BioPAX pathway converted from "Activation of SMO" in the Reactome database.Activation of SMOActivation of the transmembrane protein SMO in response to Hh stimulation is a major control point in the Hh signaling pathway (reviewed in Ayers and Therond, 2010; Jiang and Hui, 2008). In the absence of ligand, SMO is inhibited in an unknown manner by the Hh receptor PTCH. PTCH regulates SMO in a non-stoichiometric manner and there is little evidence that endogenous PTCH and SMO interact directly (Taipale et al, 2002; reviewed in Huangfu and Anderson, 2006). PTCH may regulate SMO activity by controlling the flux of sterol-related SMO agonists and/or antagonists, although this has not been fully substantiated (Khaliullina et al, 2009; reviewed in Rohatgi and Scott, 2007; Briscoe and Therond, 2013).<br><br>PTCH-mediated inhibition of SMO is relieved upon ligand stimulation of PTCH, but the mechanisms for this relief are again unknown. SMO and PTCH appear to have opposing localizations in both the 'off' and 'on' state, with PTCH exiting and SMO entering the cilium upon Hh pathway activation (Denef et al, 2000; Rohatgi et al, 2007; reviewed in Goetz and Anderson, 2010; Hui and Angers, 2011). Activation of SMO involves a conserved phosphorylation-mediated conformational change in the C-terminal tails that destabilizes an intramolecular interaction and promotes the interaction between adjacent tails in the SMO dimer. In Drosophila, this phosphorylation is mediated by PKA and CK1, while in vertebrates it appears to involve ADRBK1/GRK2 and CSNK1A1. Sequential phosphorylations along multiple serine and threonine motifs in the SMO C-terminal tail appear to allow a graded response to Hh ligand concentration in both flies and vertebrates (Zhao et al, 2007; Chen et al, 2010; Chen et al, 2011). In flies, Smo C-terminal tail phosphorylation promotes an association with the Hedgehog signaling complex (HSC) through interaction with the scaffolding kinesin-2 like protein Cos2, activating the Fu kinase and ultimately releasing uncleaved Ci from the complex (Zhang et al, 2005; Ogden et al, 2003; Lum et al, 2003; reviewed in Mukhopadhyay and Rohatgi, 2014). In vertebrates, SMO C-terminal tail phosphorylation and conformational change is linked to its KIF7-dependent ciliary accumulation (Chen et al, 2011; Zhao et al, 2007; Chen et al, 2010). In the cilium, SMO is restricted to a transition-zone proximal region known as the EvC zone (Yang et al, 2012; Blair et al, 2011; Pusapati et al, 2014; reviewed in Eggenschwiler 2012). Both SMO phosphorylation and its ciliary localization are required to promote the Hh-dependent dissociation of the GLI:SUFU complex, ultimately allowing full-length GLI transcription factors to translocate to the nucleus to activate Hh-responsive genes (reviewed in Briscoe and Therond, 2013).<br><br><br>Authored: Rothfels, Karen, 2014-10-29Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30LEFT-TO-RIGHTSMO dimer binds ARRB and KIF3ABeta-arrestin 1 and 2 (ARRB1 and 2) and the anterograde motor protein KIF3A bind to SMO and may be required for its ciliary accumulation after Hh stimulation (Kovacs et al, 2008; Barakat et al, 2013). Authored: Rothfels, Karen, 2014-10-20Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30KIF3AKinesin-like protein KIF3AKIF3A_HUMANReactome DB_ID: 984767cytosolGENE ONTOLOGYGO:0005829UniProt:Q9Y496 KIF3AKIF3AKIF3FUNCTION Microtubule-based anterograde translocator for membranous organelles. Plus end-directed microtubule sliding activity in vitro. Plays a role in primary cilia formation. Plays a role in centriole cohesion and subdistal appendage organization and function. Regulates the formation of the subdistal appendage via recruitment of DCTN1 to the centriole. Also required for ciliary basal feet formation and microtubule anchoring to mother centriole.SUBUNIT Heterodimer of KIF3A and KIF3B (By similarity). Interacts with PIFO (PubMed:20643351). Interacts with CLN3 (PubMed:22261744). Interacts with DCTN1 (By similarity). Interacts with FLCN (PubMed:27072130). Interacts with AP3B1 (PubMed:19934039).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.Homo sapiensNCBI Taxonomy9606UniProtQ9Y4961EQUAL699EQUALReactome Database ID Release 75984767Database 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=984767ReactomeR-HSA-9847671Reactome 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-984767.1Reactomehttp://www.reactome.orgSMO dimerReactome DB_ID: 5610574endocytic vesicle membraneGENE ONTOLOGYGO:0030666SMOSmoothened homologSMO_HUMANReactome DB_ID: 5610422UniProt:Q99835 SMOSMOSMOHFUNCTION 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.UniProtQ9983528EQUAL787EQUALReactome Database ID Release 755610422Database 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=5610422ReactomeR-HSA-56104221Reactome 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-5610422.12Reactome Database ID Release 755610574Database 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=5610574ReactomeR-HSA-56105741Reactome 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-5610574.1Converted from EntitySet in ReactomeARRBBeta-arrestinReactome DB_ID: 1911410ARRB1Beta-arrestin-1ARRB1_HUMANReactome DB_ID: 264470UniProt:P49407 ARRB1ARRB1ARR1FUNCTION Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils. Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3. Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates in the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).SUBUNIT Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with GPR143. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated at 'Tyr-737'); phosphorylation of AP2B1 at 'Tyr-737' disrupts the interaction. Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CCR2 and GRK2. Interacts with CRR5. Interacts with PTAFR (phosphorylated on serine residues). Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. Interacts with SRC (via the SH3 domain and the protein kinase domain); the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with TACR1. Interacts with RAF1. Interacts with CHUK, IKBKB and MAP3K14. Interacts with DVL1; the interaction is enhanced by phosphorylation of DVL1. Interacts with DVL2; the interaction is enhanced by phosphorylation of DVL2. Interacts with IGF1R. Associates with MAP kinase p38. Part of a MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 (activated). Part of a MAPK signaling complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated) (By similarity). Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4. Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538).DOMAIN The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1 (By similarity). Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface.DOMAIN The N-terminus binds InsP6 with low affinity.DOMAIN The C-terminus binds InsP6 with high affinity.PTM Constitutively phosphorylated at Ser-412 in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and ADRB2 endocytosis but not for ADRB2 binding and desensitization. Once internalized, is rephosphorylated.PTM The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33.SIMILARITY Belongs to the arrestin family.UniProtP494071EQUAL418EQUALReactome Database ID Release 75264470Database 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=264470ReactomeR-HSA-2644701Reactome 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-264470.1ARRB2Beta-arrestin-2ARRB2_HUMANReactome DB_ID: 416464UniProt:P32121 ARRB2ARRB2ARB2ARR2FUNCTION Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and P2RY11 and ATP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 and subsequent recycling or degradation. Involved in ubiquitination of IGF1R. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for the AKT1 pathway. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Increases ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Involved in CCR7-mediated ERK1/2 signaling involving ligand CCL19. Is involved in type-1A angiotensin II receptor/AGTR1-mediated ERK activity. Is involved in type-1A angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. Involved in AGTR1-mediated chemotaxis. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. Suppresses UV-induced NF-kappa-B-dependent activation by interacting with CHUK. The function is promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. Involved in p53/TP53-mediated apoptosis by regulating MDM2 and reducing the MDM2-mediated degradation of p53/TP53. May serve as nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved in regulation of gene expression during the early processes of fertilization. Also involved in regulation of receptors other than GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates TGF-beta signaling such as NF-kappa-B activation. Involved in endocytosis of low-density lipoprotein receptor/LDLR. Involved in endocytosis of smoothened homolog/Smo, which also requires GRK2. Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and subsequent TGF-beta-mediated ERK activation and migration of epithelial cells. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in insulin resistance by acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in IL8-mediated granule release in neutrophils. Involved in the internalization of the atypical chemokine receptor ACKR3. Acts as an adapter protein coupling FFAR4 receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:23809162). During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of proinflammatory cytokine release and inhibition of inflammation (PubMed:23809162).SUBUNIT Homooligomer; the self-association is mediated by InsP6-binding (Probable). Heterooligomer with ARRB1; the association is mediated by InsP6-binding. Interacts with ADRB2 AND CHRM2. Interacts with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. Interacts with SRC. Interacts with DUSP16; the interaction is interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts with RELA. Interacts with MDM2; the interaction is enhanced by activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6. Interacts with IGF1R. Interacts with ENG. Interacts with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with SMO (activated). Interacts with GSK3A and GSK3B. Associates with protein phosphatase 2A (PP2A) (By similarity). Interacts with DHX8; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with GAPDHS; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with H2AFX; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with KIF14; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with RCC1; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with CXCR4; the interaction is dependent on C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4. Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538). Interacts (via NACHT and LRR domains) with NLRP3; this interaction is direct and inducible by omega-3 polyunsaturated fatty acids (PUFAs) (PubMed:23809162). Interacts with FFAR4 (via C-terminus); this interaction is stimulated by long-chain fatty acids (LCFAs) (PubMed:22282525).DOMAIN The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1.PTM Phosphorylated at Thr-382 in the cytoplasm; probably dephosphorylated at the plasma membrane. The phosphorylation does not regulate internalization and recycling of ADRB2, interaction with clathrin or AP2B1.PTM The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33. Stimulation of a class B GPCR promotes a sustained ubiquitination.PTM Hydroxylation by PHD2 modulates the rate of internalization by slowing down recruitment to the plasma membrane and inhibiting subsequent co-internalization with class A receptors.SIMILARITY Belongs to the arrestin family.UniProtP321211EQUAL409EQUALReactome Database ID Release 75416464Database 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=416464ReactomeR-HSA-4164641Reactome 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-416464.1Reactome Database ID Release 751911410Database 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=1911410ReactomeR-HSA-19114101Reactome 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-1911410.1SMO dimer:ARRB:KIF3AReactome DB_ID: 5632599111Reactome Database ID Release 755632599Database 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=5632599ReactomeR-HSA-56325991Reactome 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-5632599.1Reactome Database ID Release 755632667Database 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=5632667ReactomeR-HSA-56326671Reactome 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-5632667.123877428Pubmed2013Interaction of smoothened with integrin-linked kinase in primary cilia mediates Hedgehog signallingBarakat, BadiaYu, LiangLo, CamdenVu, DucDe Luca, ElisabettaCain, Jason EMartelotto, Luciano GMartellotto, Luciano GDedhar, ShoukatSadler, Anthony JWang, DieWatkins, D NeilHannigan, Gregory EEMBO Rep. 14:837-4418497258Pubmed2008Beta-arrestin-mediated localization of smoothened to the primary ciliumKovacs, Jeffrey JWhalen, Erin JLiu, RenshuiXiao, KunhongKim, JiheeChen, MinyongWang, JiangboChen, WeiLefkowitz, Robert JScience 320:1777-81LEFT-TO-RIGHTSMO translocates to the ciliumBinding of ligand to the PTCH receptor activates the Hh signaling pathway and results in the accumulation of SMO in the primary cilium (Denef et al, 2000; Corbit et al, 2005; Rohatgi et al, 2007; Milenkovic et al, 2009; Wang et al, 2009; Wilson et al, 2009; reviewed in Briscoe and Therond, 2013). Neither the mechanism for how PTCH represses SMO in the absence of ligand nor how this relief is lifted upon pathway activation are fully understood, however SMO translocation to the cilium appears to depend upon complex formation with beta-arrestin proteins and the anterograde motor protein KIF3A (Chen et al, 2004; Kovacs et al, 2008). GAS8, a SMO- and microtubule-binding protein, is also required for the ciliary localization of SMO, although the mechanism is not clear (Evron et al, 2011; reviewed in Evron et al, 2012). In response to pathway activation, SMO is phosphorylated in a CKI- and ADRBK1/GRK2-dependent fashion and undergoes a conformational change, both of which are required for downstream pathway activation; accumulation of SMO in the cilium is in itself not sufficient (Chen et al, 2011; Zhao et al, 2007; Chen et al, 2010; Rohatgi et al, 2009). In the primary cilium, SMO interacts with the Ellis-van Creveld syndrome proteins 1 and 2 (EVC1 and 2) in a SMO phosphorylation-dependent manner, and the interaction with EVC1 and 2 is required for downstream signal propagation (Yang et al, 2012; Dorn et al, 2012; Capparos-Martin et al, 2013; Pusapati et al, 2014; Yang et al, 2012). SMO activation results in the concentration of SUFU and the GLI proteins in the cilium, the dissociation of the SUFU:GLI complex and the nuclear accumulation of the full length activator form of the GLI proteins (reviewed in Briscoe and Therond, 2013).Authored: Rothfels, Karen, 2014-08-06Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30SMO dimerReactome DB_ID: 5632597ciliary membraneGENE ONTOLOGYGO:0060170SMOSmoothened homologSMO_HUMANReactome DB_ID: 562409428EQUAL787EQUALReactome Database ID Release 755624094Database 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=5624094ReactomeR-HSA-56240941Reactome 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-5624094.12Reactome Database ID Release 755632597Database 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=5632597ReactomeR-HSA-56325971Reactome 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-5632597.1Reactome Database ID Release 755632668Database 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=5632668ReactomeR-HSA-56326683Reactome 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-5632668.317960137Pubmed2007Hedgehog regulates smoothened activity by inducing a conformational switchZhao, YTong, CJiang, JNature 450:252-822986504Pubmed2012Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2Yang, CuipingChen, WenlinChen, YongbinJiang, JinCell Res. 22:1593-60420844016Pubmed2010G 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. 24:2054-6710966113Pubmed2000Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothenedDenef, NNeubüser, DPerez, LCohen, SMCell 102:521-3123719536Pubmed2013The mechanisms of Hedgehog signalling and its roles in development and diseaseBriscoe, JamesThérond, Pascal PNat. Rev. Mol. Cell Biol. 14:416-2916136078Pubmed2005Vertebrate Smoothened functions at the primary ciliumCorbit, Kevin CAanstad, PiaSingla, VeenaNorman, Andrew RStainier, Didier Y RReiter, Jeremy FNature 437:1018-2115618519Pubmed2004Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2Chen, WeiRen, Xiu-RongNelson, Christopher DBarak, Larry SChen, James KBeachy, Philip Ade Sauvage, FredericLefkowitz, Robert JScience 306:2257-6021659505Pubmed2011Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signalingEvron, TamaPhilipp, MelanieLu, JiuyiMeloni, Alison RBurkhalter, MartinChen, WeiCaron, Marc GJ. Biol. Chem. 286:27676-8623026747Pubmed2013The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary ciliaCaparrós-Martín, Jose AValencia, MaríaReytor, EdelPacheco, MaríaFernandez, MargaritaPerez-Aytes, AntonioGean, EstherLapunzina, PabloPeters, HeikoGoodship, Judith ARuiz-Perez, Victor LHum. Mol. Genet. 22:124-3922277298Pubmed2012GRK2: multiple roles beyond G protein-coupled receptor desensitizationEvron, TamaDaigle, Tanya LCaron, Marc GTrends Pharmacol. Sci. 33:154-6419948480Pubmed2009Lateral transport of Smoothened from the plasma membrane to the membrane of the ciliumMilenkovic, LjiljanaScott, Matthew PRohatgi, RajatJ. Cell Biol. 187:365-7417641202Pubmed2007Patched1 regulates hedgehog signaling at the primary ciliumRohatgi, RajatMilenkovic, LjiljanaScott, Matthew PScience 317:372-619196978Pubmed2009Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulationWang, YZhou, ZheWalsh, Christopher TMcMahon, Andrew PProc. Natl. Acad. Sci. U.S.A. 106:2623-821695114Pubmed2011Sonic 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:e100108324582806Pubmed2014EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary ciliaPusapati, Ganesh VHughes, Casey EDorn, Karolin VZhang, DapengSugianto, PriscillaAravind, LRohatgi, RajatDev. Cell 28:483-9619365551Pubmed2009Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary ciliumWilson, Christopher WChen, Miao-HsuehChuang, Pao-TienPLoS ONE 4:e518222981989Pubmed2012A Smoothened-Evc2 complex transduces the Hedgehog signal at primary ciliaDorn, Karolin VHughes, Casey ERohatgi, RajatDev. Cell 23:823-3519218434Pubmed2009Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation processRohatgi, RajatMilenkovic, LjiljanaCorcoran, Ryan BScott, Matthew PProc. Natl. Acad. Sci. U.S.A. 106:3196-201ACTIVATIONReactome Database ID Release 755633056Database 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=5633056ReactomeR-HSA-56330561Reactome 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-5633056.1GAS8Reactome DB_ID: 5633057UniProt:O95995 GAS8GAS8DRC4GAS11FUNCTION Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Plays an important role in the assembly of the N-DRC linker (By similarity). Plays dual roles at both the primary (or non-motile) cilia to regulate hedgehog signaling and in motile cilia to coordinate cilia movement. Required for proper motile cilia functioning (PubMed:26387594, PubMed:27120127, PubMed:27472056). 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 in a GRK2-dependent manner (By similarity).SUBUNIT Component of the nexin-dynein regulatory complex (N-DRC). Interacts with microtubules (By similarity). Interacts with SMO (PubMed:21659505). Interacts (via coiled-coil domains) with RAB3B (in GTP-bound form) (By similarity).TISSUE SPECIFICITY Expressed in respiratory epithelial cells (at protein level) (PubMed:26387594). Expressed in the heart, skeletal muscle, pancreas, liver, brain, trachea and lung. Weakly or not expressed in placenta and kidney (PubMed:9790751).SIMILARITY Belongs to the DRC4 family.UniProtO959951EQUAL478EQUALReactome Database ID Release 755633057Database 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=5633057ReactomeR-HSA-56330571Reactome 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-5633057.1ACTIVATIONReactome Database ID Release 755632694Database 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=5632694ReactomeR-HSA-56326941Reactome 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-5632694.1Hh-Npp:CDON:PTCHReactome DB_ID: 5632590CDOCDONCell adhesion molecule-related/down-regulated by oncogenes precursorCDON_HUMANReactome DB_ID: 197892plasma membraneGENE ONTOLOGYGO:0005886UniProt:Q4KMG0 CDONCDONCDOFUNCTION Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells (By similarity).SUBUNIT Part of a complex that contains BOC, CDON, NEO1, cadherins and CTNNB1. Interacts with NTN3 (By similarity). Interacts with PTCH1 (By similarity). Interacts with GAS1 (By similarity). Interacts with DHH, IHH and SHH.PTM N-glycosylated.UniProtQ4KMG026EQUAL1287EQUALReactome Database ID Release 75197892Database 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=197892ReactomeR-HSA-1978921Reactome 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-197892.11Converted from EntitySet in ReactomeHh-Nppdelipidated Hh-NpReactome DB_ID: 5362783SHHSHH(34-?)Sonic hedgehog protein N productSHH_HUMANReactome DB_ID: 5362776extracellular regionGENE ONTOLOGYGO:0005576UniProt:Q15465 SHHSHHSUBUNIT Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus (By similarity). ShhNp is active as a multimer (PubMed:24522195). Interacts with BOC and CDON (By similarity). Interacts with HHIP (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3 (By similarity).SIMILARITY Belongs to the hedgehog family.CAUTION The several steps and mechanisms that permit controlled Shh dispersion and gradient formation remain controversial. The ShhNC C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity resulting in the cleavage and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN). The protein is further modified by covalent addition of palmitate at the N-terminal of ShhN, resulting to the dual-lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane where it forms multimers. Further solubilization and release from the cell surface seem to be achieved through different mechanisms, including the interaction with DISP1 and SCUBE2, movement by lipoprotein particles, transport by cellular extensions called cytonemes or by proteolytic removal of both terminal lipidated peptides (PubMed:26875496). Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range.UniProtQ1546534EQUAL-1EQUALReactome Database ID Release 755362776Database 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=5362776ReactomeR-HSA-53627761Reactome 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-5362776.1DHHDHH(33-?)Desert hedgehog protein N productDHH_HUMANReactome DB_ID: 5362781UniProt:O43323 DHHDHHFUNCTION Intercellular signal essential for a variety of patterning events during development. May function as a spermatocyte survival factor in the testes. Essential for testes development.SUBUNIT Interacts with BOC and CDON. Interacts with HHIP.DOMAIN The desert hedgehog protein N-product binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.PTM The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (N-product). This covalent modification appears to play an essential role in restricting the spatial distribution of the protein activity to the cell surface. The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity (By similarity).SIMILARITY Belongs to the hedgehog family.UniProtO4332333EQUAL-1EQUALReactome Database ID Release 755362781Database 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=5362781ReactomeR-HSA-53627811Reactome 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-5362781.1IHHIndian hedgehog protein N productIHHIHH_HUMANReactome DB_ID: 5362778UniProt:Q14623 IHHIHHFUNCTION Intercellular signal essential for a variety of patterning events during development. Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Implicated in endochondral ossification: may regulate the balance between growth and ossification of the developing bones. Induces the expression of parathyroid hormone-related protein (PTHRP) (By similarity).SUBUNIT Homooligomer (indian hedgehog protein N-product). Interacts with BOC and CDON. Interacts with PTCH1. Interacts with glypican GPC3 (By similarity).TISSUE SPECIFICITY Expressed in embryonic lung, and in adult kidney and liver.DOMAIN The indian hedgehog protein N-product binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.PTM The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity (By similarity).PTM Cholesterylation is required for N-product targeting to lipid rafts and multimerization.PTM Palmitoylated. N-palmitoylation is required for N-product multimerization and full activity.SIMILARITY Belongs to the hedgehog family.UniProtQ1462328EQUAL202EQUALReactome Database ID Release 755362778Database 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=5362778ReactomeR-HSA-53627782Reactome 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-5362778.2Reactome Database ID Release 755362783Database 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=5362783ReactomeR-HSA-53627831Reactome 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-5362783.11PTCH1Patched homolog 1Protein patched homolog 1PTC1_HUMANReactome DB_ID: 5610415UniProt:Q13635 PTCH1PTCH1PTCHFUNCTION Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.SUBUNIT Interacts with SNX17 (PubMed:15769472). Interacts with IHH (PubMed:21537345). Interacts with G-protein coupled receptor GPR37L1 (By similarity).TISSUE SPECIFICITY In the adult, expressed in brain, lung, liver, heart, placenta, skeletal muscle, pancreas and kidney. Expressed in tumor cells but not in normal skin.DEVELOPMENTAL STAGE In the embryo, found in all major target tissues of sonic hedgehog, such as the ventral neural tube, somites, and tissues surrounding the zone of polarizing activity of the limb bud.PTM Glycosylation is necessary for SHH binding.PTM In the absence of Hh ligands, ubiquitination by ITCH at Lys-1426 promotes endocytosis and both proteasomal and lysosomal degradation.SIMILARITY Belongs to the patched family.UniProtQ136351EQUAL1447EQUALReactome Database ID Release 755610415Database 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=5610415ReactomeR-HSA-56104151Reactome 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-5610415.11Reactome Database ID Release 755632590Database 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=5632590ReactomeR-HSA-56325901Reactome 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-5632590.1ACTIVATIONReactome Database ID Release 755632696Database 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=5632696ReactomeR-HSA-56326961Reactome 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-5632696.1Hh-Npp:BOC:PTCH1Reactome DB_ID: 56325881BOC:PTCH1Reactome DB_ID: 5632584BOCBrother of CDOBOC_HUMANReactome DB_ID: 445450UniProt:Q9BWV1 BOCBOCUNQ604/PRO1190FUNCTION Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells.SUBUNIT Part of a complex that contains BOC, CDON, NEO1, cadherins and CTNNB1. Interacts with NTN3 (By similarity). Interacts with SHH, DHH and IHH. Interacts with CDH2 and CTNNB1. Interacts with CDH15 only during the early stages of myoblast differentiation.TISSUE SPECIFICITY Detected in skeletal muscle, heart, thymus, kidney and small intestine. Detected at lower levels in brain, placenta, lung and colon mucosa.PTM N-glycosylated.MISCELLANEOUS The C-terminal cytoplasmic domain is not required for the stimulation of myogenesis.UniProtQ9BWV131EQUAL1114EQUALReactome Database ID Release 75445450Database 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=445450ReactomeR-HSA-4454501Reactome 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-445450.111Reactome Database ID Release 755632584Database 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=5632584ReactomeR-HSA-56325841Reactome 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-5632584.11Reactome Database ID Release 755632588Database 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=5632588ReactomeR-HSA-56325881Reactome 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-5632588.1ACTIVATIONactiveUnit: #Protein3activeUnit: #Protein1Reactome Database ID Release 755632690Database 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=5632690ReactomeR-HSA-56326902Reactome 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-5632690.2ACTIVATIONReactome Database ID Release 755632691Database 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=5632691ReactomeR-HSA-56326911Reactome 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-5632691.1Hh-Npp:GAS1:PTCHReactome DB_ID: 56325921GAS1Growth arrest-specific protein 1GAS1_HUMANReactome DB_ID: 449167UniProt:P54826 GAS1GAS1FUNCTION Specific growth arrest protein involved in growth suppression. Blocks entry to S phase. Prevents cycling of normal and transformed cells.UniProtP5482640EQUAL318EQUALReactome Database ID Release 75449167Database 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=449167ReactomeR-HSA-4491671Reactome 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-449167.111Reactome Database ID Release 755632592Database 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=5632592ReactomeR-HSA-56325921Reactome 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-5632592.1LEFT-TO-RIGHTCSNK1A1 binds SMO dimerActivation of SMO in vertebrate cells depends upon its sequential phosphorylation by CSNK1A1/CK1alpha and ADRBK1/GRK2 kinases. Phosphorylation is thought to promote a conformational change in the SMO C-terminal tails, destabilizing an intramolecular interaction within the tail and promoting a more open conformation that brings the two tails of the SMO dimer into closer proximity (Chen et al, 2010; Chen et al, 2011; Wilson et al, 2009). This mechanism parallels the activation of Smo in Drosophila, where phosphorylation of consensus PKA and CK1 sites in the C-terminus promotes conformational change (Zhao et al, 2007). In both Drosophila and vertebrates, the kinases interact with SMO as assessed by co-precipitation (Zhao et al, 2007; Chen et al, 2010; Chen et al, 2011). In vertebrate cells, SHH stimulation appears to promote a 2-step activation of SMO. In the first step, CSNK1A1 binds to the C-terminal tails in the closed conformation. Initial CSNK1A1-mediated phosphorylation promotes the open conformation and increases the binding affinity of both CSNK1A1 and ADRBK1/GRK2 for the SMO tail, establishing a positive feedback loop to enhance SMO phosphorylation (Chen et al, 2010; Chen et al, 2011; Meloni et al 2006; Philipp et al, 2008). CSNK1A1 accumulates in the primary cilium in an SHH-dependent manner, and the kinetics of SMO phosphorylation are faster there than in the whole cell. Phosphorylation also depends on the kinesin II ciliary motor KIF3A, and promotes the ciliary accumulation of SMO, possibly in a ARRB-dependent manner (Chen et al, 2011; Meloni et al, 2006). Authored: Rothfels, Karen, 2014-10-24Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30CSNK1A1CK1alphaCSNK1A1Reactome DB_ID: 5632507ciliumGENE ONTOLOGYGO:0005929UniProt:P48729 CSNK1A1CSNK1A1FUNCTION 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 Database ID Release 755632507Database 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=5632507ReactomeR-HSA-56325072Reactome 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-5632507.2SMO dimer:CSNK1A1Reactome DB_ID: 563260211Reactome Database ID Release 755632602Database 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=5632602ReactomeR-HSA-56326021Reactome 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-5632602.1Reactome Database ID Release 755632671Database 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=5632671ReactomeR-HSA-56326711Reactome 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-5632671.116908539Pubmed2006Smoothened 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 19:5478-89LEFT-TO-RIGHT2.7.11CSNK1A1 phosphorylates SMO dimerInitial activation of SMO in response to HH occurs with the CSNK1A1-mediated phosphorylation of serine and threonine residues in the C-terminal tail. While many potential CSNK1A1 target residues have been identified in in vitro assays, residues S588, S590, T593 and S595 in the S0 region appear to be the most critical for function (Chen et al, 2011). Initial phosphorylation increases the affinity of the C-terminal tail for both CSNK1A1 and ADRBK1/GRK2, establishing a positive feedback mechanism that promotes further phosphorylation. CSNK1A1 and ADRBK1-mediated phosphorylation is thought to promote an open, activated conformation of the C-terminal tails, analogous to that in Drosophila Smo upon pathway activation (Chen et al, 2011; Chen et al, 2010; Zhao et al, 2007).Authored: Rothfels, Karen, 2014-10-24Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 5632460ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 755632460Database 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=5632460ReactomeR-ALL-56324604Reactome 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-5632460.4COMPOUNDC00002additional informationMIMI:03618ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 5632457ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 755632457Database 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=5632457ReactomeR-ALL-56324574Reactome 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-5632457.4COMPOUNDC000088pS588,S590, T593, S595-SMO dimer:CSNK1A1Reactome DB_ID: 5632624pS588, S590, T593, S595-SMO dimerReactome DB_ID: 5632621SMO_HUMANpS588, S590, T593, S595-SMOSmoothened homologReactome DB_ID: 5632525588EQUALO-phospho-L-serineMODMOD:00046590EQUAL593EQUALO-phospho-L-threonineMODMOD:00047595EQUAL28EQUAL787EQUALReactome Database ID Release 755632525Database 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=5632525ReactomeR-HSA-56325251Reactome 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-5632525.12Reactome 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-5632621.111Reactome 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-5632624.1ACTIVATIONactiveUnit: #Protein16GENE ONTOLOGYGO:0004674gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 755632631Database 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=5632631Reactome Database ID Release 755632670Database 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=5632670ReactomeR-HSA-56326701Reactome 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-5632670.1LEFT-TO-RIGHTADRBK1 binds phosphorylated SMO dimerInitial binding and phosphorylation of the SMO C-terminal tail by CSNK1A1 increases the affinity of the tail for ADRBK1/GRK2. Like CSNK1A1, ADRBK1 phosphorylates multiple sites in the SMO tail in a Hh-dependent manner, and this phosphorylation is required for a conformational change that promotes closer association of the two tails in the SMO dimer, analogous to what is seen in Drosophila (Chen et al, 2011; Chen et al, 2010; Zhao et al, 2007; Meloni et al, 2006; Philipp et al, 2008).Authored: Rothfels, Karen, 2014-10-28Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30GRK2ADRBK1BARKBARK1Reactome DB_ID: 5632504UniProt:P25098 GRK2GRK2ADRBK1BARKBARK1FUNCTION 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.UniProtP250981EQUAL689EQUALReactome Database ID Release 755632504Database 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=5632504ReactomeR-HSA-56325042Reactome 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-5632504.2pS588, S590, T593, S595-SMO dimer:CSNK1A1:ADRBK1Reactome DB_ID: 563262211Reactome 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 Database ID Release 755632674Database 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=5632674ReactomeR-HSA-56326741Reactome 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-5632674.1LEFT-TO-RIGHT2.7.11ADRBK1 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, 2014-10-306p6S, T-SMO dimer:CSNK1A1:ADRBK1Reactome DB_ID: 56326151p6S, T-SMO dimerpS588, S590, T593, S595, S611, S615, S616-SMO dimerReactome DB_ID: 5632614SMO_HUMANpS588, S590, T593, S595, S611, S615, S616-SMOSmoothened homologReactome DB_ID: 5632528611EQUAL615EQUAL616EQUAL28EQUAL787EQUALReactome Database ID Release 755632528Database 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=5632528ReactomeR-HSA-56325281Reactome 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-5632528.12Reactome 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-5632614.111Reactome 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-5632615.16ACTIVATIONactiveUnit: #Protein18Reactome 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-5632672.115691767Pubmed2005Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptusZhang, WZhao, YTong, CWang, GWang, BJia, JJiang, JDev Cell 8:267-7814636583Pubmed2003Hedgehog 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 12:1261-7424845016Pubmed2014G-protein-coupled receptors, Hedgehog signaling and primary ciliaMukhopadhyay, SaikatRohatgi, RajatSemin. Cell Dev. Biol.14614827Pubmed2003Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2Ogden, SKAscano M, JrStegman, MASuber, LMHooper, JERobbins, DJCurr Biol 13:1998-200316630821Pubmed2006The 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, SYElifee02555LEFT-TO-RIGHTCSNK1A1 and ADRBK1 dissociate from p-SMO dimerAfter phosphorylating the SMO dimer, CSNK1A1 and ADRBK1 presumably dissociate, although this has not been demonstrated explicitly (Chen et al, 2011).Authored: Rothfels, Karen, 2014-10-28Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30Reactome Database ID Release 755633040Database 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=5633040ReactomeR-HSA-56330401Reactome 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-5633040.1LEFT-TO-RIGHTEFCAB7:IQCE binds EVC2:EVCIQCE and EFCAB7 are ciliary proteins that are required to restrict the EVC2:EVC complex to the 'EVC region' at the base of the cilium, just distal to the transition zone (Pusapati et al, 2014). EVC2 and EVC are transmembrane proteins that form a ciliary-localized complex that is a positive regulator of Hh signal transduction. The EVC2:EVC complex appears to act downstream of both SMO ciliary localization and its activation by CSNK1A1 and ADRBK1, and is required for the dissociation of the GLI:SUFU complex at the ciliary tip, although the mechanism for this is not known (Blair et al, 2011; Dorn et al, 2012; Capparos-Martin et al, 2013; Pusapati et al, 2014). EVC2 interacts with the IQCE:EFCAB7 subcomplex through the so called 'W-peptide', a stretch of amino acids in the intracellular tail that is deleted in the ciliopathy Weyers Acrofacial Dysostosis. Deletion of the W-peptide results in mislocalization of EVC2 throughout the length of the cilium, rather than being concentrated in the 'EVC zone' (Pusapati et al, 2014; Dorn et al, 2012; Capparos-Martin et al, 2011). EVC2:EVC localization to the EVC region, mediated by the IQCE:EFCAB7 complex and the W-peptide, is required for the Hh-dependent activation of full-length GLI2, but does not appear to critical for the regulation of GLI3R levels, suggesting a bifurcation of the pathway (Pusapati et al, 2014).Authored: Rothfels, Karen, 2014-10-28Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30EVC2:EVCReactome DB_ID: 5633041EVCDWF1Reactome DB_ID: 5633035UniProt:P57679 EVCEVCFUNCTION Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Involved in endochondral growth and skeletal development.SUBUNIT Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts with EVC2. Interacts with EFCAB7. Interacts with IQCE.TISSUE SPECIFICITY Found in the developing vertebral bodies, ribs, upper and lower limbs, heart, kidney, lung.UniProtP576791EQUAL992EQUALReactome Database ID Release 755633035Database 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=5633035ReactomeR-HSA-56330351Reactome 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-5633035.11EVC2LIMBINReactome DB_ID: 5633038UniProt:Q86UK5 EVC2EVC2LBNFUNCTION Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Plays a critical role in bone formation and skeletal development. May be involved in early embryonic morphogenesis.SUBUNIT Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts with EVC. Interacts (via N-terminal end) with EFCAB7. Interacts (via N-terminal end) with IQCE.TISSUE SPECIFICITY Found in the heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.UniProtQ86UK527EQUAL1308EQUALReactome Database ID Release 755633038Database 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=5633038ReactomeR-HSA-56330381Reactome 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-5633038.11Reactome Database ID Release 755633041Database 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=5633041ReactomeR-HSA-56330411Reactome 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-5633041.1EFCAB7:IQCEReactome DB_ID: 5633045IQCEReactome DB_ID: 5633055UniProt:Q6IPM2 IQCEIQCEKIAA1023FUNCTION Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling (By similarity). Required for proper limb morphogenesis (PubMed:28488682).SUBUNIT Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts (via N-terminus) with EFCAB7 (via EF-hands 1 and 2); this interaction anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia and stimulates the Hedgehog (Hh) pathway. Interacts with EVC2 (via N-terminal end). Interacts with EVC.UniProtQ6IPM21EQUAL695EQUALReactome Database ID Release 755633055Database 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=5633055ReactomeR-HSA-56330552Reactome 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-5633055.21EFCAB7Reactome DB_ID: 5633043UniProt:A8K855 EFCAB7EFCAB7KIAA1799FUNCTION Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Required for the localization of the EVC2:EVC subcomplex at the base of primary cilia.SUBUNIT Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts (via EF-hand 1 and 2) with IQCE (via N-terminus); this interaction anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia and stimulates the Hedgehog (Hh) pathway. Interacts with EVC2 (via N-terminal end). Interacts with EVC.UniProtA8K8551EQUAL629EQUALReactome Database ID Release 755633043Database 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=5633043ReactomeR-HSA-56330432Reactome 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-5633043.21Reactome Database ID Release 755633045Database 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=5633045ReactomeR-HSA-56330452Reactome 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-5633045.2IQCE:EFCAB7:EVC2:EVCReactome DB_ID: 563305011Reactome Database ID Release 755633050Database 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=5633050ReactomeR-HSA-56330501Reactome 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-5633050.1Reactome Database ID Release 755633051Database 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=5633051ReactomeR-HSA-56330511Reactome 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-5633051.121356043Pubmed2011Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleusBlair, Helen JTompson, StuartLiu, Yu-NingCampbell, JenniferMacArthur, KatiePonting, Chris PRuiz-Perez, Victor LGoodship, Judith ABMC Biol. 9:14LEFT-TO-RIGHTEVC2:EVC binds p-SMOEVC2 and EVC are components of a complex that localizes to the base of the cilium in a so-called EvC zone just distal to the transition zone. Mutations in the genes for EVC2 and EVC are associated with the ciliopathy Ellis van Creveld syndrome and result in an abrogated response to stimulation by Hh, making EVC2 and EVC positive regulators of Hh signaling (Blair et al, 2011; Dorn et al, 2012; Caparros-Martin et al, 2013). The EVC2:EVC complex interacts with SMO in the cilium after Hh stimulation and restricts SMO localization to the EvC zone (Dorn et al, 2012; Yang et al, 2012; Caparros-Martin et al, 2013). Disruption of the EVC2:EVC complex does not interfere with SMO ciliary localization or its activation by CSNK1A1 and ADRBK1, but prevents the Hh-dependent localization of the GLI transcription factors to the tip of the cilium and abrogates the dissociation of the GLI:SUFU complex (Dorn et al, 2012; Yang et al, 2012; Caparros-Martin et al, 2013). These events are required for the activation of the GLI transcription factors in response to ligand stimulation. Localization of the EVC2:EVC complex to the EVC zone depends on an interaction between the EVC2 W peptide (a stretch of 43 amino-acids in the C-terminal tail that is missing in a disease associated EVC2-variant), and the IQCE:EFCAB7 complex. Abrogation of this interaction causes the EVC2:EVC complex to localize along the length of the cilium and disrupts production and nuclear translocation of the full length GLI2 transcriptional activator (Pusapati et al, 2014). How the Hh signal is transmitted from the SMO:EVC2:EVC complex to downstream components is not known.Authored: Rothfels, Karen, 2014-10-24Reviewed: Liu, Yulu Cherry, 2014-11-09Edited: Gillespie, Marc E, 2014-10-30p6S, T-SMO dimer:EVC2:EVCReactome DB_ID: 563303911Reactome Database ID Release 755633039Database 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=5633039ReactomeR-HSA-56330391Reactome 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-5633039.1Reactome Database ID Release 755632679Database 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=5632679ReactomeR-HSA-56326791Reactome 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-5632679.1Reactome Database ID Release 755635838Database 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=5635838ReactomeR-HSA-56358381Reactome 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-5635838.119081070Pubmed2008Hedgehog signaling in development and cancerJiang, JinHui, Chi-ChungDev. Cell 15:801-1223079593Pubmed2012Hedgehog signaling and the cilium: in the zoneEggenschwiler, JonathanDev. Cell 23:677-816339192Pubmed2006Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebratesHuangfu, DAnderson, KVDevelopment 133:3-1420412775Pubmed2010The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase NotumAyers, Katie LGallet, ArmelStaccini-Lavenant, LaurenceThérond, Pascal PDev. Cell 18:605-2016459297Pubmed2006Divergence of hedgehog signal transduction mechanism between Drosophila and mammalsVarjosalo, MarkkuLi, Song-PingTaipale, JussiDev. Cell 10:177-8620395968Pubmed2010The primary cilium: a signalling centre during vertebrate developmentGoetz, Sarah CAnderson, Kathryn VNat. Rev. Genet. 11:331-4419906846Pubmed2009Patched regulates Smoothened trafficking using lipoprotein-derived lipidsKhaliullina, HelenaPanáková, DanielaEugster, ChristinaRiedel, FalkoCarvalho, MariaEaton, SuzanneDevelopment 136:4111-2121801010Pubmed2011Gli proteins in development and diseaseHui, Chi-ChungAngers, SAnnu. Rev. Cell Dev. Biol. 27:513-3717762891Pubmed2007Patching the gaps in Hedgehog signallingRohatgi, RajatScott, Matthew PNat. Cell Biol. 9:1005-912192414Pubmed2002Patched acts catalytically to suppress the activity of SmoothenedTaipale, JCooper, M KMaiti, TBeachy, P ANature 418:892-7