BioPAX pathway converted from "ADRBK1 phosphorylates SMO dimer" in the Reactome database.2.7.11ADRBK1 phosphorylates SMO dimerADRBK1 phosphorylates SMO dimerADRBK1 phosphorylates the SMO C-terminal tail after initial phosphorylation by CSNK1A1. Phosphorylation promotes an open, activated conformation of the C-terminal tails, allowing an intramolecular interaction between tails of adjacent monomers in the SMO dimer. This Hh-dependent conformational change is required for downstream signal propagation (Chen et al, 2011; Chen et al, 2010; Zhao et al, 2007; Meloni et al, 2006; Philipp et al, 2008; reviewed in Briscoe and Therond, 2013). In Drosophila, Smo C-terminal tail phosphorylation promotes an association with the Hedgehog signaling complex (HSC) through interaction with the scaffolding kinesin-2 like protein Cos2, and ultimately results in the release of full-length Ci from the complex (Zhang et al, 2005; Ogden et al, 2003; Lum et al, 2003; reviewed in Mukhopadhyay and Rohatgi, 2014). How Hh signal is transmitted from activated SMO to downstream components in vertebrate cells is not fully establishedAuthored: Rothfels, Karen, 2014-10-24Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30Reactome DB_ID: 56324606ciliumGO0005929ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPReactomehttp://www.reactome.orgChEBI30616Reactome DB_ID: 56326221ciliary membraneGO0060170pS588, S590, T593, S595-SMO dimer:CSNK1A1:ADRBK1 [ciliary membrane]pS588, S590, T593, S595-SMO dimer:CSNK1A1:ADRBK1Reactome DB_ID: 56325041UniProt:P25098 GRK2GRK2GRK2ADRBK1BARKBARK1FUNCTION Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them (PubMed:19715378). Key regulator of LPAR1 signaling (PubMed:19306925). Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor (PubMed:19306925). Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (PubMed:19306925). Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity (By similarity). Inhibits relaxation of airway smooth muscle in response to blue light (PubMed:30284927).ACTIVITY REGULATION In contrast to other AGC family kinases, the catalytic activity is solely regulated by the binding of substrates and ligands, not by phosphorylation of the kinase domain.SUBUNIT Interacts with the heterodimer formed by GNB1 and GNG2 (By similarity). Interacts with GIT1 (By similarity). Interacts with, and phosphorylates chemokine-stimulated CCR5 (PubMed:10085131). Interacts with ARRB1 (PubMed:9501202). Interacts with LPAR1 and LPAR2 (PubMed:19306925). Interacts with RALA in response to LPAR1 activation (PubMed:19306925). ADRBK1 and RALA mutually inhibit each other's binding to LPAR1 (PubMed:19306925). Interacts with ADRB2 (PubMed:19715378).TISSUE SPECIFICITY Expressed in peripheral blood leukocytes.DOMAIN The PH domain binds anionic phospholipids and helps recruiting ADRBK1 from the cytoplasm to plasma membrane close to activated receptors. It mediates binding to G protein beta and gamma subunits, competing with G-alpha subunits and other G-betagamma effectors.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.Homo sapiensNCBI Taxonomy9606UniProtP25098Chain Coordinates1EQUAL689EQUALReactome DB_ID: 56326241pS588,S590, T593, S595-SMO dimer:CSNK1A1 [ciliary membrane]pS588,S590, T593, S595-SMO dimer:CSNK1A1Reactome DB_ID: 56325071UniProt:P48729 CSNK1A1CSNK1A1CSNK1A1FUNCTION Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis (PubMed:11955436, PubMed:1409656, PubMed:18305108). May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration (PubMed:23902688).SUBUNIT Monomer. Interacts with the Axin complex. Interacts with TUT1, leading to TUT1 phosphorylation. Interacts with FAM83H; recruits CSNK1A1 to keratin filaments (PubMed:23902688).SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.UniProtP487292EQUAL337EQUALReactome DB_ID: 56326211pS588, S590, T593, S595-SMO dimer [ciliary membrane]pS588, S590, T593, S595-SMO dimerReactome DB_ID: 56325252UniProt:Q99835 SMOSMOSMOSMOHFUNCTION G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity).SUBUNIT Homodimer (PubMed:23636324). Interacts with ARRB2 (By similarity). Interacts with KIF7 (PubMed:19592253). Interacts with BBS5 and BBS7; the interactions are indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO (PubMed:22072986). Interacts with DLG5 and SDCBP (By similarity). Interacts with GAS8/DRC4 (PubMed:21659505).SIMILARITY Belongs to the G-protein coupled receptor Fz/Smo family.UniProtQ99835O-phospho-L-serine at 588588EQUALO-phospho-L-serine [MOD:00046]O-phospho-L-serine at 590590EQUALO-phospho-L-threonine at 593593EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-serine at 595595EQUAL28EQUAL787EQUALReactome Database ID Release 755632621Database 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=5632621ReactomeR-HSA-56326211Reactome 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-5632621.1Reactome Database ID Release 755632624Database 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=5632624ReactomeR-HSA-56326241Reactome 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-5632624.1Reactome Database ID Release 755632622Database 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=5632622ReactomeR-HSA-56326221Reactome 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-5632622.1Reactome DB_ID: 56324576ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Reactome DB_ID: 56326151p6S, T-SMO dimer:CSNK1A1:ADRBK1 [ciliary membrane]p6S, T-SMO dimer:CSNK1A1:ADRBK1Reactome DB_ID: 563250411EQUAL689EQUALReactome DB_ID: 56326141p6S, T-SMO dimer [ciliary membrane]p6S, T-SMO dimerpS588, S590, T593, S595, S611, S615, S616-SMO dimerReactome DB_ID: 56325282O-phospho-L-serine at 588588EQUALO-phospho-L-serine at 590590EQUALO-phospho-L-threonine at 593593EQUALO-phospho-L-serine at 595595EQUALO-phospho-L-serine at 611611EQUALO-phospho-L-serine at 615615EQUALO-phospho-L-serine at 616616EQUAL28EQUAL787EQUALReactome Database ID Release 755632614Database 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=5632614ReactomeR-HSA-56326141Reactome 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-5632614.1Reactome DB_ID: 563250712EQUAL337EQUALReactome Database ID Release 755632615Database 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=5632615ReactomeR-HSA-56326151Reactome 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-5632615.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 5632622GO0004674GO molecular functionReactome Database ID Release 755632635Database 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=5632635Reactome Database ID Release 755632672Database 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=5632672ReactomeR-HSA-56326721Reactome 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-5632672.121695114Pubmed2011Sonic Hedgehog dependent phosphorylation by CK1? and GRK2 is required for ciliary accumulation and activation of smoothenedChen, YongbinSasai, NoriakiMa, GuoqiangYue, TaoJia, JianhangBriscoe, JamesJiang, JinPLoS Biol. 9:e100108315691767Pubmed2005Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptusZhang, WZhao, YTong, CWang, GWang, BJia, JJiang, JDev Cell 8:267-7820844016Pubmed2010G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in DrosophilaChen, YongbinLi, ShuangTong, ChaoZhao, YunWang, BingLiu, YajuanJia, JianhangJiang, JinGenes Dev. 24:2054-6717960137Pubmed2007Hedgehog regulates smoothened activity by inducing a conformational switchZhao, YTong, CJiang, JNature 450:252-824845016Pubmed2014G-protein-coupled receptors, Hedgehog signaling and primary ciliaMukhopadhyay, SaikatRohatgi, RajatSemin. Cell Dev. Biol.16630821Pubmed2006The ihog cell-surface proteins bind Hedgehog and mediate pathway activationYao, SLum, LBeachy, PCell 125:343-5724925320Pubmed2014Requirement of Smurf-mediated endocytosis of Patched1 in Sonic Hedgehog signal receptionYue, ShenTang, LYTang, YingTang, YShen, Qiu-HongDing, JieChen, YanZhang, ZengdiYu, Ting-TingZhang, Ying ECheng, SYElifee0255523719536Pubmed2013The mechanisms of Hedgehog signalling and its roles in development and diseaseBriscoe, JamesThérond, Pascal PNat. Rev. Mol. Cell Biol. 14:416-2914614827Pubmed2003Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2Ogden, SKAscano M, JrStegman, MASuber, LMHooper, JERobbins, DJCurr Biol 13:1998-200316908539Pubmed2006Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2Meloni, Alison RFralish, Gregory BKelly, PatrickSalahpour, AliChen, James KWechsler-Reya, Robert JLefkowitz, Robert JCaron, Marc GMol. Cell. Biol. 26:7550-6018815277Pubmed2008Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinasePhilipp, MelanieFralish, Gregory BMeloni, Alison RChen, WeiMacInnes, Alyson WBarak, Lawrence SCaron, Marc GMol. Biol. Cell 19:5478-8914636583Pubmed2003Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2Lum, LZhang, COh, SMann, RKvon Kessler, DPTaipale, JWeis-Garcia, FGong, RWang, BBeachy, PAMol Cell 12:1261-74