BioPAX pathway converted from "ULK3 phosphorylates GLI" in the Reactome database. 2.7.11 ULK3 phosphorylates GLI 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 Reactome DB_ID: 5621782 1 ciliary tip GO 0097542 GLI1,2,3 [ciliary tip] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GLI2 [ciliary tip] GLI3 [ciliary tip] GLI1 [ciliary tip] Reactome Homo sapiens NCBI Taxonomy 9606 UniProt P10070 UniProt P10071 UniProt P08151 Reactome DB_ID: 5632460 1 cilium GO 0005929 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 5632457 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Converted from EntitySet in Reactome Reactome DB_ID: 5635089 1 p-GLI1,2,3 [ciliary tip] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-GLI3 [ciliary tip] p-GLI2 [ciliary tip] p-GLI1 [ciliary tip] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5635039 UniProt:Q6PHR2 ULK3 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 Chain Coordinates 1 EQUAL 472 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 78 5635824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome Database ID Release 78 5635842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-5635842 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: 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