BioPAX pathway converted from "GLI proteins bind CDC73" in the Reactome database. LEFT-TO-RIGHT GLI proteins bind CDC73 Each of the GLI proteins can form a complex in the nucleus with CDC73, also known as Parafibromin, a component of the PAF complex (Mosimann et al, 2009). PAF1 is a conserved protein complex that affects aspects of RNA polymerase II transcription including histone modification, transcription elongation and RNA 3' end formation, among others. In humans, the PAF1 complex consists of CDC73, PAF1, LEO1, CTR9, RTF1 and WDR61 (reviewed in Tomson and Arndt, 2013). Knockdown of CDC73 in mammalian cell culture compromises GLI1- and GLI2-dependent transcriptional activation and has been shown to abrogate expression of endogenous targets in Drosophila. CDC73 interacts with the GLI proteins through the SUFU-interacting domain in region 1 of the N-terminal (Mosimann et al, 2009). Direct binding of a CDC73:GLI complex on an endogenous human target gene has not yet been demonstrated. Authored: Rothfels, Karen, 2014-10-30 Reviewed: Liu, Yulu Cherry, 2014-11-09 Edited: Gillespie, Marc E, 2014-10-30 CDC73 Parafibromin HRPT2 Reactome DB_ID: 3322360 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:Q6P1J9 CDC73 CDC73 C1orf28 HRPT2 FUNCTION Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors.SUBUNIT Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and WDR61 (PubMed:19952111, PubMed:20178742). The PAF1 complex interacts with PHF5A. Within the PAF1 complex interacts directly with PHF5A (By similarity). Interacts with POLR2A, CPSF1, CPSF4, CSTF2, KMT2A/MLL1 and CTNNB1 (PubMed:15632063, PubMed:15923622, PubMed:16630820, PubMed:19136632, PubMed:20541477). Interacts with a Set1-like complex that has histone methyltransferase activity and methylates histone H3 (PubMed:15632063). Found in a complex with BCL9L or BCL9, CDC73, CTNNB1 and PYGO1 indicative for the participation in a nuclear Wnt signaling complex (PubMed:17113272). Interacts with PTPN11 (PubMed:26742426). Interacts with SETD5 (By similarity).SUBUNIT (Microbial infection) The PAF1 complex interacts with Zika virus French Polynesia 10087PF/2013 non-structural protein 5/NS5 (PubMed:30550790). The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription (PubMed:30550790).SUBUNIT (Microbial infection) The PAF1 complex interacts with Dengue virus DENV2 16681 non-structural protein 5/NS5 (PubMed:30550790). The PAF1 complex interacts with Dengue virus DENV4 Dominica/814669/1981 non-structural protein 5/NS5 (PubMed:30550790). The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription (PubMed:30550790).TISSUE SPECIFICITY Found in adrenal and parathyroid glands, kidney and heart.PTM Phosphorylated. Dephosphorylated by PTPN11.SIMILARITY Belongs to the CDC73 family. Homo sapiens NCBI Taxonomy 9606 UniProt Q6P1J9 2 EQUAL 531 EQUAL Reactome Database ID Release 78 3322360 Database 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=3322360 Reactome R-HSA-3322360 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322360.1 Reactome http://www.reactome.org Converted from EntitySet in Reactome 2p-GLI1,2,3 Reactome DB_ID: 5635077 2p-GLI1 Zinc finger protein GLI1 GLI1_HUMAN Reactome DB_ID: 5635057 UniProt:P08151 GLI1 GLI1 GLI FUNCTION Acts as a transcriptional activator (PubMed:19706761, PubMed:10806483, PubMed:19878745, PubMed:24311597, PubMed:24217340). Binds to the DNA consensus sequence 5'-GACCACCCA-3' (PubMed:2105456, PubMed:8378770, PubMed:24217340). Regulates the transcription of specific genes during normal development (PubMed:19706761). Plays a role in craniofacial development and digital development, as well as development of the central nervous system and gastrointestinal tract. Mediates SHH signaling (PubMed:19706761, PubMed:28973407). Plays a role in cell proliferation and differentiation via its role in SHH signaling (PubMed:11238441, PubMed:28973407).SUBUNIT Interacts with KIF7 (By similarity). Interacts with STK36 (PubMed:10806483). Interacts with ZIC1; the interaction enhances transcription activation (PubMed:11238441). Interacts with SUFU; this inhibits transcriptional activation by GLI1 (PubMed:10806483, PubMed:24311597, PubMed:24217340, PubMed:28965847).TISSUE SPECIFICITY Detected in testis (at protein level) (PubMed:2105456). Testis, myometrium and fallopian tube. Also expressed in the brain with highest expression in the cerebellum, optic nerve and olfactory tract (PubMed:19878745). Isoform 1 is detected in brain, spleen, pancreas, liver, kidney and placenta; isoform 2 is not detectable in these tissues (PubMed:19706761).INDUCTION Isoform 1 and isoform 2 are amplified in glioblastoma cells.PTM Phosphorylated in vitro by ULK3.PTM Acetylation at Lys-518 down-regulates transcriptional activity. Deacetylated by HDAC1.SIMILARITY Belongs to the GLI C2H2-type zinc-finger protein family. UniProt P08151 phosphorylated residue MOD MOD:00696 1 EQUAL 1106 EQUAL Reactome Database ID Release 78 5635057 Database 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=5635057 Reactome R-HSA-5635057 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635057.1 2p-GLI2 Zinc finger protein GLI2 GLI2_HUMAN Reactome DB_ID: 5635055 UniProt:P10070 GLI2 GLI2 THP FUNCTION Functions as transcription regulator in the hedgehog (Hh) pathway (PubMed:18455992, PubMed:26565916). Functions as transcriptional activator (PubMed:9557682, PubMed:19878745, PubMed:24311597). May also function as transcriptional repressor (By similarity). Requires STK36 for full transcriptional activator activity. Required for normal embryonic development (PubMed:15994174, PubMed:20685856).SUBUNIT Interaction with ZIC1 and ZIC2 (By similarity). Interacts with STK36 (PubMed:10806483). Interacts with SUFU; this inhibits transcriptional activation mediated by GLI2 (PubMed:24311597). Interacts (via C-terminal internal region) with FOXC1 (via N-terminus); this interaction is direct and increases GLI2 DNA-binding and transcriptional activity through a smoothened (SMO)-independent Hedgehog (Hh) signaling pathway (PubMed:26565916).TISSUE SPECIFICITY Expressed in breast cancers (at protein level) (PubMed:26565916). Isoform 1 and isoform 4 are expressed in HTLV-1-infected T-cell lines (at protein level) (PubMed:9557682). Isoform 1 and isoform 2 are strongly expressed in HTLV-1-infected T-cell lines (PubMed:9557682). Isoform 3 and isoform 4 are weakly expressed in HTLV-1-infected T-cell lines (PubMed:9557682).DOMAIN The N-terminal domain confers transcriptional repressor activity, while the C-terminal domain mediates transcriptional activation.PTM Phosphorylated in vitro by ULK3. Phosphorylated by DYRK2; this inhibits GLI2 transcription factor activity and promotes proteasomal degradation of GLI2.PTM Acetylation at Lys-757 inhibits Hh target gene expression, probably by impeding entry into chromatin thus preventing promoter occupancy.SIMILARITY Belongs to the GLI C2H2-type zinc-finger protein family. UniProt P10070 1 EQUAL 1586 EQUAL Reactome Database ID Release 78 5635055 Database 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=5635055 Reactome R-HSA-5635055 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635055.1 Gli3 2p-GLI3 Reactome DB_ID: 5635052 UniProt:P10071 GLI3 GLI3 FUNCTION Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.SUBUNIT The full-length GLI3 form (GLI3FL) interacts with SUFU and this interaction regulates the formation of either repressor or activator forms of GLI3. Its association with SUFU is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A (By similarity). Interacts with KIF7. The activator form of GLI3 (GLI3A) but not the repressor form (GLI3R) can interact with TRPS1. The phosphorylated form interacts with BTRC. Interacts with ZIC1. Interacts with ZIC3 (via C2H2-type domains 3, 4 and 5); the interaction enhances its transcriptional activity. Interacts with WRD11; the interaction associates EMX1 with GLI3 (PubMed:29263200).TISSUE SPECIFICITY Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.PTM Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylated by DYRK2 (in vitro). Phosphorylation is essential for its proteolytic processing.PTM Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3-190) through proteolytic processing. This process requires PKA-primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3.SIMILARITY Belongs to the GLI C2H2-type zinc-finger protein family. UniProt P10071 1 EQUAL 1580 EQUAL Reactome Database ID Release 78 5635052 Database 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=5635052 Reactome R-HSA-5635052 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635052.1 Reactome Database ID Release 78 5635077 Database 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=5635077 Reactome R-HSA-5635077 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635077.1 CDC73:2p-GLI Reactome DB_ID: 5635076 1 1 Reactome Database ID Release 78 5635076 Database 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=5635076 Reactome R-HSA-5635076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635076.1 Reactome Database ID Release 78 5635845 Database 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=5635845 Reactome R-HSA-5635845 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5635845.1 19368795 Pubmed 2009 The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacting protein in Hedgehog target gene control Mosimann, Christian Hausmann, George Basler, Konrad Mech. Dev. 126:394-405 22982193 Pubmed 2013 The many roles of the conserved eukaryotic Paf1 complex in regulating transcription, histone modifications, and disease states Tomson, Brett N Arndt, KM Biochim. Biophys. Acta 1829:116-26