BioPAX pathway converted from "Oxidative Stress Induced Senescence" in the Reactome database. Oxidative Stress Induced Senescence Oxidative Stress Induced Senescence This 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> 2.7.11.1 MAP3K5 phosphorylates MKK3 and MKK6 MAP3K5 phosphorylates MKK3 and MKK6 This 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> Converted from EntitySet in Reactome Reactome DB_ID: 10723950 1 cytosol GO 0005829 MAP2K3,MAP2K6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity mek-1 [cytosol] sek-5 [cytosol] jkk-1 [cytosol] sek-1 [cytosol] sek-4 [cytosol] strd-1 [cytosol] mek-1 [cytosol] sek-3 [cytosol] Reactome http://www.reactome.org Caenorhabditis elegans NCBI Taxonomy 6239 UniProt Q21307 UniProt Q58AU7 UniProt G5EDT6 UniProt G5EDF7 UniProt Q58AU8 UniProt G5ECN5 UniProt Q8MPS3 Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Converted from EntitySet in Reactome Reactome DB_ID: 10723889 1 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-mek-1 [cytosol] phospho-strd-1 [cytosol] phospho-mek-1 [cytosol] phospho-sek-1 [cytosol] phospho-sek-5 [cytosol] phospho-sek-4 [cytosol] phospho-sek-3 [cytosol] phospho-jkk-1 [cytosol] Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10741633 UniProt:Q21029 nsy-1 UniProt Q21029 Chain Coordinates 1 EQUAL 1374 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 81 10741634 Database 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=10741634 Reactome Database ID Release 81 10741636 Database 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=10741636 Reactome R-CEL-3228469 1 Reactome 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-CEL-3228469.1 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997). A conserved docking site, DVD, at the C-terminus of MAP2K3 and MAP2K6 is needed for the interaction with MAP3K5 and MAP3K5-mediated activation (Takekawa et al. 2005). 8974401 Pubmed 1997 Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways Ichijo, H Nishida, E Irie, K ten Dijke, P Saitoh, M Moriguchi, T Takagi, M Matsumoto, K Miyazono, K Gotoh, Y Science 275:90-4 15866172 Pubmed 2005 Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases Takekawa, Mutsuhiro Tatebayashi, Kazuo Saito, Haruo Mol. Cell 18:295-306 inferred by electronic annotation IEA GO IEA Phosphorylated MKK3/MKK6 migrates to nucleus Phosphorylated MKK3/MKK6 migrates to nucleus This 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> Converted from EntitySet in Reactome Reactome DB_ID: 10723889 1 Converted from EntitySet in Reactome Reactome DB_ID: 10723909 1 nucleoplasm GO 0005654 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-mek-1 [nucleoplasm] phospho-mek-1 [nucleoplasm] phospho-jkk-1 [nucleoplasm] phospho-sek-5 [nucleoplasm] phospho-sek-3 [nucleoplasm] phospho-sek-4 [nucleoplasm] phospho-sek-1 [nucleoplasm] phospho-strd-1 [nucleoplasm] Reactome Database ID Release 81 10723911 Database 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=10723911 Reactome R-CEL-450296 1 Reactome 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-CEL-450296.1 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. 7535770 Pubmed 1995 Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine Raingeaud, J Gupta, S Rogers, JS Dickens, M Han, J Ulevitch, RJ Davis, RJ J Biol Chem 270:7420-6 9768359 Pubmed 1998 Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2 Ben-Levy, R Hooper, S Wilson, R Paterson, HF Marshall, CJ Curr Biol 8:1049-57 inferred by electronic annotation IEA GO IEA 2.7.12.2 Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 This 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> Reactome DB_ID: 29358 2 Reactome DB_ID: 10723925 1 p38 MAPK:MAPKAPK2,3 [nucleoplasm] p38 MAPK:MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 10723811 1 MAPKAP2,3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity mak-2 [nucleoplasm] mak-2 [nucleoplasm] mak-1 [nucleoplasm] UniProt Q965G5 UniProt Q21360 Converted from EntitySet in Reactome Reactome DB_ID: 10723923 1 MAP kinase p38 alpha/beta [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pmk-1 [nucleoplasm] pmk-2 [nucleoplasm] pmk-3 [nucleoplasm] pmk-1 [nucleoplasm] UniProt Q17446 UniProt Q8MXI4 UniProt O44514 Reactome Database ID Release 81 10723925 Database 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=10723925 Reactome R-CEL-450269 1 Reactome 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-CEL-450269.1 Reactome DB_ID: 113582 2 Reactome DB_ID: 10723813 1 p-p38 MAPK: MAPKAPK2,3 [nucleoplasm] p-p38 MAPK: MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 10707523 1 p-p38 MAPK alpha/beta [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-pmk-3 [nucleoplasm] phospho-pmk-1 [nucleoplasm] phospho-pmk-1 [nucleoplasm] phospho-pmk-2 [nucleoplasm] Converted from EntitySet in Reactome Reactome DB_ID: 10723811 1 Reactome Database ID Release 81 10723813 Database 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=10723813 Reactome R-CEL-450213 1 Reactome 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-CEL-450213.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10723909 GO 0004708 GO molecular function Reactome Database ID Release 81 10723926 Database 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=10723926 Reactome Database ID Release 81 10723928 Database 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=10723928 Reactome R-CEL-450333 1 Reactome 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-CEL-450333.1 The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. 8622669 Pubmed 1996 MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway Raingeaud, J Whitmarsh, AJ Barrett, T Derijard, B Davis, RJ Mol Cell Biol 16:1247-55 inferred by electronic annotation IEA GO IEA 2.7.11.1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Active p38 MAPK phosphorylates MAPKAPK2 or 3 This 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> Reactome DB_ID: 29358 3 Reactome DB_ID: 10723813 1 Reactome DB_ID: 113582 3 Reactome DB_ID: 10723825 1 p-p38 MAPK:p-MAPKAPK2/3 [nucleoplasm] p-p38 MAPK:p-MAPKAPK2/3 Converted from EntitySet in Reactome Reactome DB_ID: 10707523 1 Converted from EntitySet in Reactome Reactome DB_ID: 10723823 1 Active MAPKAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-mak-2 [nucleoplasm] phospho-mak-2 [nucleoplasm] phospho-mak-1 [nucleoplasm] Reactome Database ID Release 81 10723825 Database 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=10723825 Reactome R-CEL-450254 1 Reactome 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-CEL-450254.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10723813 Reactome Database ID Release 81 10723826 Database 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=10723826 Reactome Database ID Release 81 10723828 Database 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=10723828 Reactome R-CEL-450222 1 Reactome 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-CEL-450222.1 Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).<p>Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). <p>The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).<p>MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2. 17395714 Pubmed 2007 Molecular basis of MAPK-activated protein kinase 2:p38 assembly White, A Pargellis, CA Studts, JM Werneburg, BG Farmer BT, 2nd Proc Natl Acad Sci U S A 104:6353-8 8774846 Pubmed 1996 A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress Clifton, A D Young, P R Cohen, P FEBS Lett. 392:209-14 12171911 Pubmed 2002 Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export Meng, W Swenson, LL Fitzgibbon, MJ Hayakawa, K Ter Haar, E Behrens, AE Fulghum, JR Lippke, JA J Biol Chem 277:37401-5 8626550 Pubmed 1996 Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase McLaughlin, M M Kumar, S McDonnell, P C Van Horn, S Lee, J C Livi, G P Young, P R J. Biol. Chem. 271:8488-92 8846784 Pubmed 1995 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 Ben-Levy, R Leighton, IA Doza, YN Attwood, P Morrice, N Marshall, CJ Cohen, P EMBO J 14:5920-30 15287722 Pubmed 2004 Catalysis and function of the p38 alpha.MK2a signaling complex Lukas, SM Kroe, RR Wildeson, J Peet, GW Frego, L Davidson, W Ingraham, RH Pargellis, CA Labadia, ME Werneburg, BG Biochemistry 43:9950-60 17255097 Pubmed 2007 Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer Ter Haar, E Prabhakar, P Liu, X Lepre, C J Biol Chem 282:9733-9 8622688 Pubmed 1996 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region Sithanandam, G Latif, F Duh, F M Bernal, R Smola, U Li, H Kuzmin, I Wixler, V Geil, L Shrestha, S Mol. Cell. Biol. 16:868-76 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of human JNKs by activated MKK4/MKK7 Phosphorylation of human JNKs by activated MKK4/MKK7 This 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> Converted from EntitySet in Reactome Reactome DB_ID: 10707605 1 MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity kgb-2 [cytosol] kgb-1 [cytosol] jnk-1 [cytosol] jnk-1 [cytosol] jnk-1 [cytosol] kgb-1 [cytosol] kgb-2 [cytosol] UniProt H2KZI0 UniProt O44408 UniProt Q8WQG9 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 10707625 1 p-MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-kgb-1 [cytosol] phospho-jnk-1 [cytosol] phospho-jnk-1 [cytosol] phospho-kgb-1 [cytosol] phospho-kgb-2 [cytosol] phospho-kgb-2 [cytosol] phospho-jnk-1 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10707632 UniProt:Q20347 mkk-4 UniProt Q20347 O-phospho-L-serine at 257 (in Homo sapiens) 257 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 261 (in Homo sapiens) 261 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 399 EQUAL GO 0008545 GO molecular function Reactome Database ID Release 81 10707633 Database 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=10707633 Reactome Database ID Release 81 10707635 Database 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=10707635 Reactome R-CEL-168162 1 Reactome 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-CEL-168162.1 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. <p>JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183). 16186825 Pubmed 2005 Essential function for the kinase TAK1 in innate and adaptive immune responses Sato, S Sanjo, H Takeda, K Ninomiya-Tsuji, J Yamamoto, M Kawai, T Matsumoto, K Takeuchi, O Akira, Shizuo Nat Immunol 6:1087-95 17875933 Pubmed 2007 Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death Wang, X Nadarajah, B Robinson, AC McColl, BW Jin, JW Dajas-Bailador, F Boot-Handford, RP Tournier, C Mol Cell Biol 27:7935-46 18713996 Pubmed 2008 Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases Yoshizawa, T Hammaker, D Sweeney, SE Boyle, DL Firestein, GS J Immunol 181:3252-8 9162092 Pubmed 1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K Blank, JL J Biol Chem 272:14489-96 13130464 Pubmed 2003 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK Sundarrajan, M Boyle, DL Chabaud-Riou, M Hammaker, D Firestein, GS Arthritis Rheum 48:2450-60 11062067 Pubmed 2000 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 Fleming, Y Armstrong, CG Morrice, N Paterson, A Goedert, M Cohen, P Biochem J 352:145-54 inferred by electronic annotation IEA GO IEA Activated human JNKs migrate to nucleoplasm Activated human JNKs migrate to nucleoplasm This 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> Converted from EntitySet in Reactome Reactome DB_ID: 10707625 1 Converted from EntitySet in Reactome Reactome DB_ID: 10707566 1 p-MAPK8,9,10 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-jnk-1 [nucleoplasm] phospho-kgb-1 [nucleoplasm] phospho-kgb-1 [nucleoplasm] phospho-kgb-2 [nucleoplasm] phospho-jnk-1 [nucleoplasm] phospho-kgb-2 [nucleoplasm] phospho-jnk-1 [nucleoplasm] Reactome Database ID Release 81 10723952 Database 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=10723952 Reactome R-CEL-450348 1 Reactome 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-CEL-450348.1 c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors. 9195981 Pubmed 1997 A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. Mizukami, Y Yoshioka, K Morimoto, S Yoshida, K J Biol Chem 272:16657-62 12193592 Pubmed 2002 Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP) Lutz, C Nimpf, J Jenny, M Boecklinger, K Enzinger, C Utermann, G Baier-Bitterlich, G Baier, G J Biol Chem 277:43143-51 inferred by electronic annotation IEA GO IEA 2.7.11 Activated JNKs phosphorylate c-JUN Activated JNKs phosphorylate c-JUN This 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> Reactome DB_ID: 29358 2 Reactome DB_ID: 10707578 1 UniProt:G5ECU7 jun-1 UniProt G5ECU7 1 EQUAL 331 EQUAL Reactome DB_ID: 113582 2 Reactome DB_ID: 10707582 1 O-phospho-L-serine at 63 (in Homo sapiens) 63 EQUAL O-phospho-L-serine at 73 (in Homo sapiens) 73 EQUAL 1 EQUAL 331 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10707566 GO 0004705 GO molecular function Reactome Database ID Release 81 10707583 Database 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=10707583 Reactome Database ID Release 81 10707585 Database 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=10707585 Reactome R-CEL-168136 1 Reactome 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-CEL-168136.1 JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. 10871633 Pubmed 2000 c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity Dennler, S Prunier, C Ferrand, N Gauthier, JM Atfi, A J Biol Chem 275:28858-65 9561845 Pubmed 1998 Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development Ip, YT Davis, RJ Curr Opin Cell Biol 10:205-19 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 inferred by electronic annotation IEA GO IEA KDM6B binds iron KDM6B binds iron This 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> Reactome DB_ID: 111793 1 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe(2+) Fe(II) Ferrous ion Fe2+ iron ion(2+) ChEBI 29033 Converted from EntitySet in Reactome Reactome DB_ID: 10744068 1 Homologues of KDM6B [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity utx-1 [nucleoplasm] jmjd-3.2 [nucleoplasm] jmjd-3.3 [nucleoplasm] jmjd-3.1 [nucleoplasm] UniProt A0A131MBT2 UniProt Q19760 UniProt A0A131MD13 UniProt Q95QK3 Reactome DB_ID: 10767694 1 KDM6B:Fe2+ [nucleoplasm] KDM6B:Fe2+ Reactome DB_ID: 111793 1 Converted from EntitySet in Reactome Reactome DB_ID: 10744068 1 Reactome Database ID Release 81 10767694 Database 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=10767694 Reactome R-CEL-3222589 1 Reactome 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-CEL-3222589.1 Reactome Database ID Release 81 10767696 Database 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=10767696 Reactome R-CEL-8979071 1 Reactome 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-CEL-8979071.1 KDM6B (JMJD3) binds iron. Formation of complex with Fe(II) is needed for the catalytic activity of KDM6B (De Santa et al. 2007). 17825402 Pubmed 2007 The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing De Santa, Francesca Totaro, Maria Grazia Prosperini, Elena Notarbartolo, Samuele Testa, Giuseppe Natoli, Gioacchino Cell 130:1083-94 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10772192 Database 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=10772192 Reactome R-CEL-2559580 1 Reactome 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-CEL-2559580.1 Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).<p> <br>MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.<p> <br>MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).<p> <br>Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997). <p> <br>Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).<p> <br>p16INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007). 7816143 Pubmed 1995 Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA Glover, JN Harrison, SC Nature 373:257-61 16436515 Pubmed 2006 DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation Moiseeva, Olga Mallette, Frédérick A Mukhopadhyay, Utpal K Moores, Adrian Ferbeyre, Gerardo Mol. Biol. Cell 17:1583-92 19462008 Pubmed 2009 Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence Agherbi, Hanane Gaussmann-Wenger, Anne Verthuy, Christophe Chasson, Lionel Serrano, Manuel Djabali, Malek PLoS ONE 4:e5622 17210787 Pubmed 2007 pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene Kotake, Yojiro Cao, Ru Viatour, P Sage, J Zhang, Yi Xiong, Y Genes Dev. 21:49-54 19451217 Pubmed 2009 The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence Agger, Karl Cloos, Paul A C Rudkjaer, Lise Williams, Kristine Andersen, Gitte Christensen, Jesper Helin, Kristian Genes Dev. 23:1171-6 17332741 Pubmed 2007 Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus Dietrich, Nikolaj Bracken, Adrian P Trinh, Emmanuelle Schjerling, Charlotte K Koseki, Haruhiko Rappsilber, Juri Helin, Kristian Hansen, Klaus H EMBO J. 26:1637-48 14532106 Pubmed 2003 EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer Bracken, Adrian P Pasini, Diego Capra, Maria Prosperini, Elena Colli, Elena Helin, Kristian EMBO J. 22:5323-35 12189133 Pubmed 2002 Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade Matsuura, Hiroshi Nishitoh, Hideki Takeda, Kohsuke Matsuzawa, Atsushi Amagasa, Teruo Ito, Michihiko Yoshioka, Katsuji Ichijo, Hidenori J. Biol. Chem. 277:40703-9 11564866 Pubmed 2001 Use of chromatin immunoprecipitation to clone novel E2F target promoters Weinmann, A S Bartley, S M Zhang, T Zhang, M Q Farnham, P J Mol. Cell. Biol. 21:6820-32 12435631 Pubmed 2002 Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein Kuzmichev, A Nishioka, K Erdjument-Bromage, H Tempst, P Reinberg, Danny Genes Dev 16:2893-905 15563468 Pubmed 2005 MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1 Voncken, Jan Willem Niessen, Hanneke Neufeld, Bernd Rennefahrt, Ulrike Dahlmans, Vivian Kubben, Nard Holzer, Barbara Ludwig, Stephan Rapp, Ulf R J. Biol. Chem. 280:5178-87 17344414 Pubmed 2007 The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells Bracken, Adrian P Kleine-Kohlbrecher, Daniela Dietrich, Nikolaj Pasini, Diego Gargiulo, Gaetano Beekman, Chantal Theilgaard-Mönch, Kim Minucci, Saverio Porse, Bo T Marine, Jean-Christophe Hansen, Klaus H Helin, Kristian Genes Dev. 21:525-30 9529249 Pubmed 1998 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways Zhang, Y Xiong, Y Yarbrough, W G Cell 92:725-34 22020331 Pubmed 2012 Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis Lin, T-Y Cheng, Y-C Yang, H-C Lin, W-C Wang, C-C Lai, P-L Shieh, S-Y Oncogene 31:3287-97 19528227 Pubmed 2009 Mitochondrial dysfunction contributes to oncogene-induced senescence Moiseeva, Olga Bourdeau, Véronique Roux, Antoine Deschênes-Simard, Xavier Ferbeyre, Gerardo Mol. Cell. Biol. 29:4495-507 19451218 Pubmed 2009 Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS Barradas, Marta Anderton, Emma Acosta, Juan Carlos Li, Side Banito, Ana Rodriguez-Niedenführ, Marc Maertens, Goedele Banck, Michaela Zhou, Ming-Ming Walsh, Martin J Peters, Gordon Gil, Jesús Genes Dev. 23:1177-82 7588633 Pubmed 1995 The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells Okazaki, K Sagata, N EMBO J 14:5048-59 12134156 Pubmed 2002 Molecular interpretation of ERK signal duration by immediate early gene products Murphy, LO Smith, Stuart Chen, RH Fingar, DC Blenis, J Nat Cell Biol 4:556-64 9030721 Pubmed 1997 Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents Ainbinder, E Bergelson, S Pinkus, R Daniel, V Eur J Biochem 243:49-57 22325352 Pubmed 2012 PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes Gao, Zhonghua Zhang, Jin Bonasio, Roberto Strino, Francesco Sawai, A Parisi, Fabio Kluger, Yuval Reinberg, Danny Mol. Cell 45:344-56 9564042 Pubmed 1998 Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1 Saitoh, M Nishitoh, H Fujii, M Takeda, K Tobiume, K Sawada, Y Kawabata, M Miyazono, K Ichijo, H EMBO J. 17:2596-606 12808055 Pubmed 2003 Regulation of PRAK subcellular location by p38 MAP kinases New, Liguo Jiang, Yong Han, Jiahuai Mol. Biol. Cell 14:2603-16 9628874 Pubmed 1998 PRAK, a novel protein kinase regulated by the p38 MAP kinase New, L Jiang, Y Zhao, M Liu, K Zhu, W Flood, L J Kato, Y Parry, G C Han, J EMBO J. 17:3372-84 8259215 Pubmed 1993 A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 Serrano, M Hannon, GJ Beach, D Nature 366:704-7 17254968 Pubmed 2007 PRAK is essential for ras-induced senescence and tumor suppression Sun, Peiqing Yoshizuka, Naoto New, Liguo Moser, Bettina A Li, Yilei Liao, Rong Xie, Changchuan Chen, Jianming Deng, Qingdong Yamout, Maria Dong, Meng-Qiu Frangou, Costas G Yates, John R Wright, Peter E Han, Jiahuai Cell 128:295-308 16337592 Pubmed 2005 Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells Nicke, Barbara Bastien, Julie Khanna, Sophia J Warne, Patricia H Cowling, Victoria Cook, Simon J Peters, Gordon Delpuech, Oona Schulze, Almut Berns, Katrien Mullenders, Jasper Beijersbergen, Roderick L Bernards, R Ganesan, Trivadi S Downward, Julian Hancock, David C Mol. Cell 20:673-85 inferred by electronic annotation IEA GO IEA