BioPAX pathway converted from "ULK3 phosphorylates GLI" in the Reactome database. LEFT-TO-RIGHT 2.7.11 ULK3 phosphorylates GLI Dissociation from SUFU allows the STK36/dFu homologue ULK3 to phosphorylate full-length GLI proteins. Phosphorylation promotes the nuclear translocation of the proteins and stimulates the transcription factor activity as assessed by a GLI-responsive reporter gene. In vitro, ULK3 phosphorylates GLI2 with the highest efficiency, but the kinase is also able to phosphorylate GLI1 and GLI3 (Maloverjan et al, 2010a; Maloverjan et al, 2010b). ULK3 is only one of a number of kinases that have been implicated in the regulation of GLI proteins in response to pathway stimulation, and how all the putative regulators interact to control GLI transcriptional activity remains to be elucidated (Evangelista et al, 2008; Mao et al, 2002; Varjosalo et al, 2008; reviewed in Marjosalo and Piirsoo, 2012). 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 GLI1,2,3 Reactome DB_ID: 5621782 GLI1 Zinc finger protein GLI1 GLI1_HUMAN Reactome DB_ID: 5610360 ciliary tip GENE ONTOLOGY GO:0097542 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. Homo sapiens NCBI Taxonomy 9606 UniProt P08151 1 EQUAL 1106 EQUAL Reactome Database ID Release 78 5610360 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=5610360 Reactome R-HSA-5610360 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-5610360.1 Reactome http://www.reactome.org GLI2 Zinc finger protein GLI2 GLI2_HUMAN Reactome DB_ID: 5610363 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 5610363 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=5610363 Reactome R-HSA-5610363 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-5610363.1 GLI3 Gli3 Reactome DB_ID: 5610367 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 5610367 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=5610367 Reactome R-HSA-5610367 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-5610367.1 Reactome Database ID Release 78 5621782 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=5621782 Reactome R-HSA-5621782 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-5621782.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 5632460 cilium GENE ONTOLOGY GO:0005929 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 5632460 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=5632460 Reactome R-ALL-5632460 4 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-ALL-5632460.4 COMPOUND C00002 additional information MI MI:0361 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 5632457 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 78 5632457 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=5632457 Reactome R-ALL-5632457 4 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-ALL-5632457.4 COMPOUND C00008 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 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 p-GLI1 Zinc finger protein GLI1 GLI1_HUMAN Reactome DB_ID: 5635040 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 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 ACTIVATION ULK3 Reactome DB_ID: 5635039 UniProt:Q6PHR2 ULK3 ULK3 FUNCTION Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy.SUBUNIT Interacts (via protein kinase domain) with SUFU.TISSUE SPECIFICITY Widely expressed. Highest levels observed in fetal brain. In adult tissues, high levels in brain, liver and kidney, moderate levels in testis and adrenal gland and low levels in heart, lung, stomach, thymus, prostate and placenta. In the brain, highest expression in the hippocampus, high levels also detected in the cerebellum, olfactory bulb and optic nerve. In the central nervous system, lowest levels in the spinal cord.INDUCTION Up-regulated during senescence.PTM Autophosphorylated. Autophosphorylation is blocked by interaction with SUFU.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily. UniProt Q6PHR2 1 EQUAL 472 EQUAL Reactome Database ID Release 78 5635039 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=5635039 Reactome R-HSA-5635039 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-5635039.1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 5635824 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=5635824 Reactome Database ID Release 78 5635842 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=5635842 Reactome R-HSA-5635842 2 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-5635842.2 19878745 Pubmed 2010 Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway Maloverjan, Alla Piirsoo, Marko Michelson, Piret Kogerman, Priit Osterlund, T Exp. Cell Res. 316:627-37 22391301 Pubmed 2012 Mammalian homologues of Drosophila fused kinase Maloverjan, Alla Piirsoo, Marko Vitam. Horm. 88:91-113 12050670 Pubmed 2002 Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling Mao, Bingyu Wu, Wei Davidson, Gary Marhold, Joachim Li, Mingfa Mechler, Bernard M Delius, Hajo Hoppe, Dana Stannek, Peter Walter, Carmen Glinka, Andrei Niehrs, C Nature 417:664-7 20643644 Pubmed 2010 Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway Maloverjan, Alla Piirsoo, Marko Kasak, Lagle Peil, Lauri Østerlund, Torben Kogerman, Priit J. Biol. Chem. 285:30079-90 18827223 Pubmed 2008 Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction Evangelista, Marie Lim, Tze Yang Lee, James Parker, Leon Ashique, Amir Peterson, Andrew S Ye, Weilan Davis, David P de Sauvage, Frederic J Sci Signal 1:ra7 12138125 Pubmed 2002 Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1 Mao, Junhao Maye, Peter Kogerman, Priit Tejedor, Francisco J Toftgard, Rune Xie, W Wu, Guanqing Wu, Dianqing J. Biol. Chem. 277:35156-61 18455992 Pubmed 2008 Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling Varjosalo, Markku Björklund, Mikael Cheng, Fang Syvänen, Heidi Kivioja, Teemu Kilpinen, Sami Sun, Zairen Kallioniemi, Olli Stunnenberg, Hendrik G He, Wei-Wu Ojala, Päivi Taipale, Jussi Cell 133:537-48