BioPAX pathway converted from "ISGylation of host proteins" in the Reactome database.LEFT-TO-RIGHT6.3.2.19ISGylation of host proteinsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>ISG15:UBCH8:ISG15 E3 ligaseReactome DB_ID: 9867620cytosolGENE ONTOLOGYGO:0005829ISG15:UBCH8Reactome DB_ID: 9867608Isg15ISG15D4A3X3Reactome DB_ID: 9867606UniProt:D4A3X3Isg15Rattus norvegicusNCBI Taxonomy10116UniProtD4A3X32EQUAL157EQUALReactome Database ID Release 759867606Database 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=9867606ReactomeR-RNO-9365521Reactome 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-RNO-936552.1Reactomehttp://www.reactome.org1Ube2l6UBE2L6Q4V8J2Reactome DB_ID: 9865487UniProt:Q4V8J2Ube2l6UniProtQ4V8J21EQUAL153EQUALReactome Database ID Release 759865487Database 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=9865487ReactomeR-RNO-9360141Reactome 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-RNO-936014.11Reactome Database ID Release 759867608Database 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=9867608ReactomeR-RNO-11693851Reactome 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-RNO-1169385.11Converted from EntitySet in ReactomeISG15 E3 ligasesReactome DB_ID: 9867618Arih1ARIH1D3ZXL1Reactome DB_ID: 9867612UniProt:D3ZXL1Arih1UniProtD3ZXL11EQUAL557EQUALReactome Database ID Release 759867612Database 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=9867612ReactomeR-RNO-16788251Reactome 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-RNO-1678825.1Trim25TRIM25D4A9N5Reactome DB_ID: 9867616UniProt:D4A9N5Trim25UniProtD4A9N51EQUAL630EQUALReactome Database ID Release 759867616Database 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=9867616ReactomeR-RNO-9181861Reactome 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-RNO-918186.1Reactome Database ID Release 759867618Database 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=9867618ReactomeR-RNO-11693811Reactome 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-RNO-1169381.11Reactome Database ID Release 759867620Database 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=9867620ReactomeR-RNO-11693831Reactome 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-RNO-1169383.1ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 75113592Database 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=113592ReactomeR-ALL-1135924Reactome 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-113592.4COMPOUNDC00002additional informationMIMI:0361Converted from EntitySet in ReactomeISG15 targetsReactome DB_ID: 9867671Ube2e1UBE2E1F1M3L4Reactome DB_ID: 9821788UniProt:F1M3L4Ube2e1UniProtF1M3L42EQUAL193EQUALReactome Database ID Release 759821788Database 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=9821788ReactomeR-RNO-1741001Reactome 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-RNO-174100.1Mapk3MAPK3P21708Reactome DB_ID: 9828607UniProt:P21708 Mapk3Mapk3Erk1Prkm3FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.ACTIVITY REGULATION Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-203 and Tyr-205 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, PEA15, SGK1 and MKNK2. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Interacts with TPR. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock. Interacts with CDKN2AIP (By similarity). Interacts with CAVIN4 (PubMed:24567387).TISSUE SPECIFICITY Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.DEVELOPMENTAL STAGE Increased expression during development.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Phosphorylated upon FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation (By similarity). Dephosphorylated by PTPRJ at Tyr-205 (By similarity). Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.UniProtP217082EQUAL379EQUALReactome Database ID Release 759828607Database 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=9828607ReactomeR-RNO-592841Reactome 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-RNO-59284.1Jak1JAK1G3V9W2Reactome DB_ID: 9857437UniProt:G3V9W2Jak1UniProtG3V9W21EQUAL1154EQUALReactome Database ID Release 759857437Database 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=9857437ReactomeR-RNO-4518981Reactome 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-RNO-451898.1Plcg1PLCG1P10686Reactome DB_ID: 9841968UniProt:P10686 Plcg1Plcg1FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration (By similarity).ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts (via SH3 domain) with AGAP2. Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK (By similarity). Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with RET (By similarity). Interacts with FLT1 (tyrosine-phosphorylated). Interacts with AXL, FLT4 and KIT. Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated) (By similarity). Interacts with PIP5K1C (By similarity). Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding) (By similarity). Interacts with SYK; activates PLCG1 (By similarity). Interacts with TESPA1 (By similarity). Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes (By similarity).DOMAIN The SH3 domain mediates interaction with CLNK and RALGPS1.PTM May be dephosphorylated by PTPRJ (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. Tyrosine phosphorylated in response to signaling via activated FLT1, FLT3, KIT and PDGFRB. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells (By similarity).PTM Ubiquitinated by CBLB in activated T-cells.UniProtP106862EQUAL1290EQUALReactome Database ID Release 759841968Database 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=9841968ReactomeR-RNO-2023201Reactome 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-RNO-202320.1Stat1STAT1A0A0G2JX93Reactome DB_ID: 9848868UniProt:A0A0G2JX93Stat1UniProtA0A0G2JX932EQUAL750EQUALReactome Database ID Release 759848868Database 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=9848868ReactomeR-RNO-6296221Reactome 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-RNO-629622.1Mx2MX1P18589Reactome DB_ID: 9867665UniProt:P18589Mx2UniProtP185891EQUAL662EQUALReactome Database ID Release 759867665Database 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=9867665ReactomeR-RNO-9474891Reactome 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-RNO-947489.1Q63184Eif2ak2EIF2AK2Reactome DB_ID: 9867669UniProt:Q63184Eif2ak2UniProtQ631842EQUAL551EQUALReactome Database ID Release 759867669Database 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=9867669ReactomeR-RNO-1686991Reactome 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-RNO-168699.1Reactome Database ID Release 759867671Database 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=9867671ReactomeR-RNO-11693791Reactome 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-RNO-1169379.1AMPadenosine 5'-monophosphateAdenylic acidAdenylate5'-AMP5'-Adenylic acid5'-Adenosine monophosphateAdenosine 5'-phosphateReactome DB_ID: 76577adenosine 5'-monophosphate [ChEBI:16027]adenosine 5'-monophosphateChEBICHEBI:16027Reactome Database ID Release 7576577Database 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=76577ReactomeR-ALL-765774Reactome 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-76577.4COMPOUNDC00020ISGylated host proteinsReactome DB_ID: 986767311Reactome Database ID Release 759867673Database 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=9867673ReactomeR-RNO-11693871Reactome 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-RNO-1169387.1PPipyrophosphatediphosphoric acidpyrophosphoric aciddiphosphateReactome DB_ID: 111294diphosphoric acid [ChEBI:29888]diphosphoric acidChEBICHEBI:29888Reactome Database ID Release 75111294Database 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=111294ReactomeR-ALL-1112943Reactome 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-111294.3COMPOUNDC00013ACTIVATIONactiveUnit: #Protein3GENE ONTOLOGYGO:0004842gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 759867623Database 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=9867623Reactome Database ID Release 759867675Database 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=9867675ReactomeR-RNO-11694061Reactome 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-RNO-1169406.1Many host proteins are targets for ISGylation including constitutively expressed proteins involved in various cellular pathways such as immunity, RNA splicing, chromatin remodeling/polymerase II transcription, stress responses and translation. Many ISG15 target proteins are IFN alpha/beta-induced antiviral proteins such as PKR, MxA, IRF3, and RIG-I, also included are several key regulators of signal transduction such as PLC gamma1, JAK1, STAT1 and ERK1. The contribution of most of these modified proteins to antiviral activity is unclear because the fate of the vast majority of ISGylated target proteins is unknown.12582176Pubmed2003High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transductionMalakhov, MPKim, KIMalakhova, OAJacobs, BSBorden, ECZhang, DEJ Biol Chem 278:16608-1316139798Pubmed2005Proteomic identification of proteins conjugated to ISG15 in mouse and human cellsGiannakopoulos, NVLuo, JKPapov, VZou, WLenschow, DJJacobs, BSBorden, ECLi, JVirgin, HWZhang, DEBiochem Biophys Res Commun 336:496-50616009940Pubmed2005Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathwaysZhao, CDenison, CHuibregtse, JMGygi, SKrug, RMProc Natl Acad Sci U S A 102:10200-5inferred from electronic annotationEVIDENCE CODEECO:0000203