BioPAX pathway converted from "Decay of mRNA in SMG6:SMG5:SMG7:mRNA complex" in the Reactome database.LEFT-TO-RIGHTDecay of mRNA in SMG6:SMG5:SMG7:mRNA complexSMG6 endonucleolytically cleaves an mRNA it is believed that the resulting fragments are degraded by exonucleases, possibly XRN1, a 5'-to-3' nuclease, and the exosome complex, a 3'-to-5' nuclease (Huntzinger et al. 2008, Eberle et al. 2009). Inhibition of XRN1 is observed to cause accumulation of SMG6-cleaved intermediates therefore XRN1 is postulated to act downstream of SMG6 (Huntzinger et al. 2008).<br>In general, during Nonsense-Mediated Decay mRNAs are observed to be deadenlyated (implicating the PAN2 complex, PARN complex, and CCR4 complex), decapped (implicating the DCP1:DCP2 complex), and exoribonucleolytically digested (implicating the XRN1 5'-to-3' exonuclease and exosome 3'-to-5' exonuclease) (Lykke-Andersen 2002, Chen et al. 2003, Lejeune et al. 2003, Couttet and Grange 2004, Unterholzner and Izaurralde 2004, Yamashita et al. 2005). UPF1 is observed to associate with the decapping enzymes DCP1a and DCP2, however the specific decay reactions that occur after SMG6, SMG5 and SMG7 have associated with an mRNA are unknown (Lykke-Andersen et al. 2002). Likewise, SMG6 may be present in complexes separate from SMG5 and SMG7 and these complexes may have different routes of decay (reviewed in Nicholson et al. 2010, Muhlemann and Lykke-Andersen 2010).<br>ATPase activity of UPF1 is necessary for NMD and may reflect ATP-dependent helicase activity that disassembles the mRNA-protein complex (Franks et al. 2010). UPF1 must be dephosphorylated by PP2A for NMD to continue (Ohnishi et al. 2003, Chiu et al. 2003). Presumably the dephosphoryation recycles UPF1 for interaction with other mRNA complexes.Authored: May, B, 2010-08-06Reviewed: Neu-Yilik, G, 2011-05-19Edited: May, B, 2010-08-06mRNA Cleaved by SMG6Reactome DB_ID: 927845cytosolGENE ONTOLOGYGO:0005829SMG7Protein SMG7SMG7_HUMANReactome DB_ID: 927838UniProt:Q92540 SMG7SMG7C1orf16EST1CKIAA0250FUNCTION Plays a role in nonsense-mediated mRNA decay. Recruits UPF1 to cytoplasmic mRNA decay bodies. Together with SMG5 is thought to provide a link to the mRNA degradation machinery involving exonucleolytic pathways, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation.SUBUNIT Part of a complex that contains SMG5, SMG7, PPP2CA, a short isoform of UPF3A (isoform UPF3AS, but not isoform UPF3AL) and phosphorylated UPF1.Homo sapiensNCBI Taxonomy9606UniProtQ925401EQUAL1137EQUALReactome Database ID Release 71927838Database 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=927838ReactomeR-HSA-9278381Reactome 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-927838.1Reactomehttp://www.reactome.org1SMG6Telomerase-binding protein EST1AEST1A_HUMANReactome DB_ID: 927851UniProt:Q86US8 SMG6SMG6C17orf31EST1AKIAA0732FUNCTION Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini (PubMed:19179534). May have a general role in telomere regulation (PubMed:12676087, PubMed:12699629). Promotes in vitro the ability of TERT to elongate telomeres (PubMed:12676087, PubMed:12699629). Overexpression induces telomere uncapping, chromosomal end-to-end fusions (telomeric DNA persists at the fusion points) and did not perturb TRF2 telomeric localization (PubMed:12676087, PubMed:12699629). Binds to the single-stranded 5'-(GTGTGG)(4)GTGT-3' telomeric DNA, but not to a telomerase RNA template component (TER) (PubMed:12676087, PubMed:12699629).FUNCTION Plays a role in nonsense-mediated mRNA decay (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788). Is thought to provide a link to the mRNA degradation machinery as it has endonuclease activity required to initiate NMD, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788). Degrades single-stranded RNA (ssRNA), but not ssDNA or dsRNA (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788).SUBUNIT May form homooligomers (PubMed:20930030). Associated component of the telomerase holoenzyme complex (PubMed:19179534). Interacts with TERT, independently of the telomerase RNA (PubMed:12676087, PubMed:12699629). Interacts with SMG1, SMG5, SMG7, UPF1, UPF2, UPF3B and the PP2A catalytic subunits (PubMed:12554878, PubMed:19060897, PubMed:20930030). Also interacts with the exon junction complex (EJC) composed at least of CASC3, EIF4A3, MAGOH and RBM8A; required for the process of nonsense-mediated mRNA decay (PubMed:20930030).TISSUE SPECIFICITY Ubiquitous.DOMAIN The PINc domain confers endonuclease activity and is expected to bind the catalytic metal ion.UniProtQ86US81EQUAL1419EQUALReactome Database ID Release 71927851Database 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=927851ReactomeR-HSA-9278511Reactome 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-927851.11PABPPABPC1Reactome DB_ID: 156803UniProt:P11940 PABPC1PABPC1PAB1PABP1PABPC2FUNCTION Binds the poly(A) tail of mRNA, including that of its own transcript, and regulates processes of mRNA metabolism such as pre-mRNA splicing and mRNA stability (PubMed:11051545, PubMed:17212783, PubMed:25480299). Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2 (PubMed:11051545, PubMed:20573744). Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Involved in translationally coupled mRNA turnover (PubMed:11051545). Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain (PubMed:11051545). Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed (PubMed:18447585). By binding to long poly(A) tails, may protect them from uridylation by ZCCHC6/ZCCHC11 and hence contribute to mRNA stability (PubMed:25480299).FUNCTION (Microbial infection) Positively regulates the replication of dengue virus (DENV).SUBUNIT May interact with SETX (PubMed:21700224). May form homodimers. Component of a multisubunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1 (PubMed:16356927). Directly interacts with IGF2BP1. Part of a complex associated with the FOS mCRD domain and consisting of HNRPD, SYNCRIP, PAIP1 and CSDE1/UNR (PubMed:11051545). Interacts with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1 and PAIP2 (PubMed:9548260, PubMed:11172725, PubMed:11438674, PubMed:11997512, PubMed:11287632, PubMed:20096703). Interacts with PAIP1 with a 1:1 stoichiometry and with PAIP2 with a 1:2 stoichiometry. The interaction with CSDE1 is direct and RNA-independent. Found in a mRNP complex with YBX2 (By similarity). Interacts with TENT2/GLD2 (By similarity). Identified in the spliceosome C complex (PubMed:11991638). Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with NFX1 (PubMed:17267499). Interacts with PIWIL1 (By similarity). Interacts with AGO1, AGO2, GSPT1 and GSPT2 (PubMed:17932509, PubMed:18447585, Ref.52). Interacts with LARP4B (Ref.54). Interacts (via the second and third RRM domains and the C-terminus) with PAIP2B (via central acidic portion and C-terminus) (PubMed:16804161, PubMed:11287632). Interacts with LARP1 (PubMed:20430826, PubMed:24532714, PubMed:25940091). Interacts with SHFL (PubMed:26735137). Found in a complex with SHFL and LARP1 (PubMed:26735137). Interacts with LARP4 (PubMed:21098120). Interacts with ZFC3H1 in a RNase-sensitive manner (PubMed:27871484). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with TENT5C; the interaction has no effect on TENT5C poly(A) polymerase function (PubMed:28931820). Interacts with G3BP1 and G3BP2 (PubMed:23279204).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL69.TISSUE SPECIFICITY Ubiquitous.DOMAIN The RNA-binding domains RRM1 and RRM2 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1, respectively.DOMAIN The RNA-binding domains RRM2 and RRM3 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP2, respectively.PTM Phosphorylated by MAPKAPK2.PTM Methylated by CARM1. Arg-493 is dimethylated, probably to asymmetric dimethylarginine.MISCELLANEOUS Many viruses shutoff host mRNA translational machinery by inhibiting cellular PABPC1 activity using different mechanisms. Picornaviruses, caliciviruses or lentiviruses encode proteases that cleave PABPC1 at several defined sites in the proline-rich linker region between RRMs and the C-terminal domain. Rotaviruses, gammherpesviruses and bunyamwera virus relocalize PABPC1 from the cytoplasm to the nucleus thus altering its function. Many of these viruses translate their mRNA in a PABPC1-independent manner and are unaffected by host PABPC1 inhibition.SIMILARITY Belongs to the polyadenylate-binding protein type-1 family.CAUTION Was termed (Ref.5) polyadenylate binding protein II.UniProtP119401EQUAL636EQUALReactome Database ID Release 71156803Database 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=156803ReactomeR-HSA-1568031Reactome 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-156803.11P220EIF4G1eIF4GeIF-4-gammaeIF-4Geukaryotic translation initiation factor 4 gammaEukaryotic translation initiation factor 4 gammap220Reactome DB_ID: 72584UniProt:Q04637 EIF4G1EIF4G1EIF4FEIF4GEIF4GIFUNCTION Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome.SUBUNIT eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3. Interacts with eIF3, mutually exclusive with EIF4A1 or EIFA2, EIF4E and through its N-terminus with PAPBC1. Interacts through its C-terminus with the serine/threonine kinases MKNK1, and with MKNK2. Appears to act as a scaffold protein, holding these enzymes in place to phosphorylate EIF4E. Non-phosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA. Rapamycin can attenuate insulin stimulation mediated by FKBPs. Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts with RBM4. Interacts with HNRNPD/AUF1; the interaction requires RNA.SUBUNIT (Microbial infection) Interacts with rotavirus A NSP3; in this interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of host protein synthesis.SUBUNIT (Microbial infection) Interacts with human adenovirus 5 protein 100K; this interaction promotes translational shunt in presence of polysomes containing viral tripartite leader mRNAs.PTM Phosphorylated at multiple sites in vivo. Phosphorylation at Ser-1185 by PRKCA induces binding to MKNK1.PTM Following infection by certain enteroviruses, rhinoviruses and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the leader protease in the case of aphthoviruses. This shuts down the capped cellular mRNA transcription.SIMILARITY Belongs to the eukaryotic initiation factor 4G family.UniProtQ046371EQUAL1599EQUALReactome Database ID Release 7172584Database 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=72584ReactomeR-HSA-725841Reactome 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-72584.11UPF1p-4S-UPF1UPF1 Phosphorylated at Serines 1084, 1089,1107, 1127Regulator of nonsense transcripts 1RENT1_HUMANReactome DB_ID: 927856UniProt:Q92900 UPF1UPF1KIAA0221RENT1FUNCTION RNA-dependent helicase and ATPase required for nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited to mRNAs upon translation termination and undergoes a cycle of phosphorylation and dephosphorylation; its phosphorylation appears to be a key step in NMD. Recruited by release factors to stalled ribosomes together with the SMG1C protein kinase complex to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) (located 50-55 or more nucleotides downstream from the termination codon) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Phosphorylated UPF1 is recognized by EST1B/SMG5, SMG6 and SMG7 which are thought to provide a link to the mRNA degradation machinery involving exonucleolytic and endonucleolytic pathways, and to serve as adapters to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation and allowing the recycling of NMD factors. UPF1 can also activate NMD without UPF2 or UPF3, and in the absence of the NMD-enhancing downstream EJC indicative for alternative NMD pathways. Plays a role in replication-dependent histone mRNA degradation at the end of phase S; the function is independent of UPF2. For the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed. The ATPase activity of UPF1 is required for disassembly of mRNPs undergoing NMD. Essential for embryonic viability.SUBUNIT Found in a post-splicing messenger ribonucleoprotein (mRNP) complex (PubMed:21419344). Associates with the exon junction complex (EJC) (PubMed:11546874, PubMed:16452507). Associates with the SGM1C complex; is phosphorylated by the complex kinase component SGM1 (PubMed:19417104). Interacts with UPF2 (PubMed:11163187, PubMed:11073994, PubMed:11113196, PubMed:19556969). Interacts with UPF3A and UPF3B (PubMed:11163187). Interacts with EST1A (PubMed:12554878). Interacts with SLBP (PubMed:16086026). Interacts (when hyperphosphorylated) with PNRC2 (PubMed:19150429). Interacts with AGO1 and AGO2 (PubMed:17932509). Interacts with GSPT2 (PubMed:18447585). Interacts with isoform 1 and isoform 5 of ADAR/ADAR1 (PubMed:18362360). Interacts with SMG7 (PubMed:15721257). Interacts with ZC3H12A; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs (PubMed:26000482). Interacts with CPSF6 (PubMed:19864460). Interacts with MOV10; the interaction is direct and RNA-dependent (PubMed:24726324). Interacts with SHFL; the interaction increases in presence of RNA (PubMed:27974568).SUBUNIT (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein Tax; this interaction inhibits the host nonsense-mediated mRNA decay (NMD).TISSUE SPECIFICITY Ubiquitous.DOMAIN The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.PTM Phosphorylated by SMG1; required for formation of mRNA surveillance complexes.SIMILARITY Belongs to the DNA2/NAM7 helicase family.UniProtQ929001089EQUALO-phospho-L-serineMODMOD:000461107EQUAL1084EQUAL1127EQUAL1EQUAL1129EQUALReactome Database ID Release 71927856Database 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=927856ReactomeR-HSA-9278561Reactome 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-927856.11SMG5Protein SMG5SMG5_HUMANReactome DB_ID: 927867UniProt:Q9UPR3 SMG5SMG5EST1BKIAA1089FUNCTION Plays a role in nonsense-mediated mRNA decay. Does not have RNase activity by itself. Promotes dephosphorylation of UPF1. Together with SMG7 is thought to provide a link to the mRNA degradation machinery involving exonucleolytic pathways, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation. Necessary for TERT activity.SUBUNIT Interacts with TERT, PPP2CA and SMG1. Part of a complex that contains SMG1, SMG5, SMG7, PPP2CA, a short isoform of UPF3A (isoform UPF3AS, but not isoform UPF3AL) and phosphorylated UPF1. Not detected in complexes that contain unphosphorylated UPF1.TISSUE SPECIFICITY Ubiquitous.UniProtQ9UPR31EQUAL1016EQUALReactome Database ID Release 71927867Database 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=927867ReactomeR-HSA-9278671Reactome 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-927867.11Cap Binding Complex (CBC)Reactome DB_ID: 162460NCBP1CBP8080 kDa nuclear cap binding protein (NCBP 80 kDa subunit) (CBP80)80 kDa nuclear cap binding proteinNCBP 80 kDa subunitReactome DB_ID: 162459UniProt:Q09161 NCBP1NCBP1CBP80NCBPFUNCTION Component of the cap-binding complex (CBC), which binds cotranscriptionally to the 5'-cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5'-end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2 and is required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP1/CBP80 does not bind directly capped RNAs (m7GpppG-capped RNA) but is required to stabilize the movement of the N-terminal loop of NCBP2/CBP20 and lock the CBC into a high affinity cap-binding state with the cap structure. Associates with NCBP3 to form an alternative cap-binding complex (CBC) which plays a key role in mRNA export and is particularly important in cellular stress situations such as virus infections. The conventional CBC with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus whereas the alternative CBC with NCBP3 does not bind snRNA and associates only with mRNA thereby playing a role only in mRNA export. NCBP1/CBP80 is required for cell growth and viability (PubMed:26382858).SUBUNIT Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA. Found in a U snRNA export complex containing PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with PHAX/RNUXA, SRRT/ARS2, EIF4G2, IGF2BP1, HNRNPF, HNRNPH1, KIAA0427/CTIF, PARN, DROSHA, UPF1 and ALYREF/THOC4. May interact with EIF4G1; the interaction is however controversial since it is reported by PubMed:11340157, PubMed:15059963 and PubMed:15361857, but is not observed by PubMed:19648179. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1/CBP80 and POLR2A. Component of an alternative nuclear cap-binding complex (CBC) composed of NCBP1/CBP80 and NCBP3 (PubMed:26382858). Interacts with METTL3 (PubMed:27117702). Interacts with ZFC3H1 in a RNase-insensitive manner (PubMed:27871484). Interacts with MTREX (PubMed:30842217).SIMILARITY Belongs to the NCBP1 family.UniProtQ091611EQUAL790EQUALReactome Database ID Release 71162459Database 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=162459ReactomeR-HSA-1624591Reactome 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-162459.11NIP1NCBP2CBP2020 kDa nuclear cap binding protein (NCBP 20 kDa subunit) (CBP20) (NCBP interacting protein 1) (NIP1)20 kDa nuclear cap binding proteinNCBP 20 kDa subunitNCBP interacting protein 1Reactome DB_ID: 162458UniProt:P52298 NCBP2NCBP2CBP20PIG55FUNCTION Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure. The conventional cap-binding complex with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus (PubMed:26382858).SUBUNIT Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA (PubMed:26382858). Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Interacts with PHAX/RNUXA, EIF4G1, HNRNPF, HNRNPH1 and ALYREF/THOC4/ALY. Interacts with SRRT/ARS2 and KPNA3 (PubMed:26382858).SIMILARITY Belongs to the RRM NCBP2 family.UniProtP522981EQUAL156EQUALReactome Database ID Release 71162458Database 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=162458ReactomeR-HSA-1624581Reactome 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-162458.11Reactome Database ID Release 71162460Database 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=162460ReactomeR-HSA-1624601Reactome 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-162460.113' Fragment of Cleaved mRNAReactome DB_ID: 927738Reactome Database ID Release 71927738Database 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=927738ReactomeR-ALL-9277382Reactome 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-927738.21PP2A (Aalpha:B55alpha:Calpha)Reactome DB_ID: 377182PPP2R2APP2A-regulatory subunit B55 alpha isoformReactome DB_ID: 377253UniProt:P63151 PPP2R2APPP2R2AFUNCTION The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.SUBUNIT Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (By similarity). Interacts with TP53 (PubMed:17245430). Interacts with IER5 (PubMed:25816751). Interacts with MFHAS1; the interaction is direct (PubMed:28609714). Interacts with FAM122A (PubMed:27588481). Interacts with CRTC3 (PubMed:30611118).TISSUE SPECIFICITY Expressed in all tissues examined.SIMILARITY Belongs to the phosphatase 2A regulatory subunit B family.UniProtP631512EQUAL447EQUALReactome Database ID Release 71377253Database 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=377253ReactomeR-HSA-3772531Reactome 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-377253.11PPP2CAPP2A-catalytic subunit C alpha isoformReactome DB_ID: 165971UniProt:P67775 PPP2CAPPP2CAFUNCTION PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.SUBUNIT PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:18394995, PubMed:30595372). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2 (PubMed:16580887, PubMed:16541025, PubMed:17485487). Interacts with TP53 (PubMed:17245430). Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with FAM122A (PubMed:27588481). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118).PTM Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization.PTM Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.PTM Polyubiquitinated, leading to its degradation by the proteasome.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.UniProtP677751EQUAL309EQUALReactome Database ID Release 71165971Database 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=165971ReactomeR-HSA-1659711Reactome 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-165971.11PPP2R1APP2A-subunit A alpha isoformReactome DB_ID: 165982UniProt:P30153 PPP2R1APPP2R1AFUNCTION The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT (PubMed:15525651). Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis (PubMed:16580887).SUBUNIT Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). Interacts with FOXO1; the interaction dephosphorylates FOXO1 on AKT-mediated phosphorylation sites (By similarity). PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with IPO9 (PubMed:12670497). Interacts with TP53 and SGO1 (PubMed:17245430, PubMed:16580887). Interacts with PLA2G16; this interaction might decrease PP2A activity (PubMed:17374643). Interacts with CTTNBP2NL (PubMed:18782753). Interacts with GNA12; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT (PubMed:15525651). Interacts with CIP2A; this interaction stabilizes CIP2A (PubMed:28174209). Interacts with FAM122A (PubMed:27588481). Interacts with ADCY8; antagonizes interaction between ADCY8 and calmodulin (By similarity). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118).DOMAIN Each HEAT repeat appears to consist of two alpha helices joined by a hydrophilic region, the intrarepeat loop. The repeat units may be arranged laterally to form a rod-like structure.SIMILARITY Belongs to the phosphatase 2A regulatory subunit A family.UniProtP301532EQUAL589EQUALReactome Database ID Release 71165982Database 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=165982ReactomeR-HSA-1659821Reactome 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-165982.11Reactome Database ID Release 71377182Database 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=377182ReactomeR-HSA-3771821Reactome 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-377182.115' Fragment of Cleaved mRNAReactome DB_ID: 927835Reactome Database ID Release 71927835Database 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=927835ReactomeR-ALL-9278352Reactome 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-927835.21Reactome Database ID Release 71927845Database 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=927845ReactomeR-HSA-9278451Reactome 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-927845.1UPF1Regulator of nonsense transcripts 1RENT1_HUMANReactome DB_ID: 9277341EQUAL1129EQUALReactome Database ID Release 71927734Database 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=927734ReactomeR-HSA-9277341Reactome 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-927734.1Reactome Database ID Release 71927830Database 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=927830ReactomeR-HSA-9278304Reactome 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-927830.412832468Pubmed2003Rapid deadenylation triggered by a nonsense codon precedes decay of the RNA body in a mammalian cytoplasmic nonsense-mediated decay pathwayChen, CYShyu, ABMol Cell Biol 23:4805-1312417715Pubmed2002Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decayLykke-Andersen, JMol Cell Biol 22:8114-2114742663Pubmed2004Premature termination codons enhance mRNA decapping in human cellsCouttet, PGrange, TNucleic Acids Res 32:488-9420023408Pubmed2010How and where are nonsense mRNAs degraded in mammalian cells?Muhlemann, OliverLykke-Andersen, JRNA Biol 7:28-3219060897Pubmed2009SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cellsEberle, ABLykke-Andersen, SMuhlemann, OliverJensen, THNat Struct Mol Biol 16:49-5512554878Pubmed2003Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1Chiu, SYSerin, GOhara, OMaquat, LERNA 9:77-8714527413Pubmed2003Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activitiesLejeune, FLi, XMaquat, LEMol Cell 12:675-8719859661Pubmed2010Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factorsNicholson, PYepiskoposyan, HMetze, SZamudio Orozco, RKleinschmidt, NMuhlemann, OliverCell Mol Life Sci 67:677-70021145460Pubmed2010Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decayFranks, TMSingh, GLykke-Andersen, JCell 143:938-5018974281Pubmed2008SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoanHuntzinger, EKashima, IFauser, MSaulière, JIzaurralde, ERNA 14:2609-1716284618Pubmed2005Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnoverYamashita, AChang, TCYamashita, YZhu, WZhong, ZChen, CYShyu, ABNat Struct Mol Biol 12:1054-6315546618Pubmed2004SMG7 acts as a molecular link between mRNA surveillance and mRNA decayUnterholzner, LIzaurralde, EMol Cell 16:587-9620930030Pubmed2010SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decayKashima, IJonas, SJayachandran, UBuchwald, GConti, ELupas, ANIzaurralde, EGenes Dev 24:2440-5014636577Pubmed2003Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7Ohnishi, TYamashita, AKashima, ISchell, TAnders, KRGrimson, AHachiya, THentze, MWAnderson, POhno, SMol Cell 12:1187-200ACTIVATIONReactome Database ID Release 719023974Database 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=9023974ReactomeR-HSA-90239741Reactome 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-9023974.1ACTIVATIONReactome Database ID Release 719023972Database 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=9023972ReactomeR-HSA-90239721Reactome 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-9023972.1