BioPAX pathway converted from "MAPK4,6 translocate to the cytoplasm" in the Reactome database.LEFT-TO-RIGHTMAPK4,6 translocate to the cytoplasmDespite differences in their overall cellular distribution (MAPK6 is found in both the nucleus and the cytosol, while MAPK4 is predominantly found in the cytosol), both MAPK4 and 6 shuttle between the cytosol and the nucleus. Nuclear import of both proteins occurs through an active temperature sensitive pathway, while nuclear export depends on XPO1 (Aberg et al, 2006; Julien et al, 2003). Authored: Rothfels, Karen, 2015-03-30Reviewed: Moens, Ugo, 2015-04-24Reviewed: Seternes, Ole-Morten, 2015-05-05Reviewed: Mathien, Simon, 2015-05-12Reviewed: Meloche, Sylvain, 2015-05-12Reviewed: Soulez, Mathilde, 2015-05-12Edited: Rothfels, Karen, 2015-05-13Converted from EntitySet in ReactomeMAPK4,6Reactome DB_ID: 5692704Converted from EntitySet in ReactomeMAPK6,4Reactome DB_ID: 5692701ERK4MAPK4PRKM4Reactome DB_ID: 5686975nucleoplasmGENE ONTOLOGYGO:0005654UniProt:P31152 MAPK4MAPK4ERK4PRKM4FUNCTION Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle (By similarity).ACTIVITY REGULATION Activated by phosphorylation at Ser-186.SUBUNIT Homodimer. Heterodimer with ERK3/MAPK6. Interacts with (via FRIEDE motif) MAPKAPK5 (By similarity).TISSUE SPECIFICITY High expression in heart and brain.DOMAIN The FRIEDE motif is required for docking MAPKAPK5.DOMAIN In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.PTM Phosphorylated at Ser-186 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.Homo sapiensNCBI Taxonomy9606UniProtP311521EQUAL587EQUALReactome Database ID Release 755686975Database 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=5686975ReactomeR-HSA-56869751Reactome 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-5686975.1Reactomehttp://www.reactome.orgERK3MAPK6PRKM6Reactome DB_ID: 5692686UniProt:Q16659 MAPK6MAPK6ERK3PRKM6FUNCTION Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle (By similarity).ACTIVITY REGULATION Activated by phosphorylation at Ser-189.SUBUNIT Heterodimer with ERK4/MAPK4. Interacts with (via FRIEDE motif) MAPKAPK5 (By similarity). Interacts with UBE3A; this interaction may be indirect and mediated by HERC2, possibly via HERC2 interaction with NEURL4.TISSUE SPECIFICITY Highest expression in the skeletal muscle, followed by the brain. Also found in heart, placenta, lung, liver, pancreas, kidney and skin fibroblasts.DOMAIN In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.PTM Phosphorylated at Ser-189 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites.PTM Ubiquitination at Met-1 leads to degradation by the proteasome pathway.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.UniProtQ166591EQUAL721EQUALReactome Database ID Release 755692686Database 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=5692686ReactomeR-HSA-56926861Reactome 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-5692686.1Reactome Database ID Release 755692701Database 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=5692701ReactomeR-HSA-56927011Reactome 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-5692701.1Converted from EntitySet in Reactomep-S MAPK6,4Reactome DB_ID: 5687052ERK4p-S186 MAPK4PRKM4Reactome DB_ID: 5687022186EQUALO-phospho-L-serineMODMOD:000461EQUAL587EQUALReactome Database ID Release 755687022Database 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=5687022ReactomeR-HSA-56870221Reactome 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-5687022.1ERK3p-S189 MAPK6PRKM6Reactome DB_ID: 5687015189EQUAL1EQUAL721EQUALReactome Database ID Release 755687015Database 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=5687015ReactomeR-HSA-56870151Reactome 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-5687015.1Reactome Database ID Release 755687052Database 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=5687052ReactomeR-HSA-56870521Reactome 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-5687052.1Reactome Database ID Release 755692704Database 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=5692704ReactomeR-HSA-56927041Reactome 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-5692704.1Converted from EntitySet in ReactomeMAPK4,6Reactome DB_ID: 5692706Converted from EntitySet in ReactomeMAPK6,4Reactome DB_ID: 5687037ERK4MAPK4PRKM4Reactome DB_ID: 5686973cytosolGENE ONTOLOGYGO:00058291EQUAL587EQUALReactome Database ID Release 755686973Database 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=5686973ReactomeR-HSA-56869731Reactome 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-5686973.1ERK3MAPK6PRKM6Reactome DB_ID: 56869791EQUAL721EQUALReactome Database ID Release 755686979Database 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=5686979ReactomeR-HSA-56869791Reactome 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-5686979.1Reactome Database ID Release 755687037Database 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=5687037ReactomeR-HSA-56870371Reactome 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-5687037.1Converted from EntitySet in Reactomep-S MAPK6,4Reactome DB_ID: 5687051ERK4p-S186 MAPK4PRKM4Reactome DB_ID: 56870231EQUAL587EQUALReactome Database ID Release 755687023Database 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=5687023ReactomeR-HSA-56870231Reactome 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-5687023.1ERK3p-S189 MAPK6PRKM6Reactome DB_ID: 56870191EQUAL721EQUALReactome Database ID Release 755687019Database 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=5687019ReactomeR-HSA-56870191Reactome 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-5687019.1Reactome Database ID Release 755687051Database 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=5687051ReactomeR-HSA-56870511Reactome 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-5687051.1Reactome Database ID Release 755692706Database 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=5692706ReactomeR-HSA-56927061Reactome 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-5692706.1Reactome Database ID Release 755687109Database 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=5687109ReactomeR-HSA-56871092Reactome 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-5687109.212915405Pubmed2003Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progressionJulien, CatherineCoulombe, PhilippeMeloche, SylvainJ. Biol. Chem. 278:42615-2416971392Pubmed2006Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4Aberg, EspenPerander, MariaJohansen, BjarneJulien, CatherineMeloche, SylvainKeyse, Stephen MSeternes, Ole-MortenJ. Biol. Chem. 281:35499-510ACTIVATIONReactome Database ID Release 755687133Database 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=5687133ReactomeR-HSA-56871331Reactome 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-5687133.1XPO1CRM1Reactome DB_ID: 165529UniProt:O14980 XPO1XPO1CRM1FUNCTION Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap.FUNCTION (Microbial infection) Mediates the export of unspliced or incompletely spliced RNAs out of the nucleus from different viruses including HIV-1, HTLV-1 and influenza A. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.SUBUNIT Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA (By similarity). Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1. Found in a trimeric export complex with SNUPN, RAN and XPO1. Found in a nuclear export complex with RANBP3 and RAN. Found in a 60S ribosomal subunit export complex with NMD3, RAN, XPO1. Interacts with DDX3X, NMD3, NUP42, NUP88, NUP214, RANBP3 and TERT. Interacts with NEMF (via its N-terminus). Interacts with the monomeric form of BIRC5/survivin deacetylated at 'Lys-129'. Interacts with DTNBP1 and SERTAD2; the interactions translocate DTNBP1 and SERTAD2 out of the nucleus. Interacts with ATF2. Interacts with SLC35G1 and STIM1. Interacts with DCAF8. Interacts with CPEB3 (PubMed:22730302). Interacts with HAX1 (PubMed:23164465). Interacts with BOK; translocates to the cytoplasm (PubMed:16302269). Interacts with HSP90AB1 (PubMed:22022502).SUBUNIT (Microbial infection) Interacts with HIV-1 Rev.SUBUNIT (Microbial infection) Interacts with HTLV-1 Rex.SUBUNIT (Microbial infection) Interacts with influenza A nucleoprotein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein BMLF1.SUBUNIT (Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.SUBUNIT (Microbial infection) Interacts with SARS-CoV virus protein ORF9b; this interaction mediates protein ORF9b export out of the nucleus.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Not expressed in the kidney.MISCELLANEOUS Cellular target of leptomycin B (LMB), a XPO1/CRM1 nuclear export inhibitor.SIMILARITY Belongs to the exportin family.UniProtO149801EQUAL1071EQUALReactome Database ID Release 75165529Database 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=165529ReactomeR-HSA-1655291Reactome 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-165529.1