BioPAX pathway converted from "GLI translocates to the nucleus" in the Reactome database. LEFT-TO-RIGHT GLI translocates to the nucleus Activation of SMO downstream of Hh ligand binding results in the dissociation of the SUFU:GLI complex and the translocation of the full-length GLI proteins to the nucleus where it is converted to a short-lived transcriptionally active form (Pan et al, 2006; Kim et al, 2009; Wen et al, 2010; Humke et al, 2010; Tukachinsky et al, 2010; reviewed in Briscoe and Therond, 2013). Authored: Rothfels, Karen, 2014-10-30 Reviewed: Liu, Yulu Cherry, 2014-11-09 Edited: Gillespie, Marc E, 2014-10-30 Converted from EntitySet in Reactome p-GLI1,2,3 Reactome DB_ID: 5635089 p-GLI2 Zinc finger protein GLI2 GLI2_HUMAN Reactome DB_ID: 5635044 ciliary tip GENE ONTOLOGY GO:0097542 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. Homo sapiens NCBI Taxonomy 9606 UniProt P10070 phosphorylated residue MOD MOD:00696 1 EQUAL 1586 EQUAL Reactome Database ID Release 78 5635044 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=5635044 Reactome R-HSA-5635044 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-5635044.1 Reactome http://www.reactome.org p-GLI1 Zinc finger protein GLI1 GLI1_HUMAN Reactome DB_ID: 5635040 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 1 EQUAL 1106 EQUAL Reactome Database ID Release 78 5635040 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=5635040 Reactome R-HSA-5635040 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-5635040.1 Gli3 p-GLI3 Reactome DB_ID: 5635048 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 5635048 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=5635048 Reactome R-HSA-5635048 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-5635048.1 Reactome Database ID Release 78 5635089 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=5635089 Reactome R-HSA-5635089 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-5635089.1 Converted from EntitySet in Reactome p-GLI1,2,3 Reactome DB_ID: 5635090 p-GLI1 Zinc finger protein GLI1 GLI1_HUMAN Reactome DB_ID: 5635042 nucleoplasm GENE ONTOLOGY GO:0005654 1 EQUAL 1106 EQUAL Reactome Database ID Release 78 5635042 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=5635042 Reactome R-HSA-5635042 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-5635042.1 p-GLI2 Zinc finger protein GLI2 GLI2_HUMAN Reactome DB_ID: 5635047 1 EQUAL 1586 EQUAL Reactome Database ID Release 78 5635047 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=5635047 Reactome R-HSA-5635047 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-5635047.1 Gli3 p-GLI3 Reactome DB_ID: 5635051 1 EQUAL 1580 EQUAL Reactome Database ID Release 78 5635051 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=5635051 Reactome R-HSA-5635051 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-5635051.1 Reactome Database ID Release 78 5635090 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=5635090 Reactome R-HSA-5635090 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-5635090.1 Reactome Database ID Release 78 5635843 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=5635843 Reactome R-HSA-5635843 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-5635843.1 20360384 Pubmed 2010 The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins Humke, Eric W Dorn, Karolin V Milenkovic, Ljiljana Scott, Matthew P Rohatgi, Rajat Genes Dev. 24:670-82 19996169 Pubmed 2009 Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus Kim, Jynho Kato, Masaki Beachy, Philip A Proc. Natl. Acad. Sci. U.S.A. 106:21666-71 23719536 Pubmed 2013 The mechanisms of Hedgehog signalling and its roles in development and disease Briscoe, James Thérond, Pascal P Nat. Rev. Mol. Cell Biol. 14:416-29 20956384 Pubmed 2010 A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes Tukachinsky, Hanna Lopez, Lyle V Salic, Adrian J. Cell Biol. 191:415-28 20154143 Pubmed 2010 Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation Wen, Xiaohui Lai, Cary K Evangelista, Marie Hongo, Jo-Anne de Sauvage, Frederic J Scales, Suzie J Mol. Cell. Biol. 30:1910-22 16611981 Pubmed 2006 Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation Pan, Yong Bai, Chunyang Brian Joyner, Alexandra L Wang, Baolin Mol. Cell. Biol. 26:3365-77