactome Database ID Release 75480204Database 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=480204ReactomeR-HSA-4802042Reactome 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-480204.217267691Pubmed2007Zic3 is required for maintenance of pluripotency in embryonic stem cellsLim, LSLoh, YHZhang, WLi, YChen, XWang, YBakre, MNg, HHStanton, LWMol Biol Cell 18:1348-5819522013Pubmed2009KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cellsChan, KKZhang, JChia, NYChan, YSSim, HSTan, KSOh, SKNg, HHChoo, ABStem Cells 27:2114-25LEFT-TO-RIGHTPOU5F1 (OCT4), STAT3 bind the SALL4 promoterPOU5F1 (OCT4) and STAT3 bind the promoter of the SALL4 gene and activate its transcription (Babaie et al. 2007, Tantin et al. 2008, Bard et al. 2009, Yang et al. 2010). SALL4, in turn, positively regulates POU5F1 expression (Yang et al. 2010). In mouse STAT3 is activated by Leukemia Inhibitory Factor (LIF), however LIF in humans does not have the same activity in promoting stem cell maintenance (Humphrey et al. 2004).Authored: May, B, 2013-01-01Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-01SALL4 geneReactome DB_ID: 2888956ENSEMBL:ENSG00000101115 SALL4SALL4ZNF797ENSEMBLENSG00000101115Reactome Database ID Release 752888956Database 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=2888956ReactomeR-HSA-28889561Reactome 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-2888956.12x(p-Y705-STAT3)p-Y705-STAT3 dimerReactome DB_ID: 1112525STAT3p-Y705-STAT3p(Y705)-STAT3Signal transducer and activator of transcription 3STAT3_HUMANReactome DB_ID: 1112554UniProt:P40763 STAT3STAT3APRFFUNCTION Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476, PubMed:31462771). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).SUBUNIT Forms a homodimer or a heterodimer with a related family member (at least STAT1) (PubMed:28065600). Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1 (PubMed:15994929, PubMed:15194700, PubMed:17344214, PubMed:15677474, PubMed:15467733) (By similarity). Interacts with IL23R in presence of IL23 (PubMed:12023369). Interacts (via SH2 domain) with NLK. Interacts with ARL2BP; the interaction is enhanced by LIF and JAK1 expression (By similarity). Interacts with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear import (By similarity). Interacts with CAV2; the interaction is increased on insulin-induced tyrosine phosphorylation of CAV2 and leads to STAT3 activation (By similarity). Interacts with ARL2BP; interaction is enhanced with ARL2 (PubMed:18234692). Interacts with NEK6 (By similarity). Binds to CDK9 when activated and nuclear (PubMed:17956865). Interacts with BMX (PubMed:10688651). Interacts with ZIPK/DAPK3 (PubMed:16219639). Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3 (PubMed:9388184). In prostate cancer cells, interacts with STAT3 and promotes DNA binding activity of STAT3. Interacts with STMN3, antagonizing its microtubule-destabilizing activity. Interacts with the 'Lys-129' acetylated form of BIRC5/survivin (PubMed:20826784). Interacts with FER (PubMed:19147545). Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain) (PubMed:23084476). Interacts with STAT3; the interaction is independent of STAT3 Tyr-705 phosphorylation status (PubMed:25476455). Interacts with FGFR4 (PubMed:26675719). Interacts with OCAD1 (By similarity). Interacts with ZDHHC19, leading to palmitoylation which promotes homodimerization and activation (PubMed:31462771). Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB (PubMed:31899195).SUBUNIT (Microbial infection) Interacts with HCV core protein.SUBUNIT (Microbial infection) Interacts with S.typhimurium SarA.TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in naive CD4(+) T cells as well as T-helper Th17, Th1 and Th2 cells (PubMed:31899195).INDUCTION Positive feedback loop through phosphorylation and palmitoylation in response to stimulation with palmitic acid and cytokines.PTM Tyrosine phosphorylated upon stimulation with EGF. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, LIF, CNTF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha, LEP and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Serine phosphorylation is important for the formation of stable DNA-binding STAT3 homodimers and maximal transcriptional activity. ARL2BP may participate in keeping the phosphorylated state of STAT3 within the nucleus. Upon LPS challenge, phosphorylated within the nucleus by IRAK1. Upon erythropoietin treatment, phosphorylated on Ser-727 by RPS6KA5. Phosphorylation at Tyr-705 by PTK6 or FER leads to an increase of its transcriptional activity (PubMed:12763138, PubMed:16568091, PubMed:21135090, PubMed:31462771). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling.PTM Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads to disrupt STAT3 dimerization and inhibit STAT3 transcription activity (PubMed:28065600). Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated (PubMed:28065600).PTM Some lysine residues are oxidized to allysine by LOXL3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity (PubMed:28065600). Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated (PubMed:28065600).PTM (Microbial infection) Phosphorylated on Tyr-705 in the presence of S.typhimurium SarA.PTM S-palmitoylated by ZDHHC19 in SH2 putative lipid-binding pockets, leading to homodimerization (PubMed:31462771). Nuclear STAT3 is highly palmitoylated (about 75%) compared with cytoplasmic STAT3 (about 20%) (PubMed:31462771).PTM S-stearoylated, probably by ZDHHC19.MISCELLANEOUS Involved in the gp130-mediated signaling pathway.SIMILARITY Belongs to the transcription factor STAT family.UniProtP40763705EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL770EQUALReactome Database ID Release 751112554Database 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=1112554ReactomeR-HSA-11125541Reactome 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-1112554.12Reactome Database ID Release 751112525Database 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=1112525ReactomeR-HSA-11125253Reactome 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-1112525.3ComplexPortalCPX-6049OCT4:STAT3:SALL4 genePOU5F1:STAT3:SALL4 geneReactome DB_ID: 2889026111Reactome Database ID Release 752889026Database 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=2889026ReactomeR-HSA-28890261Reactome 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-2889026.1Reactome Database ID Release 752895778Database 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=2895778ReactomeR-HSA-28957781Reactome 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-2895778.119151334Pubmed2009Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4Bard, JDGelebart, PAmin, HMYoung, LCMa, YLai, RFASEB J 23:1405-1415277698Pubmed2004Maintenance of pluripotency in human embryonic stem cells is STAT3 independentHumphrey, RKBeattie, GMLopez, ADBucay, NKing, CCFirpo, MTRose-John, StefanHayek, AStem Cells 22:522-3018212089Pubmed2008High-throughput biochemical analysis of in vivo location data reveals novel distinct classes of POU5F1(Oct4)/DNA complexesTantin, DGemberling, MCallister, CFairbrother, WGGenome Res 18:631-9LEFT-TO-RIGHTExpression of SALL4The SALL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SALL4 protein is expressed weakly in the nuclei and cytoplasm of oocytes and day-2 cleavage-stage embryos and is expressed strongly in nuclei of blastocysts (Cauffman et al. 2009) and in induced pluripotent stem cells (Nishino et al. 2010). POU5F1 (OCT4) and STAT3 bind the promoter of the SALL4 gene and enhance transcription (Yang et al. 2010, Bard et al. 2009). SALL4 activates expression of POU5F1, thus forming a self-reinforcing loop (Yang et al. 2010). SALL4 binds the promoter of the SALL4 gene and represses transcription, thus forming a negative autoregulatory loop (Yang et al. 2010). As inferred from mouse the shorter isoform of SALL4, SALL4B is more effective at maintaining pluripotency (Rao et al. 2010).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12Reactome Database ID Release 75480520Database 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=480520ReactomeR-HSA-4805206Reactome 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-480520.619489980Pubmed2009Isolation and characterization of stem cells from the human parathyroid glandShih, YRKuo, TKYang, AHLee, OKLee, CHCell Prolif 42:461-7020837710Pubmed2010Differential roles of Sall4 isoforms in embryonic stem cell pluripotencyRao, SridharZhen, ShaoRoumiantsev, SMcDonald, Lindsay TYuan, Guo-ChengOrkin, Stuart HMol. Cell. Biol. 30:5364-80INHIBITIONactiveUnit: #Protein7Reactome Database ID Release 755159192Database 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=5159192ReactomeR-HSA-51591921Reactome 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-5159192.1SALL4:SALL4 geneReactome DB_ID: 288900811Reactome Database ID Release 752889008Database 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=2889008ReactomeR-HSA-28890081Reactome 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-2889008.1ACTIVATIONactiveUnit: #Protein10activeUnit: #Complex6Reactome Database ID Release 755638451Database 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=5638451ReactomeR-HSA-56384511Reactome 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-5638451.1LEFT-TO-RIGHTSALL4 binds the SALL4 promoterSALL4 binds the promoter of the SALL4 gene and represses its own expression (Yang et al. 2010).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03Reactome Database ID Release 752972968Database 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=2972968ReactomeR-HSA-29729681Reactome 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-2972968.1POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferationPOU5F1 (OCT4), SOX2, and NANOG bind elements in the promoters of target genes. The target genes of each transcription factor overlap extensively: POU5F1, SOX2, and NANOG co-occupy at least 353 genes (Boyer et al. 2005). About half of POU5F1 targets also bind SOX2 and about 90% of these also bind NANOG (Boyer et al. 2005). Upon binding the transcription factors activate expression of one subset of target genes and repress another subset (Kim et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007). The targets listed in this module are those that have been described as composing activated genes in the core transcriptional network of pluripotent stem cells (Assou et al. 2007, Chavez et al. 2009, Jung et al. 2010). Inferences from mouse to human have been made with caution because of significant differences between the two species (Ginis et al. 2004).Authored: May, B, 2012-12-31Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2012-12-31LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind DPPA4 genePOU5F1, SOX2, and NANOG bind the promoter of the DPPA4 gene and activate transcription of DPPA4 (Player et al. 2006, Boyer et al. 2007).Authored: May, Bruce, 2015-09-27Reviewed: May, Bruce, 2015-09-27Edited: May, Bruce, 2015-09-27DPPA4 geneReactome DB_ID: 6800123ENSEMBL:ENSG00000121570 DPPA4DPPA4ENSEMBLENSG00000121570Reactome Database ID Release 756800123Database 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=6800123ReactomeR-HSA-68001231Reactome 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-6800123.1POU5F1:SOX2:NANOG:DPPA4 geneReactome DB_ID: 68001141111Reactome Database ID Release 756800114Database 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=6800114ReactomeR-HSA-68001141Reactome 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-6800114.1Reactome Database ID Release 756800120Database 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=6800120ReactomeR-HSA-68001201Reactome 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-6800120.116846370Pubmed2006Comparisons between transcriptional regulation and RNA expression in human embryonic stem cell linesPlayer, AWang, YBhattacharya, BRao, MPuri, RKKawasaki, ESStem Cells Dev 15:315-23LEFT-TO-RIGHTExpression of DPPA4DPPA4 is expressed in pluripotent stem cells. The promoter of the DPPA4 gene binds OCT4 (POU5F1), SOX2, and NANOG (Player et al. 2006, Boyer et al. 2007, inferred from mouse homologs in Chakravarthy et al. 2008). OCT4 Knockdown experiments show OCT4 enhances expression of DPPA4 (Babaie et al. 2007).Authored: May, B, 2010-01-15Reviewed: May, Bruce, 2015-09-27Edited: May, Bruce, 2015-09-27DPPA4Developmental pluripotency-associated protein 4DPPA4_HUMANReactome DB_ID: 452999UniProt:Q7L190 DPPA4DPPA4FUNCTION May be involved in the maintenance of active epigenetic status of target genes. May inhibit differentiation of embryonic cells into a primitive ectoderm lineage.SUBUNIT Interacts with DPPA2 (By similarity). Interacts with PCGF1 (PubMed:26687479).UniProtQ7L1901EQUAL304EQUALReactome Database ID Release 75452999Database 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=452999ReactomeR-HSA-4529991Reactome 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-452999.1Reactome Database ID Release 75452701Database 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=452701ReactomeR-HSA-4527014Reactome 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-452701.418366076Pubmed2008Identification of DPPA4 and other genes as putative Sox2:Oct-3/4 target genes using a combination of in silico analysis and transcription-based assaysChakravarthy, HBoer, BDesler, MMallanna, SKMcKeithan, TWRizzino, AJ Cell Physiol 216:651-62ACTIVATIONThe OCT4 (POU5F1) transcription factor binds the promoter of the DPPA4 gene and activates expression of DPPA4 (Player et al. 2006, Boyer et al. 2007, Babaie et al. 2007, also inferred from mouse homologs in Chakravarthy et al. 2008). OCT4 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA. NANOG also binds the promoter.activeUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 75452214Database 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=452214ReactomeR-HSA-4522142Reactome 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-452214.2LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the EPHA1 promoterThe EPHA1 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Jung et al. 2010, Kunarso et al. 2010, Goke et al. 2011), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009, Kunarso et al. 2010) and expression of the EPHA1 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03EPHA1 geneReactome DB_ID: 2888982ENSEMBL:ENSG00000146904 EPHA1EPHA1EPHEPHTEPHT1ENSEMBLENSG00000146904Reactome Database ID Release 752888982Database 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=2888982ReactomeR-HSA-28889821Reactome 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-2888982.1OCT4:SOX2:NANOG:EPHA1 genePOU5F1:SOX2:NANOG:EPHA1 geneReactome DB_ID: 28890141111Reactome Database ID Release 752889014Database 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=2889014ReactomeR-HSA-28890142Reactome 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-2889014.2Reactome Database ID Release 752972967Database 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=2972967ReactomeR-HSA-29729672Reactome 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-2972967.220526341Pubmed2010Transposable elements have rewired the core regulatory network of human embryonic stem cellsKunarso, GalihChia, Na-YuJeyakani, JustinHwang, CatalinaLu, XinyiChan, Yun-ShenNg, Huck-HuiBourque, GuillaumeNat. Genet. 42:631-4LEFT-TO-RIGHTExpression of EPHA1The EPHA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EPHA1 is expressed most highly in epidermis of skin and is downregulated in nonmelanomal skin cancers (Hafner et al. 2006). EPHA1 is expressed at lower levels in liver, colon, small intestine, bladder, kidney, prostate, and thymus (Hafner et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the EPHA1 gene and OCT4 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007) and NANOG (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the promoter of EPHA1 (Boyer et al. 2005). Expression and kinase activity of EPHA1 correlate with maintenance of pluripotency (Son et al. 2013).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12EPHA1EphA1Reactome DB_ID: 211415plasma membraneGENE ONTOLOGYGO:0005886UniProt:P21709 EPHA1EPHA1EPHEPHTEPHT1FUNCTION Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Plays also a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis.SUBUNIT Homodimer. Forms a signaling complex with LCK; PTK2B/PYK2 and PI3-kinase upon activation by EFNA1; regulates T-lymphocytes migration. Interacts (via SAM domain) with ILK (via ANK repeats); stimulated by EFNA1 but independent of the kinase activity of EPHA1. Interacts (kinase activity-dependent) with PTK2/FAK1.TISSUE SPECIFICITY Overexpressed in several carcinomas.PTM Phosphorylated. Autophosphorylation is stimulated by its ligand EFNA1.PTM Ubiquitinated.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.UniProtP2170926EQUAL976EQUALReactome Database ID Release 75211415Database 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=211415ReactomeR-HSA-2114151Reactome 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-211415.1Reactome Database ID Release 75480509Database 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=480509ReactomeR-HSA-4805095Reactome 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-480509.516862074Pubmed2006Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancerHafner, CBecker, BLandthaler, MVogt, TMod Pathol 19:1369-7724218367Pubmed2013Comparative receptor tyrosine kinase profiling identifies a novel role for AXL in human stem cell pluripotencySon, Mi-YoungSeol, BinnaHan, YMCho, Yee SookHum. Mol. Genet.ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638455Database 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=5638455ReactomeR-HSA-56384551Reactome 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-5638455.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the FGF2 promoterThe FGF2 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009) and expression of the FGF2 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03FGF2 geneReactome DB_ID: 2888971ENSEMBL:ENSG00000138685 FGF2FGF2FGFBENSEMBLENSG00000138685Reactome Database ID Release 752888971Database 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=2888971ReactomeR-HSA-28889711Reactome 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-2888971.1OCT4:SOX2:NANOG:FGF2 genePOU5F1:SOX2:NANOG:FGF2 geneReactome DB_ID: 28890151111Reactome Database ID Release 752889015Database 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=2889015ReactomeR-HSA-28890151Reactome 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-2889015.1Reactome Database ID Release 752972960Database 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=2972960ReactomeR-HSA-29729601Reactome 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-2972960.1LEFT-TO-RIGHTExpression of FGF2The FGF2 (bFGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FGF2 is expressed in most tissues including kidney, skin, liver, ureter, and vasculature (Hughes and Hall 1993). FGF2 is expressed in about 35% of tumor lines (Chandler et al. 1999). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FGF2 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the FGF2 promoter (Boyer et al. 2005). FGF2 maintains human embryonic stem cells in an undifferentiated state (Dvorak et al. 2005, Eiselleova et al. 2009).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12FGF2FGF2(10-155)Fibroblast growth factor-2Heparin-binding growth factor 2FGF2_HUMANBasic fibroblast growth factorbFGFReactome DB_ID: 189898extracellular regionGENE ONTOLOGYGO:0005576UniProt:P09038 FGF2FGF2FGFBFUNCTION Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:8663044). Also acts as an integrin ligand which is required for FGF2 signaling (PubMed:28302677). Binds to integrin ITGAV:ITGB3 (PubMed:28302677). Plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration (PubMed:8663044, PubMed:28302677). Functions as a potent mitogen in vitro (PubMed:1721615, PubMed:3964259, PubMed:3732516). Can induce angiogenesis (PubMed:23469107, PubMed:28302677). Mediates phosphorylation of ERK1/2 and thereby promotes retinal lens fiber differentiation (PubMed:29501879).SUBUNIT Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Interacts with CSPG4, FGFBP1 and TEC. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP3 (PubMed:18669637). Interacts with integrin ITGAV:ITGB3; the interaction is required for FGF2 signaling (PubMed:28302677). Interacts with SNORC (via the extracellular domain) (By similarity). Interacts with glypican GPC3 (By similarity).TISSUE SPECIFICITY Expressed in granulosa and cumulus cells. Expressed in hepatocellular carcinoma cells, but not in non-cancerous liver tissue.PTM Phosphorylation at Tyr-215 regulates FGF2 unconventional secretion.PTM Several N-termini starting at positions 94, 125, 126, 132, 143 and 162 have been identified by direct sequencing.MISCELLANEOUS This protein binds heparin more strongly than does aFGF.SIMILARITY Belongs to the heparin-binding growth factors family.UniProtP0903810EQUAL155EQUALReactome Database ID Release 75189898Database 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=189898ReactomeR-HSA-1898981Reactome 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-189898.1Reactome Database ID Release 75480515Database 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=480515ReactomeR-HSA-4805155Reactome 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-480515.59807024Pubmed1998Expression of fetal kidney growth factors in a kidney tumor line: role of FGF2 in kidney developmentDrummond, IAMukhopadhyay, DSukhatme, VPExp Nephrol 6:522-3319544431Pubmed2009A complex role for FGF-2 in self-renewal, survival, and adhesion of human embryonic stem cellsEiselleova, LiviaMatulka, KamilKriz, VitezslavKunova, MichaelaSchmidtova, ZuzanaNeradil, JakubTichy, BorisDvorakova, DanaPospisilova, SarkaHampl, AlesDvorak, PetrStem Cells 27:1847-5710209961Pubmed1999Prevalent expression of fibroblast growth factor (FGF) receptors and FGF2 in human tumor cell linesChandler, LASosnowski, BAGreenlees, LAukerman, SLBaird, APierce, GFInt J Cancer 81:451-815955829Pubmed2005Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cellsDvorak, PetrDvorakova, DanaKoskova, StanislavaVodinska, MartinaNajvirtova, MiroslavaKrekac, DanielHampl, AlesStem Cells 23:1200-117688835Pubmed1993Immunolocalization of fibroblast growth factor receptor 1 and its ligands in human tissuesHughes, SEHall, PALab Invest 69:173-82ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638457Database 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=5638457ReactomeR-HSA-56384571Reactome 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-5638457.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the FOXD3 promoterThe FOXD3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 activates expression (Babaie et al. 2007, Kunarso et al. 2010).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03FOXD3 geneReactome DB_ID: 2888992ENSEMBL:ENSG00000187140 FOXD3FOXD3HFH2ENSEMBLENSG00000187140Reactome Database ID Release 752888992Database 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=2888992ReactomeR-HSA-28889921Reactome 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-2888992.1OCT4:SOX2:NANOG:FOXD3 genePOU5F1:SOX2:NANOG:FOXD3 geneReactome DB_ID: 28890321111Reactome Database ID Release 752889032Database 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=2889032ReactomeR-HSA-28890321Reactome 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-2889032.1Reactome Database ID Release 752972964Database 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=2972964ReactomeR-HSA-29729641Reactome 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-2972964.1LEFT-TO-RIGHTExpression of FOXD3The Forkhead box protein D3 (FOXD3) gene is transcribed and translated to yield FOXD3 protein. FOXD3 is expressed in blastomeres of the inner cell mass (Galan et al. 2010, Arduini et al. 2012). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FOXD3 gene and POU5F1 enhances transcription (Babaie et al. 2007, Kunarso et al. 2010). The binding site of POU5F1 is not adjacent to the binding site of SOX2 on the FOXD3 promoter (Boyer et al. 2005). FOXD3 is a molecular marker of stem cells (Calloni et al.2013) and a balance of FOXD3 expression is required to maintain pluripotency (Arduini and Brinvalou 2012, inferred from mouse in Liu and Labosky 2008).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12FOXD3Forkhead box protein D3FOXD3_HUMANReactome DB_ID: 452918UniProt:Q9UJU5 FOXD3FOXD3HFH2FUNCTION Binds to the consensus sequence 5'-A[AT]T[AG]TTTGTTT-3' and acts as a transcriptional repressor. Also acts as a transcriptional activator. Promotes development of neural crest cells from neural tube progenitors. Restricts neural progenitor cells to the neural crest lineage while suppressing interneuron differentiation. Required for maintenance of pluripotent cells in the pre-implantation and peri-implantation stages of embryogenesis.SUBUNIT Interacts with POU5F1.TISSUE SPECIFICITY Expressed in chronic myeloid leukemia, Jurkat T-cell leukemia and teratocarcinoma cell lines, but not in any other cell lines or normal tissues examined.UniProtQ9UJU51EQUAL478EQUALReactome Database ID Release 75452918Database 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=452918ReactomeR-HSA-4529181Reactome 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-452918.1Reactome Database ID Release 75452750Database 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=452750ReactomeR-HSA-4527506Reactome 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-452750.622887036Pubmed2012Modulation of FOXD3 activity in human embryonic stem cells directs pluripotency and paraxial mesoderm fatesArduini, Brigitte LBrivanlou, Ali HStem Cells 30:2188-9821049019Pubmed2010Functional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysisGalán, AMontaner, DPóo, MEValbuena, DRuiz, VAguilar, CDopazo, JSimón, CPLoS One 5:e1361518653770Pubmed2008Regulation of embryonic stem cell self-renewal and pluripotency by Foxd3Liu, YingLabosky, Patricia AStem Cells 26:2475-84ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638447Database 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=5638447ReactomeR-HSA-56384472Reactome 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-5638447.2LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG Bind the SALL1 PromoterPOU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SALL1 gene (Boyer et al. 2005, Yang et al. 2010) and activate expression (Babaie et al. 2007). SALL4 binds the SALL1 promoter and represses expression thus making SALL4 and POU5F1 antagonistic (Yang et al. 2010).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03SALL1 geneReactome DB_ID: 2888989ENSEMBL:ENSG00000103449 SALL1SALL1SAL1ZNF794ENSEMBLENSG00000103449Reactome Database ID Release 752888989Database 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=2888989ReactomeR-HSA-28889891Reactome 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-2888989.1OCT4:SOX2:NANOG:SALL1 genePOU5F1:SOX2:NANOG:SALL1 geneReactome DB_ID: 28890291111Reactome Database ID Release 752889029Database 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=2889029ReactomeR-HSA-28890291Reactome 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-2889029.1Reactome Database ID Release 752972975Database 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=2972975ReactomeR-HSA-29729751Reactome 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-2972975.1LEFT-TO-RIGHTExpression of SALL1The SALL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SALL1 mRNA and protein are expressed in pituitary, adrenal cortex and the placenta in addition to kidney, testicular, and ovarian cells (Ma et al 2002, Chai et al. 2006). Mutations in SALL1 cause Townes-Brocks syndrome. The protein localizes to pericentric heterochromatin (Netzer et al. 2001). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SALL1 gene and enhance transcription (Boyer et al. 2005, Fong et al. 2008). SOX2 binds a site in the SALL1 promoter adjacent to the site bound by POU5F1 (Boyer et al. 2005). SALL4 binds the promoter of the SALL1 gene and represses transcription by associating with Mi-2 (NuRD) repressor complex (Lu et al. 2009, Yang et al. 2010).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12SALL1Sal-like protein 1SALL1_HUMANReactome DB_ID: 452500UniProt:Q9NSC2 SALL1SALL1SAL1ZNF794FUNCTION Transcriptional repressor involved in organogenesis.SUBUNIT Interacts with HDAC1, HDAC2, RBBP4, RBPP7, MTA1 and MTA2 (By similarity). Interacts with CCNQ. Probably associates with NuRD histone deacetylase complex (HDAC).TISSUE SPECIFICITY Highest levels in kidney. Lower levels in adult brain (enriched in corpus callosum, lower expression in substantia nigra) and liver.DEVELOPMENTAL STAGE In fetal brain exclusively in neurons of the subependymal region of hypothalamus lateral to the third ventricle.SIMILARITY Belongs to the sal C2H2-type zinc-finger protein family.UniProtQ9NSC21EQUAL1324EQUALReactome Database ID Release 75452500Database 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=452500ReactomeR-HSA-4525001Reactome 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-452500.1Reactome Database ID Release 75452958Database 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=452958ReactomeR-HSA-4529584Reactome 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-452958.412065233Pubmed2002SALL1 expression in the human pituitary-adrenal/gonadal axisMa, YChai, LCortez, SCStopa, EGSteinhoff, MMFord, DMorgan, JMaizel, ALJ Endocrinol 173:437-4819440552Pubmed2009Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complexLu, JJeong, HWKong, NYang, YCarroll, JLuo, HRSilberstein, LEYupoma, LEChai, LPLoS One 4:e557711751684Pubmed2001SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatinNetzer, CRieger, LBrero, AZhang, CDHinzke, MKohlhase, JBohlander, SKHum Mol Genet 10:3017-2418388306Pubmed2008Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cellsFong, HHohenstein, KADonovan, PJStem Cells 26:1931-819696931Pubmed2009Expression of stem cell markers in the human fetal kidneyMetsuyanim, SHarari-Steinberg, OBuzhor, EOmer, DPode-Shakked, NBen-Hur, HHalperin, RSchneider, DDekel, BPLoS One 4:e670916670092Pubmed2006Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney developmentChai, LYang, JDi, CCui, WKawakami, KLai, RMa, YJ Biol Chem 281:18918-26INHIBITIONactiveUnit: #Protein7Reactome Database ID Release 755159229Database 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=5159229ReactomeR-HSA-51592291Reactome 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-5159229.1SALL4:SALL1 geneReactome DB_ID: 288901011Reactome Database ID Release 752889010Database 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=2889010ReactomeR-HSA-28890101Reactome 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-2889010.1ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 756800076Database 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=6800076ReactomeR-HSA-68000761Reactome 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-6800076.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the STAT3 promoterThe STAT3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Lister et al. 2009, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007) activate expression.Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03STAT3 geneReactome DB_ID: 2888995ENSEMBL:ENSG00000168610 STAT3STAT3APRFENSEMBLENSG00000168610Reactome Database ID Release 752888995Database 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=2888995ReactomeR-HSA-28889951Reactome 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-2888995.1OCT4:SOX2:NANOG:STAT3 genePOU5F1:SOX2:NANOG:STAT3 geneReactome DB_ID: 28890031111Reactome Database ID Release 752889003Database 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=2889003ReactomeR-HSA-28890031Reactome 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-2889003.1Reactome Database ID Release 752972956Database 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=2972956ReactomeR-HSA-29729561Reactome 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-2972956.1LEFT-TO-RIGHTExpression of STAT3The STAT3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. STAT3 is expressed in embryonic stem cells (Schuringa et al. 2002, Fong et al. 2008). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the STAT3 gene and enhance transcription (Boyer et al. 2005, Greber et al. 2007, Fong et al. 2008). The binding site of POU5F1 is adjacent to the binding site of SOX2 in the STAT3 promoter (Boyer et al. 2005). Signaling by LIF via STAT3 in murine but not human stem cells is sufficient to prevent differentiation (Schuringa et al. 2002, Humphrey et al. 2004, Daheron et al. 2004).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12STAT3Signal transducer and activator of transcription 3STAT3_HUMANReactome DB_ID: 5390441EQUAL770EQUALReactome Database ID Release 75539044Database 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=539044ReactomeR-HSA-5390442Reactome 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-539044.2Reactome Database ID Release 75452515Database 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=452515ReactomeR-HSA-4525155Reactome 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-452515.515342941Pubmed2004LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cellsDahéron, LaurenceOpitz, Sarah LZaehres, HolmLensch, M WilliamLensch, William MAndrews, Peter WItskovitz-Eldor, JosephDaley, George QStem Cells 22:770-87545930Pubmed1994Stat3 and Stat4: members of the family of signal transducers and activators of transcriptionZhong, ZWen, ZDarnell JE, JrProc Natl Acad Sci U S A 91:4806-1011855863Pubmed2002LIF-induced STAT3 signaling in murine versus human embryonal carcinoma (EC) cellsSchuringa, JJvan der Schaaf, SVellenga, EEggen, BJKruijer, WExp Cell Res 274:119-29ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638448Database 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=5638448ReactomeR-HSA-56384481Reactome 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-5638448.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the TDGF1 promoterThe TDGF1 (CRIPTO) gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Tantin et al. 2008, Jung et al. 2010, Watanabe et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009, Watanabe et al. 2010). POU5F1 (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007, Watanabe et al. 2010) activate expression. Embryonal carcinoma cells that express higher levels of TDGF1 are more tumorigenic (Watanabe et al. 2010).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03TDGF1 geneReactome DB_ID: 2888987ENSEMBL:ENSG00000241186 TDGF1TDGF1CRIPTOENSEMBLENSG00000241186Reactome Database ID Release 752888987Database 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=2888987ReactomeR-HSA-28889871Reactome 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-2888987.1POU5F1:SOX2:NANOG:TDGF1 geneOCT4:SOX2:NANOG:TDGF1 (CRIPTO) geneReactome DB_ID: 28890181111Reactome Database ID Release 752889018Database 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=2889018ReactomeR-HSA-28890181Reactome 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-2889018.1Reactome Database ID Release 752972962Database 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=2972962ReactomeR-HSA-29729621Reactome 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-2972962.120549704Pubmed2010Cripto-1 is a cell surface marker for a tumorigenic, undifferentiated subpopulation in human embryonal carcinoma cellsWatanabe, KazuhideMeyer, Matthew JStrizzi, LLee, Joseph MGonzales, MonicaBianco, CaterinaNagaoka, TadahiroFarid, Shahram SMargaryan, NairaHendrix, Mary J CVonderhaar, Barbara KSalomon, David SStem Cells 28:1303-14LEFT-TO-RIGHTExpression of TDGF1 (CRIPTO)The TDGF1 (CRIPTO) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. TDGF1/CRIPTO is expressed in embryonic stem cells (Adewumi et al. 2007, Li et al. 2006, Assou et al. 2009). GCNF (NR6A1) binds to the promoter of the TDGF1 (CRIPTO) gene and downregulates expression of TDGF1 (CRIPTO) during differentiation (Hentschke et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the TDGF1 gene and enhance transcription (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010). SOX2 binds the TDGF1 promoter adjacent to POU5F1 (Boyer et al. 2005). TDGF1 is a marker of undifferentiated stem cells (reviewed in Bianco et al. 2010, de Castro et al. 2010). Expression of TDGF1 is associated with tumorigenesis (Ciardiello et al. 1991).Authored: May, B, 2010-11-12Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-11-12TDGF1N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188)CRIPTOTDGF1 (CRIPTO)Teratocarcinoma-derived growth factor 1TDGF1_HUMANReactome DB_ID: 452300UniProt:P13385 TDGF1TDGF1CRIPTOFUNCTION GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated TDGF1 acts as a Nodal coreceptor in cis. Shedding of TDGF1 by TMEM8A modulates Nodal signaling by allowing soluble TDGF1 to act as a Nodal coreceptor on other cells (PubMed:27881714). Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm (PubMed:11909953).SUBUNIT Interacts with the activin type-1 receptor ACVR1B.TISSUE SPECIFICITY Preferentially expressed in gastric and colorectal carcinomas than in their normal counterparts. Expressed in breast and lung.PTM The GPI-anchor is attached to the protein in the endoplasmic reticulum and serves to target the protein to the cell surface. There, it is processed by GPI processing phospholipase A2 (TMEM8A), removing an acyl-chain at the sn-2 position of GPI and releasing TDGF1 as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D (GPLD1) into a soluble form.SIMILARITY Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.UniProtP13385150EQUALN-aspartyl-glycosylphosphatidylinositolethanolamineMODMOD:0016831EQUAL188EQUALReactome Database ID Release 75452300Database 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=452300ReactomeR-HSA-4523001Reactome 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-452300.1Reactome Database ID Release 75452338Database 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=452338ReactomeR-HSA-4523385Reactome 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-452338.520616345Pubmed2010Role of Cripto-1 in stem cell maintenance and malignant progressionBianco, CaterinaRangel, Maria CristinaCastro, Nadia PNagaoka, TadahiroRollman, KellyGonzales, MonicaSalomon, David SAm. J. Pathol. 177:532-4019128516Pubmed2009A gene expression signature shared by human mature oocytes and embryonic stem cellsAssou, SCerecedo, DTondeur, SPantesco, VHovatta, OKlein, BHamamah, SDe Vos, JBMC Genomics 10:1016954206Pubmed2006Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3Hentschke, MKurth, IBorgmeyer, UHübner, CAJ Biol Chem 281:33497-50420624125Pubmed2010Cripto-1: an embryonic gene that promotes tumorigenesisde Castro, Nadia PereiraRangel, Maria CristinaNagaoka, TadahiroSalomon, David SBianco, CaterinaFuture Oncol 6:1127-421715580Pubmed1991Differential expression of epidermal growth factor-related proteins in human colorectal tumorsCiardiello, FKim, NSaeki, TDono, RPersico, MGPlowman, GDGarrigues, JRadke, STodaro, GJSalomon, DSProc Natl Acad Sci U S A 88:7792-6INHIBITIONactiveUnit: #Protein25Reactome Database ID Release 755159208Database 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=5159208ReactomeR-HSA-51592081Reactome 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-5159208.1GCNF:TDGF1 geneNR6A1(GCNF):TDGF1 geneReactome DB_ID: 28922301NR6A1-1Nuclear receptor subfamily 6 group A member 1 isoform 1Reactome DB_ID: 3008764UniProt:Q15406-1 NR6A1NR6A1GCNFFUNCTION Orphan nuclear receptor. Binds to a response element containing the sequence 5'-TCAAGGTCA-3'. May be involved in the regulation of gene expression in germ cell development during gametogenesis (By similarity).SUBUNIT Homodimer. Interacts with UIMC1 (By similarity).TISSUE SPECIFICITY Shows highest expression in the germ cells of the adult testis.SIMILARITY Belongs to the nuclear hormone receptor family. NR6 subfamily.UniProt IsoformQ15406-11EQUAL480EQUALReactome Database ID Release 753008764Database 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=3008764ReactomeR-HSA-30087641Reactome 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-3008764.11Reactome Database ID Release 752892230Database 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=2892230ReactomeR-HSA-28922301Reactome 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-2892230.1ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638449Database 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=5638449ReactomeR-HSA-56384491Reactome 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-5638449.1LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the ZIC3 promoterPOU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) activate expression. In mouse, Zic3 binds the Nanog promoter and activates transcription, thus forming a positive feedback loop (Lim et al. 2010).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03ZIC3 geneReactome DB_ID: 2888979ENSEMBL:ENSG00000156925 ZIC3ZIC3ZNF203ENSEMBLENSG00000156925Reactome Database ID Release 752888979Database 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=2888979ReactomeR-HSA-28889791Reactome 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-2888979.1OCT4:SOX2:NANOG:ZIC3 genePOU5F1:SOX2:NANOG:ZIC3 geneReactome DB_ID: 28890301111Reactome Database ID Release 752889030Database 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=2889030ReactomeR-HSA-28890301Reactome 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-2889030.1Reactome Database ID Release 752972978Database 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=2972978ReactomeR-HSA-29729781Reactome 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-2972978.120872845Pubmed2010The pluripotency regulator Zic3 is a direct activator of the Nanog promoter in ESCsLim, Linda ShushanHong, Felicia HuimeiKunarso, GalihStanton, Lawrence WStem Cells 28:1961-9LEFT-TO-RIGHTExpression of ZIC3The ZIC3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhances transcription. SOX2 binds adjacent to POU5F1 on the ZIC3 promoter (Boyer et al. 2005). ZIC3 is expressed in embryonic stem cells where it maintains pluripotency (Lim et al. 2007). As inferred from mouse, ZIC3 is involved in correct patterning during gastrulation (Ware et al. 2006) and mutations in ZIC3 cause heterotaxy in humans (Gebbia et al. 1997, Ware et al. 2004).Authored: May, B, 2010-01-15Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2010-01-15Reactome Database ID Release 75480470Database 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=480470ReactomeR-HSA-4804705Reactome 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-480470.514681828Pubmed2004Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defectsWare, SMPeng, JZhu, LijunFernbach, SColicos, SCasey, BTowbin, JBelmont, JWAm J Hum Genet 74:93-10516397896Pubmed2006Zic3 is critical for early embryonic patterning during gastrulationWare, Stephanie MHarutyunyan, Karine GBelmont, John WDev. Dyn. 235:776-859354794Pubmed1997X-linked situs abnormalities result from mutations in ZIC3Gebbia, MFerrero, GBPilia, GBassi, MTAylsworth, APenman-Splitt, MBird, LMBamforth, JSBurn, JSchlessinger, DNelson, DLCasey, BNat Genet 17:305-8ACTIVATIONactiveUnit: #Protein6activeUnit: #Protein10activeUnit: #Protein11Reactome Database ID Release 755638453Database 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=5638453ReactomeR-HSA-56384531Reactome 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-5638453.1Reactome Database ID Release 752892247Database 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=2892247ReactomeR-HSA-28922473Reactome 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-2892247.315110706Pubmed2004Differences between human and mouse embryonic stem cellsGinis, ILuo, YMiura, TThies, SBrandenberger, RGerecht-Nir, SAmit, MHoke, ACarpenter, MKItskovitz-Eldor, JRao, MSDev Biol 269:360-8017183653Pubmed2006Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profilingMatoba, RNiwa, HMasui, SOhtsuka, SCarter, MGSharov, AAKo, MSPLoS One 1:e2616819296Pubmed2006Profiling of differentially expressed genes in human stem cells by cDNA microarrayKim, CGLee, JJJung, DYJeon, JHeo, HSKang, HCShin, JHCho, YSCha, KJKim, CGDo, BRKim, KSKim, HSMol Cells 21:343-55POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiationPOU5F1 (OCT4), SOX2, and NANOG bind elements in the promoters of target genes. The target genes of each transcription factor overlap extensively: POU5F1, SOX2, and NANOG co-occupy at least 353 genes (Boyer et al. 2005). About half of POU5F1 targets also bind SOX2 and about 90% of these also bind NANOG (Boyer et al. 2005). Upon binding the transcription factors activate expression of one subset of target genes in the core transcriptional network of pluripotent stem cells and repress another subset (Kim et al. 2006, Matoba et al. 2006, Player et al. 2006, Assou et al. 2007, Babaie et al. 2007, Chavez et al. 2009, Jung et al. 2010). The target genes listed in this module are the repressed genes. Caution must be used when making inferences about human stem cells from mouse stem cells because of significant differences between the two species (Ginis et al. 2004).Authored: May, B, 2012-12-31Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2012-12-31LEFT-TO-RIGHTPOU5F1 (OCT4), NANOG bind the CDX2 promoterThe CDX2 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Lister et al. 2009), SOX2 (Lister et al. 2009) and NANOG ( Boyer et al. 2005, Lister et al. 2009) and POU5F1 repress expression of CDX2 (Babaie et al. 2007). CDX2 and T (Brachyury) mediate the differentiation of stem cells induced by BMP (Bernardo et al. 2011).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03CDX2 geneReactome DB_ID: 2888961ENSEMBL:ENSG00000165556 CDX2CDX2CDX3ENSEMBLENSG00000165556Reactome Database ID Release 752888961Database 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=2888961ReactomeR-HSA-28889611Reactome 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-2888961.1OCT4:SOX2:NANOG:CDX2 genePOU5F1:SOX2:NANOG:CDX2 geneReactome DB_ID: 28890221111Reactome Database ID Release 752889022Database 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=2889022ReactomeR-HSA-28890221Reactome 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-2889022.1Reactome Database ID Release 752972979Database 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=2972979ReactomeR-HSA-29729791Reactome 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-2972979.121816365Pubmed2011BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineagesBernardo, Andreia SFaial, TiagoGardner, LucyNiakan, Kathy KOrtmann, DanielSenner, Claire ECallery, Elizabeth MTrotter, Matthew WHemberger, MyriamSmith, James CBardwell, LeeMoffett, AshleyPedersen, Roger ACell Stem Cell 9:144-55LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the DKK1 promoterThe DKK1 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Jung et al. 2010), SOX2 (Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) in embryonic stem cells and POU5F1 (Babaie et al. 2007, Kunarso et al. 2010) represses expression. In mesenchymal stem cells, however, SOX2 appears to activate DKK1 expression (Park et al. 2012). DKK1 is a soluble inhibitor of Wnt signaling that binds the LRP5 receptor (reviewed in Pinzone et al. 2009). As inferred from mouse, DKK1 induces differentiation to neuroectoderm (Kong and Zhang 2009).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03DKK1 geneReactome DB_ID: 2888959ENSEMBL:ENSG00000107984 DKK1DKK1UNQ492/PRO1008ENSEMBLENSG00000107984Reactome Database ID Release 752888959Database 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=2888959ReactomeR-HSA-28889591Reactome 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-2888959.1OCT4:SOX2:NANOG:DKK1 genePOU5F1:SOX2:NANOG:DKK1 geneReactome DB_ID: 28889981111Reactome Database ID Release 752888998Database 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=2888998ReactomeR-HSA-28889981Reactome 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-2888998.1Reactome Database ID Release 752972977Database 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=2972977ReactomeR-HSA-29729771Reactome 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-2972977.118687985Pubmed2009The role of Dickkopf-1 in bone development, homeostasis, and diseasePinzone, Joseph JHall, Brett MThudi, Nanda KVonau, MartinQiang, Ya-WeiRosol, Thomas JShaughnessy, John DBlood 113:517-2522015605Pubmed2012SOX2 has a crucial role in the lineage determination and proliferation of mesenchymal stem cells through Dickkopf-1 and c-MYCPark, SBSeo, K WSo, A YSeo, M SYu, K RKang, S KKang, K SCell Death Differ. 19:534-4519057969Pubmed2009Dickkopf (Dkk) 1 promotes the differentiation of mouse embryonic stem cells toward neuroectodermKong, Xiang BoZhang, CongIn Vitro Cell. Dev. Biol. Anim. 45:185-93LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the EOMES promoterThe EOMES gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Jung et al. 2010), SOX2 (Boyer et al. 2005), and NANOG (Boyer et al. 2005, Lister et al. 2009) in embryonic stem cells. POU5F1 (Babaie et al. 2007, Kunarso et al. 2010) and SOX2 (Teo et al. 2011) repress expression, however NANOG enhances expression (Teo et al. 2011). As inferred from mouse, EOMES is required for differentiation of mesoderm (Russ et al. 2000) and directly activates Mesp1, a regulator of cardiovascular differentiation (van den Ameele et al. 2012).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03EOMES geneReactome DB_ID: 2888969ENSEMBL:ENSG00000163508 EOMESEOMESTBR2ENSEMBLENSG00000163508Reactome Database ID Release 752888969Database 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=2888969ReactomeR-HSA-28889691Reactome 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-2888969.1OCT4:SOX2:NANOG:EOMES genePOU5F1:SOX2:NANOG:EOMES geneReactome DB_ID: 28890001111Reactome Database ID Release 752889000Database 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=2889000ReactomeR-HSA-28890001Reactome 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-2889000.1Reactome Database ID Release 752972949Database 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=2972949ReactomeR-HSA-29729491Reactome 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-2972949.121245162Pubmed2011Pluripotency factors regulate definitive endoderm specification through eomesoderminTeo, Adrian Kee KeongArnold, Sebastian JTrotter, Matthew W BBrown, StephanieAng, Lay TengChng, ZhenzhiRobertson, Elizabeth JDunn, N RayVallier, LudovicGenes Dev. 25:238-5010716450Pubmed2000Eomesodermin is required for mouse trophoblast development and mesoderm formationRuss, A PWattler, SColledge, W HAparicio, S ACarlton, M BPearce, J JBarton, S CSurani, M ARyan, KNehls, M CWilson, VEvans, M JNature 404:95-922402664Pubmed2012Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activinvan den Ameele, JelleTiberi, LucaBondue, AntoinePaulissen, CatherineHerpoel, AdèleIacovino, MichelinaKyba, MichaelBlanpain, CédricVanderhaeghen, PierreEMBO Rep. 13:355-62LEFT-TO-RIGHTPOU5F1 (OCT4), NANOG bind the GATA6 promoterPOU5F1 (OCT4) (Boyer et al. 2005) and NANOG (Boyer et al. 2005, Lister et al. 2009) bind the promoter of the GATA6 gene and POU5F1 represses expression (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010). As inferred from mouse GATA6 is required for endoderm differentiatiation where it directly activates Bmp2 expression (Wang et al. 2011, Rong et al. 2012).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03GATA6 geneReactome DB_ID: 2888975ENSEMBL:ENSG00000141448 GATA6GATA6ENSEMBLENSG00000141448Reactome Database ID Release 752888975Database 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=2888975ReactomeR-HSA-28889751Reactome 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-2888975.1OCT4:NANOG:GATA6 genePOU5F1:NANOG:GATA6 geneReactome DB_ID: 2889009111Reactome Database ID Release 752889009Database 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=2889009ReactomeR-HSA-28890091Reactome 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-2889009.1Reactome Database ID Release 752972952Database 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=2972952ReactomeR-HSA-29729521Reactome 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-2972952.122855527Pubmed2012GATA-6 promotes cell survival by up-regulating BMP-2 expression during embryonic stem cell differentiationRong, LiLiu, JieQi, YanmeiGraham, Alan MParmacek, Michael SLi, ShaohuaMol. Biol. Cell 23:3754-6320925113Pubmed2011Ectopic expression of GATA6 bypasses requirement for Grb2 in primitive endoderm formationWang, YingSmedberg, Jennifer LCai, Kathy QiCapo-Chichi, D CalliniceXu, Xiang-XiDev. Dyn. 240:566-76LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the GSC promoterPOU5F1 (OCT4), SOX2, and NANOG bind the promoter of the GSC gene (Boyer et al. 2005, Lister et al. 2009) and POU5F1 represses expression (Babaie et al. 2007, Kunarso et al. 2010). GSC represses EVX1 and is required for formation of anterior streak-like progeny in response to Activin (Kalisz et al. 2012). As inferred from mouse, GSC is required for craniofacial development and rib development (Rivera-Perez et al. 1995).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03GSC geneReactome DB_ID: 2888980ENSEMBL:ENSG00000133937 GSCGSCENSEMBLENSG00000133937Reactome Database ID Release 752888980Database 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=2888980ReactomeR-HSA-28889801Reactome 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-2888980.1OCT4:SOX2:NANOG:GSC genePOU5F1:SOX2:NANOG:GSC geneReactome DB_ID: 28890331111Reactome Database ID Release 752889033Database 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=2889033ReactomeR-HSA-28890331Reactome 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-2889033.1Reactome Database ID Release 752972948Database 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=2972948ReactomeR-HSA-29729481Reactome 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-2972948.122178155Pubmed2012EVEN-SKIPPED HOMEOBOX 1 controls human ES cell differentiation by directly repressing GOOSECOID expressionKalisz, MarkWinzi, MariaBisgaard, Hanne CathrineSerup, PDev. Biol. 362:94-1037555726Pubmed1995Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib developmentRivera-Pérez, J AMallo, MGendron-Maguire, MGridley, TBehringer, R RDevelopment 121:3005-12LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the HHEX promoterThe HHEX gene is bound by POU5F1 (OCT4) (Boyer et al. 2005), SOX2 (Boyer et al. 2005), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 represses expression (Babaie et al. 2007, Kunarso et al. 2010). POU5F1, SOX2, and NANOG bind adjacently (Boyer et al. 2005) therefore POU5F1 and SOX2 may heterodimerize. As inferred from mouse, HHEX is required for hepatic differentiation (Hunter et al. 2007), hematopoiesis (Jayaraman et al. 2000), and endodermal tissues for forebrain and thyroid (Martinez Barbera et al. 2000).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03HHEX geneReactome DB_ID: 2888976ENSEMBL:ENSG00000152804 HHEXHHEXHEXPRHPRHXENSEMBLENSG00000152804Reactome Database ID Release 752888976Database 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=2888976ReactomeR-HSA-28889761Reactome 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-2888976.1OCT4:SOX2:NANOG:HHEX genePOU5F1:SOX2:NANOG:HHEX geneReactome DB_ID: 28890201111Reactome Database ID Release 752889020Database 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=2889020ReactomeR-HSA-28890201Reactome 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-2889020.1Reactome Database ID Release 752972966Database 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=2972966ReactomeR-HSA-29729661Reactome 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-2972966.117580084Pubmed2007The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesisHunter, Michael PWilson, Christine MJiang, XiaobingCong, RongVasavada, HemaxiKaestner, Klaus HBogue, Clifford WDev. Biol. 308:355-6711077116Pubmed2000The homeodomain protein PRH influences the differentiation of haematopoietic cellsJayaraman, P SFrampton, JGoodwin, GLeuk. Res. 24:1023-3110804184Pubmed2000The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formationMartinez Barbera, J PClements, MThomas, PRodriguez, TMeloy, DKioussis, DBeddington, R SDevelopment 127:2433-45LEFT-TO-RIGHTPOU5F1 (OCT4), SOX2, NANOG bind the TSC22D1 promoterPOU5F1 (OCT4), SOX2, and NANOG bind the promoter of the TSC22D1 gene (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007) repress expression. TSC22D1 promotes TGFbeta-mediated cardiac myofibroblast differentiation (Yan et al. 2011), regulates hematopoietic cell proliferation (inferred from mouse in Yu et al. 2009), and associates with Smad4 to induce erythroid cell differentiation (inferred from mouse in Choi et al. 2005).Authored: May, B, 2013-01-03Reviewed: Wang, Jianlong, 2014-01-22Edited: May, B, 2013-01-03TSC22D1 geneReactome DB_ID: 2888994ENSEMBL:ENSG00000102804 TSC22D1TSC22D1KIAA1994TGFB1I4TSC22hucep-2ENSEMBLENSG00000102804Reactome Database ID Release 752888994Database 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=2888994ReactomeR-HSA-28889941Reactome 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-2888994.1OCT4:SOX2:NANOG:TSC22D1 genePOU5F1:SOX2:NANOG:TSC22D1 geneReactome DB_ID: 28890061111Reactome Database ID Release 752889006Database 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=2889006ReactomeR-HSA-28890061Reactome 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-2889006.1Reactome Database ID Release 752972965Database 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=2972965ReactomeR-HSA-29729651Reactome 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-2972965.119329776Pubmed2009TSC-22 contributes to hematopoietic precursor cell proliferation and repopulation and is epigenetically silenced in large granular lymphocyte leukemiaYu, JianhuaErshler, MaximYu, LiWei, MinHackanson, BjörnYokohama, AkihikoMitsui, TakekiLiu, ChunhuiMao, HsiaoyinLiu, ShujunLiu, ZhongfaTrotta, RossanaLiu, Chang-gongLiu, XiupingHuang, KunVisser, JanMarcucci, GuidoPlass, ChristophBelyavsky, Alexander VCaligiuri, Michael ABlood 113:5558-6715881652Pubmed2005Tsc-22 enhances TGF-beta signaling by associating with Smad4 and induces erythroid cell differentiationChoi, So-JungMoon, Jae-HoonAhn, Young-WookAhn, Jin-HyunKim, Dong-UkHan, Tae-HeeMol. Cell. Biochem. 271:23-821791611Pubmed2011TSC-22 promotes transforming growth factor ?-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activityYan, XZhang, JunyuPan, LinWang, PengXue, HuaZhang, LongGao, XiaZhao, XingangNing, YuanhengChen, Ye-GuangMol. Cell. Biol. 31:3700-9Reactome Database ID Release 752892245Database 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=2892245ReactomeR-HSA-28922451Reactome 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-2892245.1Reactome Database ID Release 75452723Database 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=452723ReactomeR-HSA-4527232Reactome 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-452723.222083510Pubmed2012Oct4 links multiple epigenetic pathways to the pluripotency networkDing, JunjunXu, HuileiFaiola, FrancescoMa'ayan, AviWang, JianlongCell Res. 22:155-6720300647Pubmed2010Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cellsCai, JunXie, DanFan, ZhewenChipperfield, HiramMarden, JohnWong, Wing HZhong, ShengPLoS Comput. Biol. 6:e100070723166394Pubmed2013Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriersSeisenberger, StefaniePeat, Julian RHore, Timothy ASantos, FátimaDean, WendyReik, WolfPhilos. Trans. R. Soc. Lond., B, Biol. Sci. 368:2011033022463982Pubmed2012Accessing naïve human pluripotencyDe Los Angeles, AlejandroLoh, Yuin-HanTesar, Paul JDaley, George QCurr. Opin. Genet. Dev. 22:272-8219480567Pubmed2009Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAsKashyap, VasundhraRezende, Naira CScotland, Kymora BShaffer, Sebastian MPersson, Jenny LiaoGudas, Lorraine JMongan, Nigel PStem Cells Dev. 18:1093-10817093407Pubmed2006A protein interaction network for pluripotency of embryonic stem cellsWang, JianlongRao, SridharChu, JianlinShen, XiaohuaLevasseur, Dana NTheunissen, Thorold WOrkin, Stuart HNature 444:364-812923055Pubmed2003Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancersReményi, ALins, KNissen, LJReinbold, RSchöler, HRWilmanns, MGenes Dev 17:2048-5918923680Pubmed2008Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiationSun, YLi, HLiu, YMattson, MPRao, MSZhan, MPLoS One 3:e340622394165Pubmed2012The architectural organization of human stem cell cycle regulatory machineryStein, Gary SStein, Janet Lvan J Wijnen, AndreLian, Jane BMontecino, MartinMedina, RicardoKapinas, KristieGhule, PrachiGrandy, RodrigoZaidi, Sayyed KBecker, Klaus ACurr. Pharm. Des. 18:1679-8522122341Pubmed2011Transcriptional control of embryonic and induced pluripotent stem cellsGuenther, Matthew GEpigenomics 3:323-4322443931Pubmed2012Pluripotency and nuclear reprogrammingDejosez, MarionZwaka, Thomas PAnnu. Rev. Biochem. 81:737-6523248145Pubmed2012Embryonic stem cells and inducible pluripotent stem cells: two faces of the same coin?Romeo, FrancescoCostanzo, FrancescoAgostini, MassimilianoAging (Albany NY) 4:878-8621044011Pubmed2011Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cellsKatoh, MasaruCurr Pharm Biotechnol 12:160-7022909387Pubmed2012DNA-dependent Oct4-Sox2 interaction and diffusion properties characteristic of the pluripotent cell state revealed by fluorescence spectroscopyLam, Chen SokMistri, Tapan KumarFoo, Yong HweeSudhaharan, ThankiahGan, Hui ThengRodda, DavidLim, Leng HiongChou, ChaiRobson, PaulWohland, ThorstenAhmed, SohailBiochem. J. 448:21-3323306458Pubmed2013Characterization of pluripotent stem cellsMartí, MercèMulero, LolaPardo, CristinaMorera, CristinaCarrió, MeritxellLaricchia-Robbio, LeopoldoEsteban, Concepcion RodriguezIzpisua Belmonte, Juan CarlosNat Protoc 8:223-5320207225Pubmed2010Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cellsGreber, BorisWu, GuangmingBernemann, ChristofJoo, Jin YoungHan, Dong WookKo, KinarmTapia, NataliaSabour, DavoodSterneckert, JaredTesar, PaulSchöler, Hans RCell Stem Cell 6:215-26GENE ONTOLOGYGO:0035019gene ontology term for cellular processMIMI:0359