BioPAX pathway converted from "Toll Like Receptor 2 (TLR2) Cascade" in the Reactome database. Toll Like Receptor 2 (TLR2) Cascade 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> Toll Like Receptor TLR1:TLR2 Cascade 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> MyD88:MAL(TIRAP) cascade initiated on plasma membrane 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> LEFT-TO-RIGHT MAL binds PIP2-rich regions in the plasma membrane TIRAP binds PIP2-rich regions in the plasma membrane 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> PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 plasma membrane GENE ONTOLOGY GO:0005886 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate ChEBI CHEBI:58456 Reactome Database ID Release 82 179856 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=179856 Reactome R-ALL-179856 4 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-ALL-179856.4 Reactome http://www.reactome.org COMPOUND C04637 additional information MI MI:0361 Tirap TIRAP Q99JY1 Reactome DB_ID: 9878548 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q99JY1 Tirap Mus musculus NCBI Taxonomy 10090 UniProt Q99JY1 1 EQUAL 221 EQUAL Reactome Database ID Release 82 9878548 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=9878548 Reactome R-MMU-166141 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-MMU-166141.1 TIRAP:PI(4,5)P2 Reactome DB_ID: 9878550 1 1 Reactome Database ID Release 82 9878550 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=9878550 Reactome R-MMU-2559415 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-MMU-2559415.1 Reactome Database ID Release 82 9878552 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=9878552 Reactome R-MMU-2559456 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-MMU-2559456.1 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain [Kagan JC and Medzithov R 2007]. TLR2 or 4 associates with Mal(TIRAP) on the cell surface, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel R et al 2007, Nagpal K et al 2009]. 19509286 Pubmed 2009 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling Nagpal, Kamalpreet Plantinga, Theo S Wong, Joyce Monks, BG Gay, Nicholas J Netea, Mihai G Fitzgerald, Katherine A Golenbock, DT J. Biol. Chem. 284:25742-8 16751103 Pubmed 2006 Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling Kagan, JC Medzhitov, R Cell 125:943-55 15585605 Pubmed 2005 TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR Takeda, K Akira, Shizuo Int Immunol 17:1-14 11544529 Pubmed 2001 Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction Fitzgerald, K A Palsson-McDermott, E M Bowie, A G Jefferies, C A Mansell, A S Brady, G Brint, E Dunne, A Gray, P Harte, MT McMurray, D Smith, D E Sims, J E Bird, T A O'Neill, L A Nature 413:78-83 inferred from electronic annotation EVIDENCE CODE ECO:0000203 IRAK2 mediated activation of TAK1 complex 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> LEFT-TO-RIGHT IRAK2 induces TRAF6 oligomerization 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> Traf6 TRAF6 P70196 Reactome DB_ID: 9828388 UniProt:P70196 Traf6 Traf6 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:15322147, PubMed:17633018). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By similarity). Leads to the activation of NF-kappa-B and JUN. Seems to also play a role in dendritic cells (DCs) maturation and/or activation (PubMed:14499111). Represses c-Myb-mediated transactivation, in B-lymphocytes (By similarity). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:10421844, PubMed:10215628). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (PubMed:10421844, PubMed:17092936). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (PubMed:12881420).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer (By similarity). Homooligomer (By similarity). N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt P70196 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9828388 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=9828388 Reactome R-MMU-166366 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-MMU-166366.1 2 TRAF6:p-IRAK2 Reactome DB_ID: 9854046 Traf6 TRAF6 P70196 Reactome DB_ID: 9854042 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9854042 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=9854042 Reactome R-MMU-936955 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-MMU-936955.1 1 Q8CFA1 phospho-p-IRAK2 Reactome DB_ID: 9854044 UniProt:Q8CFA1 UniProt Q8CFA1 phosphorylated residue MOD MOD:00696 1 EQUAL 625 EQUAL Reactome Database ID Release 82 9854044 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=9854044 Reactome R-MMU-936949 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-MMU-936949.1 1 Reactome Database ID Release 82 9854046 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=9854046 Reactome R-MMU-936961 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-MMU-936961.1 p-IRAK2:oligo-TRAF6 Reactome DB_ID: 9854048 1 2 Reactome Database ID Release 82 9854048 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=9854048 Reactome R-MMU-936990 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-MMU-936990.1 Reactome Database ID Release 82 9854075 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=9854075 Reactome R-MMU-936963 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-MMU-936963.1 The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization. 17878161 Pubmed 2007 IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination Keating, SE Maloney, GM Moran, EM Bowie, AG J Biol Chem 282:33435-43 LEFT-TO-RIGHT 6.3.2.19 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 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 Ub ubiquitin Reactome DB_ID: 9816098 Ubiquitin (Uba52) Reactome DB_ID: 940365 UniProt:P62984 Uba52 Uba52 Ubcep2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62984 1 EQUAL 76 EQUAL Reactome Database ID Release 82 940365 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=940365 Reactome R-MMU-940365 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-MMU-940365.1 Ubiquitin (Ubb 1) Reactome DB_ID: 940364 UniProt:P0CG49 Ubb Ubb SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG49 1 EQUAL 76 EQUAL Reactome Database ID Release 82 940364 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=940364 Reactome R-MMU-940364 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-MMU-940364.1 Ubiquitin (Pps27a) Reactome DB_ID: 940370 UniProt:P62983 Rps27a Rps27a Uba80 Ubcep1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62983 1 EQUAL 76 EQUAL Reactome Database ID Release 82 940370 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=940370 Reactome R-MMU-940370 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-MMU-940370.1 Rps27a UBB(77-152) P62983 Reactome DB_ID: 9816094 77 EQUAL 152 EQUAL Reactome Database ID Release 82 9816094 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=9816094 Reactome R-MMU-939213 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-MMU-939213.1 Ubiquitin (Ubc 1) Reactome DB_ID: 940382 UniProt:P0CG50 Ubc Ubc MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG50 1 EQUAL 76 EQUAL Reactome Database ID Release 82 940382 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=940382 Reactome R-MMU-940382 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-MMU-940382.1 Ubiquitin (Ubc 2) Reactome DB_ID: 940388 77 EQUAL 152 EQUAL Reactome Database ID Release 82 940388 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=940388 Reactome R-MMU-940388 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-MMU-940388.1 Ubiquitin (Ubc 3) Reactome DB_ID: 940362 153 EQUAL 228 EQUAL Reactome Database ID Release 82 940362 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=940362 Reactome R-MMU-940362 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-MMU-940362.1 Ubiquitin related 1 (Ubc r1) Reactome DB_ID: 940386 229 EQUAL 304 EQUAL Reactome Database ID Release 82 940386 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=940386 Reactome R-MMU-940386 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-MMU-940386.1 Ubiquitin (Ubc 4) Reactome DB_ID: 940359 305 EQUAL 380 EQUAL Reactome Database ID Release 82 940359 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=940359 Reactome R-MMU-940359 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-MMU-940359.1 Ubiquitin (Ubc 5) Reactome DB_ID: 940360 381 EQUAL 456 EQUAL Reactome Database ID Release 82 940360 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=940360 Reactome R-MMU-940360 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-MMU-940360.1 Ubiquitin (Ubc 6) Reactome DB_ID: 940384 457 EQUAL 532 EQUAL Reactome Database ID Release 82 940384 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=940384 Reactome R-MMU-940384 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-MMU-940384.1 Ubiquitin (Ubc 7) Reactome DB_ID: 940371 533 EQUAL 608 EQUAL Reactome Database ID Release 82 940371 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=940371 Reactome R-MMU-940371 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-MMU-940371.1 Ubiquitin (Ubc 8) Reactome DB_ID: 940379 609 EQUAL 684 EQUAL Reactome Database ID Release 82 940379 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=940379 Reactome R-MMU-940379 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-MMU-940379.1 Reactome Database ID Release 82 9816098 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=9816098 Reactome R-MMU-113595 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-MMU-113595.1 9 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 9854053 Traf6 K63polyUb-TRAF6 P70196 Reactome DB_ID: 9854051 124 EQUAL ubiquitinylated lysine MOD MOD:01148 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9854051 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=9854051 Reactome R-MMU-936980 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-MMU-936980.1 3 1 Reactome Database ID Release 82 9854053 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=9854053 Reactome R-MMU-936988 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-MMU-936988.1 ACTIVATION activeUnit: #Protein3 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 9854054 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=9854054 Reactome Database ID Release 82 9854056 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=9854056 Reactome R-MMU-936942 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-MMU-936942.1 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 LEFT-TO-RIGHT 6.3.2.19 Activated TRAF6 synthesizes unanchored polyubiquitin chains 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> K63polyUb Reactome DB_ID: 9828692 Reactome Database ID Release 82 9828692 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=9828692 Reactome R-MMU-450152 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-MMU-450152.1 ACTIVATION activeUnit: #Protein20 Reactome Database ID Release 82 9854078 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=9854078 Traf6 K63polyUb-TRAF6 P70196 Reactome DB_ID: 9849780 endosome membrane GENE ONTOLOGY GO:0010008 124 EQUAL 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9849780 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=9849780 Reactome R-MMU-450227 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-MMU-450227.1 Reactome Database ID Release 82 9854080 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=9854080 Reactome R-MMU-936986 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-MMU-936986.1 Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase. 19675569 Pubmed 2009 Direct activation of protein kinases by unanchored polyubiquitin chains Xia, ZP Sun, L Chen, X Pineda, G Jiang, X Adhikari, A Zeng, W Chen, ZJ Nature LEFT-TO-RIGHT Activated TRAF6:p-IRAK2 interacts with TAK1 complex 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> TAK1 complex Reactome DB_ID: 9849204 Tab1 TAB1 Q8CF89 Reactome DB_ID: 9849194 UniProt:Q8CF89 Tab1 Tab1 Map3k7ip1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7. Interacts with TRAF6 and MAP3K7; during IL-1 signaling. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (By similarity).PTM Monoubiquitinated.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q8CF89 1 EQUAL 504 EQUAL Reactome Database ID Release 82 9849194 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=9849194 Reactome R-MMU-167923 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-MMU-167923.1 1 MAP3K7 Q62073 Reactome DB_ID: 9849191 UniProt:Q62073 Map3k7 Map3k7 Tak1 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570).ACTIVITY REGULATION Activated by pro-inflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with DYNC2I2 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (PubMed:27084103). Interacts with SASH1 (By similarity). Interacts with RIPK1 (PubMed:31519887).PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt Q62073 1 EQUAL 606 EQUAL Reactome Database ID Release 82 9849191 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=9849191 Reactome R-MMU-168156 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-MMU-168156.1 1 Converted from EntitySet in Reactome TAB2,TAB3 Reactome DB_ID: 9849202 Tab2 TAB2 Q99K90 Reactome DB_ID: 9849196 UniProt:Q99K90 Tab2 Tab2 Kiaa0733 Map3k7ip2 FUNCTION Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF) (By similarity). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains (By similarity). The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 (PubMed:19927120). Regulates the IL1-mediated translocation of NCOR1 out of the nucleus (PubMed:12150997). Involved in heart development (By similarity).SUBUNIT Interacts with MAP3K7 and TRAF6. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2. Binds 'Lys-63'-linked polyubiquitin chains (By similarity). Interacts with NCOR1 and HDAC3 to form a ternary complex (PubMed:12150997). Interacts (via C-terminal) with NUMBL (via PTB domain). Interacts (via the C-terminus) with DYNC2I2 (via WD domains). Interacts with RBCK1. Interacts with TRIM5 (By similarity). Interacts with TRIM38 (via B30.2/SPRY domain), leading to its translocation to lysosomes and degradation (By similarity).TISSUE SPECIFICITY Widely expressed.DOMAIN The RanBP2-type zinc finger (NZF) mediates binding to two consecutive 'Lys-63'-linked ubiquitins.PTM Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation.PTM Degraded in a lysosome-dependent manner following interactiuon with TRIM38.PTM Phosphorylated. UniProt Q99K90 1 EQUAL 693 EQUAL Reactome Database ID Release 82 9849196 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=9849196 Reactome R-MMU-168117 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-MMU-168117.1 Tab3 TAB3 Q571K4 Reactome DB_ID: 9849200 UniProt:Q571K4 Tab3 UniProt Q571K4 2 EQUAL 712 EQUAL Reactome Database ID Release 82 9849200 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=9849200 Reactome R-MMU-450264 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-MMU-450264.1 Reactome Database ID Release 82 9849202 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=9849202 Reactome R-MMU-446874 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-MMU-446874.1 1 Reactome Database ID Release 82 9849204 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=9849204 Reactome R-MMU-446878 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-MMU-446878.1 3 3 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex Reactome DB_ID: 9854071 1 3 3 Reactome Database ID Release 82 9854071 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=9854071 Reactome R-MMU-936953 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-MMU-936953.1 Reactome Database ID Release 82 9854073 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=9854073 Reactome R-MMU-936960 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-MMU-936960.1 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains (Kulathu Y et al 2009). TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.<p>As a de-ubiquitinating/de-ISGylating enzyme, severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) 1a-encoded papain-like protease (PLPro or nsp3) antagonizes the host type I interferon (IFN) response by removing Lys63-linked ubiquitin chains of TRAF3 and TRAF6 (Li SW et al. 2016). 19935683 Pubmed 2009 Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain Kulathu, Yogesh Akutsu, Masato Bremm, Anja Hofmann, K Komander, David Nat. Struct. Mol. Biol. 16:1328-30 10882101 Pubmed 2000 TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway Takaesu, G Kishida, S Hiyama, A Yamaguchi, K Shibuya, H Irie, K Ninomiya-Tsuji, J Matsumoto, K Mol Cell 5:649-58 27164085 Pubmed 2016 SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6 Li, Shih-Wen Wang, Ching-Ying Jou, Yu-Jen Huang, Su-Hua Hsiao, Li-Hsin Wan, Lei Lin, Ying-Ju Kung, Szu-Hao Lin, Cheng-Wen Int J Mol Sci 17: 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 LEFT-TO-RIGHT 2.7.11 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 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> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 82 113592 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=113592 Reactome R-ALL-113592 5 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-ALL-113592.5 COMPOUND C00002 6 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 82 29370 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=29370 Reactome R-ALL-29370 5 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-ALL-29370.5 COMPOUND C00008 6 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 9854082 3 Q62073 phospho-p-T184,T187-MAP3K7 Reactome DB_ID: 9835825 184 EQUAL O-phospho-L-threonine MOD MOD:00047 187 EQUAL 1 EQUAL 606 EQUAL Reactome Database ID Release 82 9835825 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=9835825 Reactome R-MMU-202527 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-MMU-202527.1 3 1 3 3 Reactome Database ID Release 82 9854082 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=9854082 Reactome R-MMU-937008 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-MMU-937008.1 ACTIVATION activeUnit: #Protein22 GENE ONTOLOGY GO:0008349 Reactome Database ID Release 82 9854083 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=9854083 Reactome Database ID Release 82 9854085 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=9854085 Reactome R-MMU-936991 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-MMU-936991.1 The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 10838074 Pubmed 2000 Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1 Sakurai, H Miyoshi, H Mizukami, J Sugita, T FEBS Lett. 474:141-5 16289117 Pubmed 2005 Structural basis for the interaction of TAK1 kinase with its activating protein TAB1 Brown, Kieron Vial, Sarah C M Dedi, Neesha Long, Joanna M Dunster, Nicholas J Cheetham, Graham M T J. Mol. Biol. 354:1013-20 16260493 Pubmed 2005 TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo Shim, JH Xiao, C Paschal, AE Bailey, ST Rao, P Hayden, MS Lee, KY Bussey, C Steckel, M Tanaka, N Yamada, G Akira, Shizuo Matsumoto, K Ghosh, S Genes Dev 19:2668-81 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 8638164 Pubmed 1996 TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction Shibuya, H Yamaguchi, K Shirakabe, K Tonegawa, A Gotoh, Y Ueno, N Irie, K Nishida, E Matsumoto, K Science 272:1179-82 11323434 Pubmed 2001 An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK Ono, K Ohtomo, T Sato, S Sugamata, Y Suzuki, M Hisamoto, N Ninomiya-Tsuji, J Tsuchiya, M Matsumoto, K J. Biol. Chem. 276:24396-400 Reactome Database ID Release 82 9927268 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=9927268 Reactome R-MMU-937042 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-MMU-937042.1 Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.<p>IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). 21606490 Pubmed 2011 Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha Flannery, Sinead M Keating, Sinead E Szymak, Joanna Bowie, Andrew G J. Biol. Chem. 286:23688-97 16831874 Pubmed 2006 The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4 Dong, W Liu, Y Peng, J Chen, L Zou, T Xiao, H Liu, Z Li, W Bu, Y Qi, Y J Biol Chem 281:26029-40 12140561 Pubmed 2002 Distinct molecular mechanism for initiating TRAF6 signalling Ye, H Arron, JR Lamothe, B Cirilli, M Kobayashi, T Shevde, NK Segal, D Dzivenu, OK Vologodskaia, M Yim, M Du, K Singh, S Pike, JW Darnay, BG Choi, Y Wu, H Nature 418:443-7 IRAK1 recruits IKK complex 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> LEFT-TO-RIGHT Pellino binds hp-IRAK1:TRAF6 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> TRAF6:hp-IRAK1 Reactome DB_ID: 9854099 1 Q62406 phospho-p-2S,S376,T,T209,T387-IRAK1 Reactome DB_ID: 9854097 UniProt:Q62406 Irak1 Irak1 Il1rak FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3 (By similarity).SUBUNIT Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (By similarity). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (By similarity). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (By similarity). Interacts with IL1RL1 (By similarity). Interacts (when polyubiquitinated) with IKBKG/NEMO (By similarity). Interacts with RSAD2/viperin (PubMed:21435586). Interacts with IRAK1BP1 (PubMed:11096118). Interacts with PELI2 (PubMed:12370331). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (PubMed:22037600). Interacts with IRAK4 (By similarity). Interacts with PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity). Interacts (via C-terminus) with NFATC4 (via N-terminus) (By similarity).TISSUE SPECIFICITY Highly expressed in liver, followed by kidney and skeletal muscle.DEVELOPMENTAL STAGE Expressed from 11 dpc to 18 dpc.DOMAIN The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation (By similarity).PTM Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity (By similarity).PTM Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation (By similarity).DISRUPTION PHENOTYPE Mice show a loss in TLR7- and TLR9-mediated IFN-alpha production in plasmacytoid dendritic cells demonstrating an important role in innate immune response.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt Q62406 387 EQUAL 376 EQUAL O-phospho-L-serine MOD MOD:00046 209 EQUAL 1 EQUAL 712 EQUAL Reactome Database ID Release 82 9854097 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=9854097 Reactome R-MMU-937011 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-MMU-937011.1 1 Reactome Database ID Release 82 9854099 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=9854099 Reactome R-MMU-937036 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-MMU-937036.1 Converted from EntitySet in Reactome p-Pellino-1,2,(3) Reactome DB_ID: 9850034 Q8C669 phospho-Peli1 p-PELI1 Reactome DB_ID: 9850026 UniProt:Q8C669 Peli1 UniProt Q8C669 1 EQUAL 418 EQUAL Reactome Database ID Release 82 9850026 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=9850026 Reactome R-MMU-450815 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-MMU-450815.1 Q8BST6 phospho-Peli2 p-PELI2 Reactome DB_ID: 9850029 UniProt:Q8BST6 Peli2 UniProt Q8BST6 1 EQUAL 420 EQUAL Reactome Database ID Release 82 9850029 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=9850029 Reactome R-MMU-450825 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-MMU-450825.1 Q8BXR6 phospho-Peli3 p-PELI3 Reactome DB_ID: 9850032 UniProt:Q8BXR6 Peli3 UniProt Q8BXR6 1 EQUAL 469 EQUAL Reactome Database ID Release 82 9850032 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=9850032 Reactome R-MMU-450806 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-MMU-450806.1 Reactome Database ID Release 82 9850034 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=9850034 Reactome R-MMU-450819 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-MMU-450819.1 TRAF6:hp-IRAK1:Pellino Reactome DB_ID: 9854101 1 1 Reactome Database ID Release 82 9854101 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=9854101 Reactome R-MMU-937020 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-MMU-937020.1 Reactome Database ID Release 82 9854106 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=9854106 Reactome R-MMU-937044 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-MMU-937044.1 Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1. <p>All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro. 17997719 Pubmed 2008 The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1 Ordureau, A Smith, H Windheim, M Peggie, M Carrick, E Morrice, N Cohen, P Biochem J 409:43-52 16884718 Pubmed 2006 Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases Schauvliege, R Janssens, S Beyaert, R FEBS Lett 580:4697-702 12496252 Pubmed 2003 Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex Jiang, Z Johnson, HJ Nie, H Qin, J Bird, TA Li, X J Biol Chem 278:10952-6 17675297 Pubmed 2007 Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases Butler, MP Hanly, JA Moynagh, PN J Biol Chem 282:29729-37 19022706 Pubmed 2009 The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling Moynagh, PN Trends Immunol 30:33-42 15917247 Pubmed 2005 Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent manner Butler, MP Hanly, JA Moynagh, PN J Biol Chem 280:27759-68 12860405 Pubmed 2003 Characterization of Pellino2, a substrate of IRAK1 and IRAK4 Strelow, A Kollewe, C Wesche, H FEBS Lett 547:157-61 18326498 Pubmed 2008 Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation Xiao, H Qian, W Staschke, K Qian, Y Cui, G Deng, L Ehsani, M Wang, X Qian, YW Chen, ZJ Gilmour, R Jiang, Z Li, X J Biol Chem 283:14654-64 LEFT-TO-RIGHT IRAK1 phosphorylates Pellino 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> ACTIVATION activeUnit: #Protein27 GENE ONTOLOGY GO:0004672 Reactome Database ID Release 82 9854102 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=9854102 Reactome Database ID Release 82 9854104 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=9854104 Reactome R-MMU-937034 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-MMU-937034.1 Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo. 19264966 Pubmed 2009 Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4 Smith, H Peggie, M Campbell, DG Vandermoere, F Carrick, E Cohen, P Proc Natl Acad Sci U S A 106:4584-90 LEFT-TO-RIGHT Pellino ubiquitinates hp-IRAK1 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 UBE2N:UBE2V1 Reactome DB_ID: 9828731 Ube2n UBE2N P61089 Reactome DB_ID: 9828725 UniProt:P61089 Ube2n UniProt P61089 1 EQUAL 152 EQUAL Reactome Database ID Release 82 9828725 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=9828725 Reactome R-MMU-206072 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-MMU-206072.1 1 Ube2v1 UBE2V1 Q9CZY3 Reactome DB_ID: 9828729 UniProt:Q9CZY3 Ube2v1 UniProt Q9CZY3 2 EQUAL 147 EQUAL Reactome Database ID Release 82 9828729 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=9828729 Reactome R-MMU-205753 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-MMU-205753.1 1 Reactome Database ID Release 82 9828731 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=9828731 Reactome R-MMU-202463 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-MMU-202463.1 K63-linked polyUb p-IRAK1:TRAF6 Reactome DB_ID: 9854091 1 Q62406 phospho-K63polyUb-hp-IRAK1 Reactome DB_ID: 9850180 134 EQUAL 160 EQUAL 1 EQUAL 712 EQUAL Reactome Database ID Release 82 9850180 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=9850180 Reactome R-MMU-451565 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-MMU-451565.1 1 Reactome Database ID Release 82 9854091 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=9854091 Reactome R-MMU-937043 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-MMU-937043.1 ACTIVATION activeUnit: #Protein28 GENE ONTOLOGY GO:0034450 Reactome Database ID Release 82 9854107 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=9854107 Reactome Database ID Release 82 9854109 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=9854109 Reactome R-MMU-937050 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-MMU-937050.1 IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.<p>IRAK1 is ubiquitinated on Lys134 and Lys180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is a stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al 2008; Butler et al 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008). 18724939 Pubmed 2008 Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies Newton, Kim Matsumoto, Marissa L Wertz, Ingrid E Kirkpatrick, Donald S Lill, Jennie R Tan, Jenille Dugger, Debra Gordon, Nathaniel Sidhu, SS Fellouse, FA Komuves, Laszlo French, Dorothy M Ferrando, Ronald E Lam, Cynthia Compaan, Deanne Yu, Christine Bosanac, Ivan Hymowitz, Sarah G Kelley, Robert F Dixit, Vishva M Cell 134:668-78 18180283 Pubmed 2008 Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase Windheim, M Stafford, M Peggie, M Cohen, P Mol Cell Biol 28:1783-91 18347055 Pubmed 2008 Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation Conze, DB Wu, CJ Thomas, JA Landstrom, A Ashwell, JD Mol Cell Biol 28:3538-47 LEFT-TO-RIGHT NEMO subunit of IKK complex binds to activated IRAK1 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> CHUK:IKBKB:IKBKG Reactome DB_ID: 9835816 IKBKB O88351 Reactome DB_ID: 9832572 UniProt:O88351 UniProt O88351 1 EQUAL 756 EQUAL Reactome Database ID Release 82 9832572 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=9832572 Reactome R-MMU-168114 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-MMU-168114.1 1 IKBKG O88522 Reactome DB_ID: 9828515 UniProt:O88522 UniProt O88522 1 EQUAL 419 EQUAL Reactome Database ID Release 82 9828515 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=9828515 Reactome R-MMU-168108 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-MMU-168108.1 1 CHUK Q60680 Reactome DB_ID: 9833419 UniProt:Q60680 UniProt Q60680 1 EQUAL 745 EQUAL Reactome Database ID Release 82 9833419 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=9833419 Reactome R-MMU-168104 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-MMU-168104.1 1 Reactome Database ID Release 82 9835816 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=9835816 Reactome R-MMU-168113 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-MMU-168113.1 TRAF6:K63-linked polyUb p-IRAK1:IKK complex Reactome DB_ID: 9854093 1 1 Reactome Database ID Release 82 9854093 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=9854093 Reactome R-MMU-937038 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-MMU-937038.1 Reactome Database ID Release 82 9854095 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=9854095 Reactome R-MMU-937032 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-MMU-937032.1 NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008). 16547522 Pubmed 2006 Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected] Wu, CJ Conze, DB Li, T Srinivasula, SM Ashwell, JD Nat Cell Biol 8:398-406 16603398 Pubmed 2006 Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO Ea, CK Deng, L Xia, ZP Pineda, G Chen, ZJ Mol Cell 22:245-57 Reactome Database ID Release 82 9927270 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=9927270 Reactome R-MMU-937039 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-MMU-937039.1 GENE ONTOLOGY GO:0043123 gene ontology term for cellular process MI MI:0359 The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].<p> IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B. </p><p>Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003]. 12856330 Pubmed 2003 IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression Nguyen, H Chatterjee-Kishore, M Jiang, Z Qing, Y Ramana, CV Bayes, J Commane, M Li, X Stark, GR J Interferon Cytokine Res 23:183-92 15767370 Pubmed 2005 Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction Uematsu, S Sato, S Yamamoto, M Hirotani, T Kato, H Takeshita, F Matsuda, M Coban, C Ishii, KJ Kawai, T Takeuchi, O Akira, Shizuo J Exp Med 201:915-23 18276832 Pubmed 2008 Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity Liu, G Park, YJ Abraham, E FASEB J 22:2285-96 14625308 Pubmed 2004 Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling Kollewe, C Mackensen, AC Neumann, D Knop, J Cao, P Li, S Wesche, H Martin, MU J Biol Chem 279:5227-36 15695821 Pubmed 2005 The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling Schoenemeyer, A Barnes, BJ Mancl, ME Latz, E Goutagny, N Pitha-Rowe, Paula M Fitzgerald, Katherine A Golenbock, DT J Biol Chem 280:17005-12 14661019 Pubmed 2004 Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3 Huang, Q Yang, J Lin, Y Walker, Graham C Cheng, J Liu, ZG Su, B Nat Immunol 5:98-103 16477006 Pubmed 2006 IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation Song, YJ Jen, KY Soni, V Kieff, E Cahir-McFarland, E Proc Natl Acad Sci U S A 103:2689-94 LEFT-TO-RIGHT TRAF6 binds MEKK1 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> MAP3K1 P53349 Reactome DB_ID: 9828385 UniProt:P53349 Map3k1 Map3k1 Mekk Mekk1 FUNCTION Component of a protein kinase signal transduction cascade (PubMed:14500727). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:14500727). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:14500727).ACTIVITY REGULATION Activated by autophosphorylation on Thr-1381 and Thr-1393 following oligomerization.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus. Oligomerizes after binding MAP4K2 or TRAF2. Interacts with AXIN1. Interacts (via the kinase catalytic domain) with STK38 (By similarity). Interacts with GRIPAP1 (By similarity).TISSUE SPECIFICITY Highly expressed in the heart and spleen while a lower level expression is seen in the liver.PTM Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt P53349 2 EQUAL 1512 EQUAL Reactome Database ID Release 82 9828385 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=9828385 Reactome R-MMU-166866 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-MMU-166866.1 MEKK1:activated TRAF6 Reactome DB_ID: 9828390 1 1 Reactome Database ID Release 82 9828390 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=9828390 Reactome R-MMU-166867 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-MMU-166867.1 Reactome Database ID Release 82 9828396 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=9828396 Reactome R-MMU-166869 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-MMU-166869.1 TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway or in short ECSIT (Kopp E et al 1999). Induced MEKK1 can activate both IKK alpha and IKK beta thus leading to induction of NF-kappa-B activation. MEKK1 was also shown to induce ERK1/2 and JNK activation [Yujiri T et al 1998].<p>Although TRAF6 interacts with several upstream mediators (IRAK1, IRAK2, TRIF), there is no data showing MEKK1 participating in the interaction with the TRAF6 activators. Therefore this reaction is simplified to include only TRAF6 and MEKK1. 9008162 Pubmed 1997 Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway Lee, FS Hagler, J Chen, ZJ Maniatis, T Cell 88:213-22 10465784 Pubmed 1999 ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway Kopp, E Medzhitov, R Carothers, J Xiao, C Douglas, I Janeway, CA Ghosh, S Genes Dev 13:2059-71 9836645 Pubmed 1998 Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption Yujiri, T Sather, S Fanger, GR Johnson, GL Science 282:1911-4 9689078 Pubmed 1998 MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta Lee, FS Peters, RT Dang, LC Maniatis, T Proc Natl Acad Sci U S A 95:9319-24 ACTIVATION Reactome Database ID Release 82 9828397 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=9828397 Ecsit ECSIT Q9QZH6 Reactome DB_ID: 9828394 UniProt:Q9QZH6 Ecsit UniProt Q9QZH6 49 EQUAL 431 EQUAL Reactome Database ID Release 82 9828394 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=9828394 Reactome R-MMU-168064 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-MMU-168064.1 TAK1-dependent IKK and NF-kappa-B activation 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> LEFT-TO-RIGHT CHUK, IKBKB and IKBKG form IKK complex IKBKA, IKBKB and IKBKG form IKK complex 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 Database ID Release 82 9888320 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=9888320 Reactome R-MMU-5609665 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-MMU-5609665.1 The multimeric I kappa B kinase (IKK) complex is a key regulator of NF-kappa-B signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading to proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKa (IKBKA, IKK1 or CHUK) and IKKb (IKK2 or IKBKB) kinases, and a regulatory subunit, NF-kappa-B essential modulator (NEMO, IKKg or IKBKG). IKBKG (NEMO) associates with the C-termini of unphosphorylated IKKs and promotes the IKK complex activation (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008). 20066092 Pubmed 2009 The NF-kappaB family of transcription factors and its regulation Oeckinghaus, Andrea Ghosh, Sankar Cold Spring Harb Perspect Biol 1:a000034 7479848 Pubmed 1995 Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Alkalay, I Yaron, A Hatzubai, A Orian, A Ciechanover, A Ben-Neriah, Y Proc Natl Acad Sci U S A 92:10599-603 9751060 Pubmed 1998 IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex Rothwarf, D M Zandi, E Natoli, G Karin, M Nature 395:297-300 18462684 Pubmed 2008 Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site Rushe, Mia Silvian, Laura Bixler, Sarah Chen, Ling Ling Cheung, Anne Bowes, Scott Cuervo, Hernan Berkowitz, Steven Zheng, Timothy Guckian, Kevin Pellegrini, Maria Lugovskoy, Alexey Structure 16:798-808 17000764 Pubmed 2006 Dimerization of the I kappa B kinase-binding domain of NEMO is required for tumor necrosis factor alpha-induced NF-kappa B activity Marienfeld, Ralf B Palkowitsch, Lysann Ghosh, Sankar Mol. Cell. Biol. 26:9209-19 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of IKBKG by TRAF6 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> 3 CHUK:p-S177,S181-IKBKB:IKBKG Reactome DB_ID: 9835818 O88351 phospho-p-S177,S181-IKBKB Reactome DB_ID: 9828527 177 EQUAL 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 82 9828527 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=9828527 Reactome R-MMU-202506 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-MMU-202506.1 1 1 1 Reactome Database ID Release 82 9835818 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=9835818 Reactome R-MMU-202513 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-MMU-202513.1 CHUK:p-S177,S181-IKBKB:pUb-IKBKG Reactome DB_ID: 9835848 O88522 K63polyUb-IKBKG Reactome DB_ID: 9835846 321 EQUAL 325 EQUAL 326 EQUAL 1 EQUAL 419 EQUAL Reactome Database ID Release 82 9835846 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=9835846 Reactome R-MMU-202530 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-MMU-202530.1 1 1 1 Reactome Database ID Release 82 9835848 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=9835848 Reactome R-MMU-202562 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-MMU-202562.1 ACTIVATION activeUnit: #Protein43 Converted from EntitySet in Reactome K63pUb-TRAF6:TAK1 complexes activated TRAF6:TAK1 complexes Reactome DB_ID: 9924898 hp-IRAK1:K63polyUboligo-TRAF6:Activated TAK1 complex Reactome DB_ID: 9849675 hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1 Reactome DB_ID: 9849222 hp-IRAK1:K63polyUb-TRAF6 Reactome DB_ID: 9849206 Q62406 phospho-p-2S,S376,T,T209,T387-IRAK1 Reactome DB_ID: 9849178 1 EQUAL 712 EQUAL Reactome Database ID Release 82 9849178 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=9849178 Reactome R-MMU-446682 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-MMU-446682.1 1 Traf6 K63polyUb-TRAF6 P70196 Reactome DB_ID: 9835794 124 EQUAL 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9835794 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=9835794 Reactome R-MMU-2685681 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-MMU-2685681.1 1 Reactome Database ID Release 82 9849206 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=9849206 Reactome R-MMU-450147 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-MMU-450147.1 1 2 3 Reactome Database ID Release 82 9849222 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=9849222 Reactome R-MMU-450144 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-MMU-450144.1 1 1 Reactome Database ID Release 82 9849675 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=9849675 Reactome R-MMU-450186 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-MMU-450186.1 K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1 Reactome DB_ID: 9849758 2 2 2 1 2 Reactome Database ID Release 82 9849758 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=9849758 Reactome R-MMU-847073 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-MMU-847073.1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 9849762 3 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 9849760 3 Q8CFA1 phospho-p-IRAK2 Reactome DB_ID: 9849158 1 EQUAL 625 EQUAL Reactome Database ID Release 82 9849158 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=9849158 Reactome R-MMU-446636 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-MMU-446636.1 1 Reactome Database ID Release 82 9849760 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=9849760 Reactome R-MMU-937064 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-MMU-937064.1 1 3 Reactome Database ID Release 82 9849762 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=9849762 Reactome R-MMU-937060 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-MMU-937060.1 ALPK1:ADP-heptose:p-T9-TIFA:polyUb-TRAF6:p-T184,T187-TAK1:TAB1:TAB2/TAB3: free polyUb chain Reactome DB_ID: 9921769 2 2 2 ALPK1:ADP-heptose:p-T9-TIFA oligomer:K63-linked pUb-TRAF6 oligomer Reactome DB_ID: 9921753 ALPK1:ADP-heptose:p-T9-TIFA oligomer Reactome DB_ID: 9921751 ALPK1:ADP heptose Reactome DB_ID: 9921742 ALPK1 Q9CXB8 Reactome DB_ID: 9921740 UniProt:Q9CXB8 UniProt Q9CXB8 1 EQUAL 1244 EQUAL Reactome Database ID Release 82 9921740 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=9921740 Reactome R-MMU-9645473 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-MMU-9645473.1 1 ADP-heptose ADP-L-beta-D-heptose ADP-L-glycero-D-manno-heptose Reactome DB_ID: 9645519 ADP-L-glycero-D-manno-heptose [ChEBI:15915] ADP-L-glycero-D-manno-heptose ChEBI CHEBI:15915 Reactome Database ID Release 82 9645519 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=9645519 Reactome R-ALL-9645519 10 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-ALL-9645519.10 1 Reactome Database ID Release 82 9921742 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=9921742 Reactome R-MMU-9645521 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-MMU-9645521.1 3 p-T9-TIFA:p-T9-TIFA Reactome DB_ID: 9921749 Q793I8 phospho-Tifa p-T9-TIFA Reactome DB_ID: 9921747 UniProt:Q793I8 Tifa UniProt Q793I8 9 EQUAL 1 EQUAL 184 EQUAL Reactome Database ID Release 82 9921747 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=9921747 Reactome R-MMU-9645512 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-MMU-9645512.1 2 Reactome Database ID Release 82 9921749 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=9921749 Reactome R-MMU-9645453 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-MMU-9645453.1 3 Reactome Database ID Release 82 9921751 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=9921751 Reactome R-MMU-9645404 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-MMU-9645404.1 1 3 Reactome Database ID Release 82 9921753 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=9921753 Reactome R-MMU-9645508 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-MMU-9645508.1 1 2 Reactome Database ID Release 82 9921769 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=9921769 Reactome R-MMU-9645449 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-MMU-9645449.1 Reactome Database ID Release 82 9924898 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=9924898 Reactome R-MMU-9758606 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-MMU-9758606.1 Reactome Database ID Release 82 9924899 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=9924899 Reactome Database ID Release 82 9924903 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=9924903 Reactome R-MMU-9758604 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-MMU-9758604.1 During the phosphorylation of the IKK beta (IKBKB), the regulatory subunit NEMO (IKBKG) undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 acts as a E3 ligase and induces this ubiquitination. Studies of different NF-kappa-B signaling pathways revealed several potential ubiquitination sites on IKBKG (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009). 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 17728323 Pubmed 2007 Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti Sebban-Benin, H Pescatore, A Fusco, F Pascuale, V Gautheron, J Yamaoka, S Moncla, A Ursini, MV Courtois, G Hum Mol Genet 127: INHIBITION Reactome Database ID Release 82 9924904 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=9924904 CHUK:IKBKB:IKBKG:USP18 Reactome DB_ID: 9924901 Usp18 USP18 Q9WTV6 Reactome DB_ID: 9852747 UniProt:Q9WTV6 Usp18 UniProt Q9WTV6 1 EQUAL 372 EQUAL Reactome Database ID Release 82 9852747 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=9852747 Reactome R-MMU-912325 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-MMU-912325.1 1 1 Reactome Database ID Release 82 9924901 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=9924901 Reactome R-MMU-9761338 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-MMU-9761338.1 LEFT-TO-RIGHT NF-kappa-B inhibitor binds NF-kappa-B complex 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 IkB NFkB inhibitor NF-kappaB inhibitor IkBA, IkBB NFKBIA, NFKBIB Reactome DB_ID: 9828499 Nfkbia NFKBIA Q9Z1E3 Reactome DB_ID: 9828493 UniProt:Q9Z1E3 Nfkbia UniProt Q9Z1E3 1 EQUAL 317 EQUAL Reactome Database ID Release 82 9828493 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=9828493 Reactome R-MMU-168151 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-MMU-168151.1 Nfkbib NFKBIB Q60778 Reactome DB_ID: 9828497 UniProt:Q60778 Nfkbib UniProt Q60778 1 EQUAL 356 EQUAL Reactome Database ID Release 82 9828497 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=9828497 Reactome R-MMU-168132 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-MMU-168132.1 Reactome Database ID Release 82 9828499 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=9828499 Reactome R-MMU-168143 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-MMU-168143.1 NFKB1(1-433), NFKB2(1-454):RELA Reactome DB_ID: 9828489 Converted from EntitySet in Reactome NFkB NFKB1(1-433), NFKB2(1-454) Nuclear factor NF-kappa-B Reactome DB_ID: 9828487 Nfkb1 NFKB1(1-433) P25799 Reactome DB_ID: 9828481 UniProt:P25799 Nfkb1 UniProt P25799 1 EQUAL 433 EQUAL Reactome Database ID Release 82 9828481 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=9828481 Reactome R-MMU-168168 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-MMU-168168.1 Nfkb2 NFKB2(1-454) Q9WTK5 Reactome DB_ID: 9828485 UniProt:Q9WTK5 Nfkb2 UniProt Q9WTK5 1 EQUAL 454 EQUAL Reactome Database ID Release 82 9828485 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=9828485 Reactome R-MMU-168144 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-MMU-168144.1 Reactome Database ID Release 82 9828487 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=9828487 Reactome R-MMU-177656 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-MMU-177656.1 1 Rela RELA Q04207 Reactome DB_ID: 9828477 UniProt:Q04207 Rela UniProt Q04207 1 EQUAL 551 EQUAL Reactome Database ID Release 82 9828477 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=9828477 Reactome R-MMU-168172 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-MMU-168172.1 1 Reactome Database ID Release 82 9828489 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=9828489 Reactome R-MMU-168155 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-MMU-168155.1 NFkB inhibitor:NFkB complex Reactome DB_ID: 9828501 1 1 Reactome Database ID Release 82 9828501 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=9828501 Reactome R-MMU-168130 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-MMU-168130.1 Reactome Database ID Release 82 9921303 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=9921303 Reactome R-MMU-9630923 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-MMU-9630923.1 NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NF-kappa-B inhibitors (IkBs, NFKBIA or NFKBIB). IkBs proteins such as NFKBIA, NFKBIB or NFKBIE are characterized by the presence of six to seven ankyrin repeat motifs, which mediate interaction with the Rel homology domain (RHD). RHD mediates DNA binding, dimerization and nuclear localization (Jacobs MD & Harrison SC 1998; Manavalan B et al. 2010). NF-kappa-B inhibitors (IkBs) mask the nuclear localization signal (NLS) of the NF-kappa-B p65 subunit (ReLA, p65) preventing the nuclear translocation of NF-kappa-B (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NF-kappa-B activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta) by the IκB kinase (IKK) complex. The phosphorylated NFKBIA is recognized by the E3 ligase complex leading to K48-linked ubiquitination, and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kappa-B dimer p50/p65 (RelA:NFKB1) into the nucleus to turn on target genes (Karin M & Ben-Neriah Y 2000, Kanarek N & Ben-Neriah Y 2012; Hoffmann A et al. 2006). Crystal structures of NF-kappa-B inhibitors:NF-kappaB complexes revealed that an NF-kappa-B dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012). 22435548 Pubmed 2012 Regulation of NF-κB by ubiquitination and degradation of the IκBs Kanarek, Naama Ben-Neriah, Yinon Immunol. Rev. 246:77-94 9865693 Pubmed 1998 Structure of an IkappaBalpha/NF-kappaB complex Jacobs, M D Harrison, S C Cell 95:749-58 17072323 Pubmed 2006 Transcriptional regulation via the NF-kappaB signaling module Hoffmann, A Natoli, G Ghosh, G Oncogene 25:6706-16 10837071 Pubmed 2000 Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity Karin, M Ben-Neriah, Y Annu. Rev. Immunol. 18:621-63 22435546 Pubmed 2012 NF-κB regulation: lessons from structures Ghosh, Gourisankar Wang, Vivien Ya-Fan Huang, De-Bin Fusco, Amanda Immunol. Rev. 246:36-58 15145317 Pubmed 2004 The two NF-kappaB activation pathways and their role in innate and adaptive immunity Bonizzi, G Karin, M Trends Immunol 25:280-8 21203422 Pubmed 2010 Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysis Manavalan, Balachandran Basith, Shaherin Choi, Yong-Min Lee, Gwang Choi, Sangdun PLoS ONE 5:e15782 21094161 Pubmed 2011 The RelA nuclear localization signal folds upon binding to IκBα Cervantes, Carla F Bergqvist, Simon Kjaergaard, Magnus Kroon, Gerard Sue, Shih-Che Dyson, H Jane Komives, Elizabeth A J. Mol. Biol. 405:754-64 LEFT-TO-RIGHT 2.7.11.1 Active IKBKB phosphorylates NF-kappa-B inhibitor 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> 4 Converted from EntitySet in Reactome Phospho-NF-kappaB Inhibitor Reactome DB_ID: 9828511 Q9Z1E3 phospho-Nfkbia p-S32,S36-NFKBIA Reactome DB_ID: 9828505 32 EQUAL 36 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 82 9828505 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=9828505 Reactome R-MMU-177677 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-MMU-177677.1 Q60778 phospho-Nfkbib p-S19,S23-NFKBIB Reactome DB_ID: 9828509 19 EQUAL 23 EQUAL 1 EQUAL 356 EQUAL Reactome Database ID Release 82 9828509 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=9828509 Reactome R-MMU-177670 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-MMU-177670.1 Reactome Database ID Release 82 9828511 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=9828511 Reactome R-MMU-177678 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-MMU-177678.1 4 ACTIVATION activeUnit: #Protein40 GENE ONTOLOGY GO:0004674 Reactome Database ID Release 82 9925084 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=9925084 Reactome Database ID Release 82 9925086 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=9925086 Reactome R-MMU-9773803 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-MMU-9773803.1 In human, IkBs (NFKBIA, NFKBIB or NFKBIE) are inhibitory proteins that sequesters NF-kappa-B in the cytoplasm by masking a nuclear localization signal, located just at the C-terminal end of the RelA (p65) subunit of the RelA:NFKB1 heterodimer.<p>A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.<br> 19666475 Pubmed 2009 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation Solt, LA Madge, LA May, MJ J Biol Chem 10723127 Pubmed 2000 Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex Gil, J Alcami, J Esteban, M Oncogene 19:1369-78 27701768 Pubmed 2017 Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB Yazdi, Samira Naumann, Michael Stein, Matthias Proteins 85:17-29 12221085 Pubmed 2002 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program Li, X Massa, PE Hanidu, A Peet, GW Aro, P Savitt, A Mische, S Li, J Marcu, KB J Biol Chem 277:45129-40 INHIBITION Reactome Database ID Release 82 9828543 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=9828543 Converted from EntitySet in Reactome NKIRAS Reactome DB_ID: 9828540 Q8CEC5 NKIRAS1 Reactome DB_ID: 9828534 UniProt:Q8CEC5 UniProt Q8CEC5 1 EQUAL 192 EQUAL Reactome Database ID Release 82 9828534 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=9828534 Reactome R-MMU-8952686 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-MMU-8952686.1 Q9CR56 NKIRAS2 Reactome DB_ID: 9828538 UniProt:Q9CR56 UniProt Q9CR56 1 EQUAL 191 EQUAL Reactome Database ID Release 82 9828538 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=9828538 Reactome R-MMU-8952684 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-MMU-8952684.1 Reactome Database ID Release 82 9828540 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=9828540 Reactome R-MMU-8952687 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-MMU-8952687.1 LEFT-TO-RIGHT NF-kappa-B complex is transported from cytosol 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> NFKB1(1-433), NFKB2(1-454):RELA Reactome DB_ID: 9828583 nucleoplasm GENE ONTOLOGY GO:0005654 Converted from EntitySet in Reactome NFKB1, NFKB2 Nuclear factor NF-kappa-B p50 Reactome DB_ID: 9828579 Nfkb1 NFKB1(1-433) P25799 Reactome DB_ID: 9828575 1 EQUAL 433 EQUAL Reactome Database ID Release 82 9828575 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=9828575 Reactome R-MMU-177655 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-MMU-177655.1 Nfkb2 NFKB2(1-454) Q9WTK5 Reactome DB_ID: 9828577 1 EQUAL 454 EQUAL Reactome Database ID Release 82 9828577 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=9828577 Reactome R-MMU-177674 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-MMU-177674.1 Reactome Database ID Release 82 9828579 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=9828579 Reactome R-MMU-177662 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-MMU-177662.1 1 Rela RELA Q04207 Reactome DB_ID: 9828581 1 EQUAL 551 EQUAL Reactome Database ID Release 82 9828581 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=9828581 Reactome R-MMU-177676 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-MMU-177676.1 1 Reactome Database ID Release 82 9828583 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=9828583 Reactome R-MMU-177673 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-MMU-177673.1 Reactome Database ID Release 82 9828609 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=9828609 Reactome R-MMU-168166 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-MMU-168166.1 NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NF-kappa-B2). All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefore, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.<br> 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 ACTIVATION Reactome Database ID Release 82 9828610 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=9828610 AGER ligands:AGER Reactome DB_ID: 9828607 Converted from EntitySet in Reactome AGER ligands Reactome DB_ID: 9828605 AGE adducts:Peptide Reactome DB_ID: 879479 extracellular region GENE ONTOLOGY GO:0005576 Peptide Reactome DB_ID: 879484 peptide [ChEBI:16670] peptide peptido peptidos Peptid ChEBI CHEBI:16670 Reactome Database ID Release 82 879484 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=879484 Reactome R-ALL-879484 2 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-ALL-879484.2 1 Converted from EntitySet in Reactome AGE adducts Reactome DB_ID: 879487 NECML N(6)-carboxymethyl-lysine N(6)-carboxymethyl-L-lysine Reactome DB_ID: 879473 N(6)-carboxymethyl-L-lysine [ChEBI:53014] N(6)-carboxymethyl-L-lysine ChEBI CHEBI:53014 Reactome Database ID Release 82 879473 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=879473 Reactome R-ALL-879473 3 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-ALL-879473.3 N(6)-(1-carboxyethyl)-L-lysine N-epsilon-(1-(1-carboxy)ethyl)lysine Reactome DB_ID: 938699 N(6)-(1-carboxyethyl)-L-lysine [ChEBI:60125] N(6)-(1-carboxyethyl)-L-lysine ChEBI CHEBI:60125 Reactome Database ID Release 82 938699 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=938699 Reactome R-ALL-938699 3 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-ALL-938699.3 Reactome Database ID Release 82 879487 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=879487 Reactome R-ALL-879487 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-ALL-879487.1 1 Reactome Database ID Release 82 879479 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=879479 Reactome R-ALL-879479 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-ALL-879479.1 S100B homodimer Reactome DB_ID: 9828593 S100B P50114 Reactome DB_ID: 9828591 UniProt:P50114 UniProt P50114 2 EQUAL 92 EQUAL Reactome Database ID Release 82 9828591 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=9828591 Reactome R-MMU-879433 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-MMU-879433.1 2 Reactome Database ID Release 82 9828593 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=9828593 Reactome R-MMU-879449 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-MMU-879449.1 HMGB1 P63158 Reactome DB_ID: 9828597 UniProt:P63158 UniProt P63158 2 EQUAL 215 EQUAL Reactome Database ID Release 82 9828597 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=9828597 Reactome R-MMU-879382 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-MMU-879382.1 P12023 APP(672-713) Reactome DB_ID: 9828601 UniProt:P12023 UniProt P12023 672 EQUAL 713 EQUAL Reactome Database ID Release 82 9828601 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=9828601 Reactome R-MMU-879340 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-MMU-879340.1 P12023 APP(672-711) Reactome DB_ID: 9828603 672 EQUAL 711 EQUAL Reactome Database ID Release 82 9828603 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=9828603 Reactome R-MMU-976740 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-MMU-976740.1 Reactome Database ID Release 82 9828605 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=9828605 Reactome R-MMU-879455 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-MMU-879455.1 1 Ager AGER Q62151 Reactome DB_ID: 9828587 UniProt:Q62151 Ager UniProt Q62151 23 EQUAL 404 EQUAL Reactome Database ID Release 82 9828587 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=9828587 Reactome R-MMU-197639 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-MMU-197639.1 1 Reactome Database ID Release 82 9828607 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=9828607 Reactome R-MMU-879365 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-MMU-879365.1 Regulation of NF-kappa B signaling 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> LEFT-TO-RIGHT LRRC14 binds IKBKB and CHUK LRRC14 binds IKBKB and IKBKA 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> Lrrc14 LRRC14 Q8VC16 Reactome DB_ID: 9924611 UniProt:Q8VC16 Lrrc14 UniProt Q8VC16 1 EQUAL 493 EQUAL Reactome Database ID Release 82 9924611 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=9924611 Reactome R-MMU-9749455 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-MMU-9749455.1 CHUK:IKBKB:LRRC14 Reactome DB_ID: 9924613 1 1 1 Reactome Database ID Release 82 9924613 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=9924613 Reactome R-MMU-9749467 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-MMU-9749467.1 Reactome Database ID Release 82 9924615 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=9924615 Reactome R-MMU-9749505 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-MMU-9749505.1 GENE ONTOLOGY GO:0043124 Leucine-rich repeat-containing protein 14 (LRRC14) binds to the helix-loop-helix (HLH) domain of IKBKB (Wu C et al. 2016). This binding blocks IKBKB interaction with IKBKG (NEMO) disrupting IκB kinase (IKK) complex formation and NF-kappa-B activation (Wu C et al. 2016). 27426725 Pubmed 2016 LRRC14 attenuates Toll-like receptor-mediated NF-κB signaling through disruption of IKK complex Wu, Chenglei Yang, Yexin Ou, Jiayu Zhu, Liang Zhao, W Cui, Jun Exp Cell Res 347:65-73 LEFT-TO-RIGHT NLRX1 binds CHUK:IKBKB:IKBKG NLRX1 binds activated IKK complex 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> Q3TL44 K63polyUb-NLRX1 Reactome DB_ID: 9924603 UniProt:Q3TL44 UniProt Q3TL44 87 EQUAL 975 EQUAL Reactome Database ID Release 82 9924603 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=9924603 Reactome R-MMU-9749510 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-MMU-9749510.1 CHUK:IKBKB:IKBKG:K63polyUb-NLRX1 Reactome DB_ID: 9924605 1 1 Reactome Database ID Release 82 9924605 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=9924605 Reactome R-MMU-9749472 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-MMU-9749472.1 Reactome Database ID Release 82 9924607 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=9924607 Reactome R-MMU-9749471 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-MMU-9749471.1 Nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family member X1 (NLRX1) has been implicated in regulation of the Toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-kappa-B) signaling pathway. NLRX1 deficiency enhanced phosphorylation of catalytic subunits (CHUK and IKBKB) of the IkB kinase (IKK) complex and NF-kappa-B activation and led to elevated production of inflammatory cytokines in mouse cells in response to bacterial lipopolysaccharide (LPS, a TLR4 ligand) (Allen IC et al. 2011; Xia X et al. 2011; Ma D et al. 2019). NLRX1-knockdown mice showed enhanced susceptibility to LPS-induced septic shock thus further confirming that NLRX1 functions as a negative regulator of TLR signaling in vivo (Xia X et al. 2011). NLRX1 was shown to interact with TRAF6 (Allen et al. 2011; Xia X et al. 2011) and the IKK complex (CHUK:IKBKB:IKBKG) (Xia X et al. 2011) in human and mouse cells. Specifically, in unstimulated cells, NLRX1 was shown to associate with TRAF6 (Xia X et al. 2011). Upon stimulation with LPS, NLRX1 is thought to undergo K63-linked polyubiquitination. Although TRAF6 possesses E3 ubiquitin ligase activity, the TRAF6 deficiency did not affect NLRX1 ubiquitination in mouse embryonic fibroblast (MEF) (Xia X et al. 2011). Further studies are required to identify E3 ubiquitin ligase which is responsible for the ubiquitination of NLRX1. Ubiquitinated NLRX1 then binds to the IKK complex, blocking phosphorylation of the catalytic subunits CHUK (IKBKA) and IKBKB (Xia X et al. 2011). Mutagenesis studies showed that the C-terminal leucine-rich repeat (LRR) domain of NLRX1 binds to the kinase domain of IKBKB (Xia X et al. 2011). <p>The regulatory effects of NLRX1 are highly cell type specific (reviewed in Fekete T et al. 2021). As a regulator of inflammation, NLRX1 has been implicated in the pathology of diverse diseases (reviewed in Pickering RJ & Booty LM 2021).<p>This Reactome event shows interaction between NLRX1 and the IKK complex. 30861394 Pubmed 2019 NLRX1 alleviates lipopolysaccharide-induced apoptosis and inflammation in chondrocytes by suppressing the activation of NF-κB signaling Ma, Ding Zhao, Yangxue She, Jiang Zhu, Yandong Zhao, Y Liu, Liang Zhang, Yingang Int Immunopharmacol 71:7-13 33525671 Pubmed 2021 Focusing on the Cell Type Specific Regulatory Actions of NLRX1 Fekete, Tünde Bencze, Dóra Bíró, Eduárd Benko, Szilvia Pázmándi, Kitti Int J Mol Sci 22: 21703539 Pubmed 2011 NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK Xia, Xiaojun Cui, Jun Wang, Helen Y Zhu, Liang Matsueda, Satoko Wang, Qinfu Yang, Xiaoang Hong, Jun Songyang, Z Chen, Zhijian J Wang, Rong-Fu Immunity 34:843-53 33314068 Pubmed 2021 NLR in eXile: Emerging roles of NLRX1 in immunity and human disease Pickering, Robert J Booty, Lee M Immunology 162:268-280 21703540 Pubmed 2011 NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways Allen, Irving C Moore, Chris B Schneider, Monika Lei, Yu Davis, Beckley K Scull, Margaret A Gris, Denis Roney, Kelly E Zimmermann, Albert G Bowzard, John B Ranjan, Priya Monroe, Kathryn M Pickles, Raymond J Sambhara, Suryaprakash Ting, Jenny P Y Immunity 34:854-65 LEFT-TO-RIGHT NLRC5 binds IKBKB and CHUK NLRC5 binds IKBKB and IKBKA 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> NLRC5 C3VPR6 Reactome DB_ID: 9924653 UniProt:C3VPR6 UniProt C3VPR6 1 EQUAL 1866 EQUAL Reactome Database ID Release 82 9924653 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=9924653 Reactome R-MMU-937324 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-MMU-937324.1 CHUK:IKBKB:NLRC5 Reactome DB_ID: 9924655 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 1 1 1 Reactome Database ID Release 82 9924655 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=9924655 Reactome R-MMU-9750228 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-MMU-9750228.1 Reactome Database ID Release 82 9924660 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=9924660 Reactome R-MMU-9750226 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-MMU-9750226.1 The I-kappa-B-kinase (IKK) complex, a key regulator of the nuclear factor kappa B (NF-kB) signaling pathway, consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). The IKK complex is responsible for the phosphorylation of inhibitors of NF-kB (IkBs), such as NFKBIA or NFKBIB. Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing the transcription factor NF-kB thereby allowing translocation of NF-kB to the nucleus to regulate gene expression (Oeckinghaus A and Ghosh S 2009). NOD-like receptor C5 (NLRC5), the transcriptional activator of genes coding for MHC-I, has been implicated in the regulation of inflammatory pathways and IFN-dependent antiviral defense (Benko S et al. 2010; Cui J et al. 2010). Overexpression of NLRC5 inhibited NFkB-luciferase reporter activity in human embryonic kidney 293T (HEK293T) cells treated with interleukin (IL)-1β, TNF-α or toll-like receptor (TLR) agonists such as bacterial LPS (TLR4 ligand) or R848 (TLR7/8 ligand) (Cui J et al. 2010). Similar findings were obtained with human monocytic THP-1 cells and murine embryonic fibroblasts (MEFs) (Cui J et al. 2010). Further, NLRC5 deficiency resulted in enhanced phosphorylation of IKBKB, CHUK, and increased expression of NF-kB-responsive cytokines (such as TNF-α and IL-6), in LPS-stimulated THP-1 and mouse macrophage RAW264.7 cells (Cui J et al. 2010). NLRC5 deficiency enhanced NF‐kB activation in mouse cells in response to TLR3, TLR4, TLR7, TLR9 ligands (Tong Y et al. 2012) and TLR2 ligand (Wang M et al. 2019). Knockdown of NLRC5 also enhanced cytokine response and antiviral immunity in vesicular stomatitis virus (VSV)-treated primary human monocytes, primary murine macrophages and RAW264.7 cells. Studies with NLRC5-deficient mice confirmed the regulatory role of NLRC5 in the induction of NF-kB and type I interferon in response to LPS or VSV infection (Tong Y et al. 2012). Moreover, NLRC5 co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in HEK293T cells (Cui J et al. 2010). Mutagenesis analysis revealed that human NLRC5 targets the amino-terminal kinase domain (KD) of IKBKB. Fractionation of RAW264.7 cells extracts on a size-exclusion column followed by immunoblotting analysis showed that both CHUK:IKBKB:IKBKG and CHUK:IKBKB:NLRC5 complexes co-exist in unstimulated cells suggesting that NLRC5 inhibits the interaction between IKBKG (NEMO) and IKBKB/CHUK (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK upon stimulation is regulated by TRAF2/TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). These data suggest that NLRC5 negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK. 20610642 Pubmed 2010 NLRC5 limits the activation of inflammatory pathways Benko, Szilvia Magalhaes, Joao G Philpott, Dana J Girardin, Stephen E J Immunol 185:1681-91 22473004 Pubmed 2012 Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice Tong, Yanzheng Cui, Jun Li, Qingtian Zou, Jia Wang, Helen Y Wang, Rong-Fu Cell Res 22:822-35 26620909 Pubmed 2015 Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch Meng, Qingcai Cai, Chunmei Sun, Tingzhe Wang, Qianliang Xie, Weihong Wang, Rongfu Cui, Jun J Cell Biol 211:1025-40 20434986 Pubmed 2010 NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways Cui, J Zhu, Lijun Xia, X Wang, HY Legras, X Hong, J Ji, J Shen, P Zheng, S Chen, ZJ Wang, RF Cell 141:483-96 30945291 Pubmed 2019 NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation Wang, Muzi Wang, Lixia Fang, Lei Li, Shuai Liu, Rongyu J Cell Physiol 234:19990-20001 INHIBITION Reactome Database ID Release 82 9924661 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=9924661 C3VPR6 K63polyUb-NLRC5 Reactome DB_ID: 9924658 1178 EQUAL 87 EQUAL 975 EQUAL Reactome Database ID Release 82 9924658 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=9924658 Reactome R-MMU-9750938 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-MMU-9750938.1 ACTIVATION Reactome Database ID Release 82 9924662 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=9924662 Usp14 USP14 Q9JMA1 Reactome DB_ID: 9894637 UniProt:Q9JMA1 Usp14 UniProt Q9JMA1 1 EQUAL 494 EQUAL Reactome Database ID Release 82 9894637 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=9894637 Reactome R-MMU-5689541 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-MMU-5689541.1 LEFT-TO-RIGHT 6.3.2.19 TRAF2,6 ubiquitinates NLRC5 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> 3 ACTIVATION Converted from EntitySet in Reactome TRAF2, TRAF6 Reactome DB_ID: 9911551 Traf2 TRAF2 P39429 Reactome DB_ID: 9821994 UniProt:P39429 Traf2 UniProt P39429 2 EQUAL 501 EQUAL Reactome Database ID Release 82 9821994 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=9821994 Reactome R-MMU-66370 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-MMU-66370.1 Reactome Database ID Release 82 9911551 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=9911551 Reactome R-MMU-918188 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-MMU-918188.1 Reactome Database ID Release 82 9924687 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=9924687 Reactome Database ID Release 82 9924689 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=9924689 Reactome R-MMU-9750946 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-MMU-9750946.1 NOD-like receptor C5 (NLRC5) functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). Active TRAF2/6 catalyzed K63-linked polyubiquitination of NLRC5 at K1178 in human and mouse cells in response to LPS stimulation. The ubiquitinated NLRC5 (K63-polyUb-NLRC5) blocked NLRC5 interaction with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. The TRAF2/TRAF6-mediated ubiquitination of NLRC5 was reversely regulated by USP14 (Meng Q et al. 2015). LEFT-TO-RIGHT USP14 deubiquitinates NLRC5 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> H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 82 29356 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=29356 Reactome R-ALL-29356 5 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-ALL-29356.5 COMPOUND C00001 3 ACTIVATION GENE ONTOLOGY GO:0061578 Reactome Database ID Release 82 9924684 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=9924684 Reactome Database ID Release 82 9924686 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=9924686 Reactome R-MMU-9750942 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-MMU-9750942.1 NLRC5 functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent K63-linked polyubiquitination of NLRC5 at K1178 (Meng Q et al. 2015). The ubiquitinated NLRC5 (K63-polyUb-NLRC5) showed lower ability to interact with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. Ubiquitin-specific protease 14 (USP14) was found to remove the polyUb chains from NLRC5 and thereby enhanced the NLRC5-mediated inhibition of NF-kB signaling (Meng Q et al. 2015). LEFT-TO-RIGHT USP18 binds IKBKG within IKK complex 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 Database ID Release 82 9925010 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=9925010 Reactome R-MMU-9761344 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-MMU-9761344.1 Expression of ubiquitin-specific protease 18 (USP18) is induced by various Toll-like receptor (TLR) ligands in human monocytes and macrophages (Yang Z et al. 2015). A nuclear factor kappa B (NF-kappa-B, NF-κB) luciferase reporter gene assay showed that expression of tagged USP18 negatively regulates TLR-mediated activation of NF-kappa B in human embryonic kidney HEK293T cells. USP18 also inhibited the degradation of endogenous IκBα protein in HEK293T cells (Yang Z et al. 2015). Further, knockdown of USP18 by USP18-specific small interfering RNAs (siRNA) enhanced NF-kappaB activity in LPS- stimulated human monocyte-like THP-1 cells (Yang Z et al. 2015). Co-immunoprecipitation and immunoblot analysis revealed that USP18 targets the regulatory subunit IKBKG (NEMO) of the IKK (CHUK:IKBKB:IKBKG) complex upon co-expression of tagged proteins in HEK293T cells. Mutagenesis analysis using HEK293T cells showed that USP18 directly binds to the UBAN motif of IKBKG inhibiting K63-linked ubiquitination of IKBKG by masking the ubiquitination sites at K325 and K326 (Yang Z et al. 2015). In addition, USP18 targets the TAK1-TAB1 complex and cleaves the K63-linked polyubiquitin chains of TAK1 in a protease-dependent manner (Liu X et al. 2013; Yang Z et al. 2015). These data suggest that USP18 functions as a negative regulator of NF-kappa-B activation.<p>This Reactome events shows USP18 binding to IKBKG within the IKK (CHUK:IKBKB:IKBKG) complex. 23825189 Pubmed 2013 USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex Liu, Xikui Li, Hongxiu Zhong, Bo Blonska, Marzenna Gorjestani, Sara Yan, Ming Tian, Qiang Zhang, Dong-Er Lin, Xin Dong, Chen J. Exp. Med. 210:1575-90 26240016 Pubmed 2015 USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms Yang, Zhifen Xian, Huifang Hu, Jiajia Tian, Shuo Qin, Yunfei Wang, Rong-Fu Cui, Jun Sci Rep 5:12738 LEFT-TO-RIGHT N4BP1 binds IKBKG 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> N4bp1 N4BP1 Q6A037 Reactome DB_ID: 9924878 UniProt:Q6A037 N4bp1 UniProt Q6A037 1 EQUAL 896 EQUAL Reactome Database ID Release 82 9924878 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=9924878 Reactome R-MMU-9757941 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-MMU-9757941.1 IKBKG:N4BP1 Reactome DB_ID: 9924887 1 1 Reactome Database ID Release 82 9924887 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=9924887 Reactome R-MMU-9757950 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-MMU-9757950.1 Reactome Database ID Release 82 9924889 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=9924889 Reactome R-MMU-9757954 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-MMU-9757954.1 NEDD4-binding protein 1 (N4BP1) negatively regulates Toll-like receptor (TLR)-induced activation of NF-kappaB and cytokine production in human and mouse cells (Shi H et al. 2021; Gitlin AD et al. 2020). N4BP1 was found to target IKBKG (NEMO, IKKg), the regulatory subunit of the IkB kinase (IKK) complex, which is essential for NF-kappa-B activation. N4BP1 co-immunoprecipitated with IKBKG (NEMO) upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Shi H et al. 2021). The interaction between endogenous N4BP1 and IKBKG was also detected in mouse peritoneal macrophages (Shi H et al. 2021). Linear and K63-linked polyubiquitin chains promoted the interaction between N4BP1 and IKBKG. Binding of N4BP1 to IKBKG is thought to block homooligomerization of IKBKG thereby leading to destabilization of the IKK complex (Shi H et al. 2021). In addition, N4BP1 deficiency in mice and mouse cells increased the production of select NF-kappa-B-dependent cytokines via TICAM1 (TRIF)-independent TLR2, TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). Similar results were observed in human monocytic THP-1 cells (Shi H et al. 2021). Further, TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Downregulation of N4BP1 was not observed in TICAM-1-deficient mouse macrophages treated with LPS (Shi H et al. 2021). These data suggest that N4BP1 limits TICAM1-independent TLR-induced NF-kappa-B activation by blocking the function of the IKK complex, while TICAM1-dependent TLR signaling leads to CASP8-mediated inactivation of N4BP1(Shi H et al. 2021; Gitlin AD et al. 2020). 32971525 Pubmed 2020 Integration of innate immune signalling by caspase-8 cleavage of N4BP1 Gitlin, Alexander D Heger, Klaus Schubert, Alexander F Reja, Rohit Yan, Donghong Pham, Victoria C Suto, Eric Zhang, Juan Kwon, Youngsu C Freund, Emily C Kang, Jing Pham, Anna Caothien, Roger Bacarro, Natasha Hinkle, Trent Xu, Min McKenzie, Brent S Haley, Benjamin Lee, Wyne P Lill, Jennie R Roose-Girma, Merone Dohse, Monika Webster, Joshua D Newton, Kim Dixit, Vishva M Nature 587:275-280 33654074 Pubmed 2021 N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization Shi, Hexin Sun, Lei Wang, Ying Liu, Aijie Zhan, Xiaoming Li, Xiaohong Tang, Miao Anderton, Priscilla Hildebrand, Sara Quan, Jiexia Ludwig, Sara Moresco, Eva Marie Y Beutler, B Nat Commun 12:1379 INHIBITION Reactome Database ID Release 82 9924890 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=9924890 active caspase-8 Reactome DB_ID: 9824349 Caspase-8 dimer Reactome DB_ID: 9824347 Casp8 CASP8(385-479) O89110 Reactome DB_ID: 9824345 UniProt:O89110 Casp8 UniProt O89110 385 EQUAL 479 EQUAL Reactome Database ID Release 82 9824345 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=9824345 Reactome R-MMU-76158 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-MMU-76158.1 1 Casp8 CASP8(217-374) O89110 Reactome DB_ID: 9824343 217 EQUAL 374 EQUAL Reactome Database ID Release 82 9824343 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=9824343 Reactome R-MMU-75975 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-MMU-75975.1 1 Reactome Database ID Release 82 9824347 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=9824347 Reactome R-MMU-139950 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-MMU-139950.1 2 Reactome Database ID Release 82 9824349 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=9824349 Reactome R-MMU-2562550 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-MMU-2562550.1 LEFT-TO-RIGHT 3.4 CASP8 cleaves N4BP1 at D424, D490 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 N4bp1 N4BP1(1-424) Q6A037 Reactome DB_ID: 9924880 1 EQUAL 424 EQUAL Reactome Database ID Release 82 9924880 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=9924880 Reactome R-MMU-9757940 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-MMU-9757940.1 ACTIVATION GENE ONTOLOGY GO:0008234 Reactome Database ID Release 82 9924883 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=9924883 Reactome Database ID Release 82 9924885 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=9924885 Reactome R-MMU-9757951 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-MMU-9757951.1 GENE ONTOLOGY GO:0043122 NEDD4-binding protein 1 (N4BP1) limits the activation of NF-kappaB downstream of TICAM1 (TRIF)-independent Toll-like receptor 2 (TLR2), TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Functional studies of N4BP1 mutants expressed in human embryonic kidney 293T (HEK293T) cells suggest that human N4BP1 is cleaved after D424 and/or D490 (Shi H et al. 2021). Reactome Database ID Release 82 9928560 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=9928560 Reactome R-MMU-9758274 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-MMU-9758274.1 Nuclear factor kappa B (NF-kappa-B, NF-κB) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-κB is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-κB inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-κB preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-κB activation involves phosphorylation of IkBs by the IκB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israël A 2010). The activated NF-κB signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-κB activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-κB is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019).<p>This Reactome module describes several molecular mechanisms that regulate TLR-mediated NF-κB signaling at the level of the IKK signaling complex. <br><br> 34977871 Pubmed 2021 NF-κB signaling in inflammation and cancer Zhang, Tao Ma, Chao Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo MedComm (2020) 2:618-653 24611065 Pubmed 2014 Regulation of the NF-κB-Mediated Transcription of Inflammatory Genes Bhatt, Dev Ghosh, Sankar Front Immunol 5:71 22586649 Pubmed 2011 NF-κB in cancer: a matter of life and death Aggarwal, Bharat B Sung, Bokyung Cancer Discov 1:469-71 34269817 Pubmed 2021 Inhibitory feedback control of NF-κB signalling in health and disease Prescott, Jack A Mitchell, Jennifer P Cook, Simon J Biochem J 478:2619-2664 32958760 Pubmed 2020 Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study Yu, Hui Lin, Liangbin Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo Signal Transduct Target Ther 5:209 31024544 Pubmed 2019 NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration Dorrington, Michael G Fraser, Iain D C Front Immunol 10:705 29158945 Pubmed 2017 NF-κB signaling in inflammation Liu, Ting Zhang, Lingyun Joo, Donghyun Sun, Shao-Cong Signal Transduct Target Ther 2: 34434197 Pubmed 2021 NF-κB: At the Borders of Autoimmunity and Inflammation Barnabei, Laura Laplantine, Emmanuel Mbongo, William Rieux-Laucat, Frederic Weil, Robert Front Immunol 12:716469 30778349 Pubmed 2019 Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis Mussbacher, Marion Salzmann, Manuel Brostjan, Christine Hoesel, Bastian Schoergenhofer, Christian Datler, Hannes Hohensinner, Philipp Basílio, José Petzelbauer, Peter Assinger, Alice Schmid, Johannes A Front Immunol 10:85 20300203 Pubmed 2010 The IKK complex, a central regulator of NF-kappaB activation Israel, A Cold Spring Harb Perspect Biol 2:a000158 Reactome Database ID Release 82 9926114 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=9926114 Reactome R-MMU-445989 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-MMU-445989.1 GENE ONTOLOGY GO:0051092 NF-kappa-B is sequestered in the cytoplasm in a complex with inhibitor of NF-kappa-B (IkB). Almost all NF-kappa-B activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappa-B from the complex. This allows translocation of NF-kappa-B to the nucleus where it regulates gene expression. 15837794 Pubmed 2005 Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes Thiefes, A Wolter, S Mushinski, JF Hoffmann, E Dittrich-Breiholz, O Graue, N Dörrie, A Schneider, H Wirth, D Luckow, B Resch, K Kracht, M J Biol Chem 280:27728-41 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 MAP kinase activation 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> JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 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> LEFT-TO-RIGHT 2.7.11.1 Activated TAK1 phosphorylates 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> 2 Converted from EntitySet in Reactome MKK4, MKK7 MAP2K7,MAP2K4 Reactome DB_ID: 9849747 MAP2K7 Q8CE90 Reactome DB_ID: 9849743 UniProt:Q8CE90 UniProt Q8CE90 2 EQUAL 419 EQUAL Reactome Database ID Release 82 9849743 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=9849743 Reactome R-MMU-450276 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-MMU-450276.1 MAP2K4 P47809 Reactome DB_ID: 9849745 UniProt:P47809 Map2k4 Map2k4 Jnkk1 Mek4 Mkk4 Prkmk4 Sek1 Serk1 Skk1 FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to pro-inflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.ACTIVITY REGULATION Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.SUBUNIT Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 (By similarity).TISSUE SPECIFICITY Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain.DOMAIN The DVD domain (residues 362-385) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity).DOMAIN The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.PTM Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase kinase kinases (MAP3Ks).DISRUPTION PHENOTYPE Causes irregular alignment of Purkinje cells in the cerebellum and delayed radial migration in the cortex during brain development. The cardiac-specific deletion prevents pathological cardiac hypertrophy.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt P47809 1 EQUAL 399 EQUAL Reactome Database ID Release 82 9849745 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=9849745 Reactome R-MMU-168107 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-MMU-168107.1 Reactome Database ID Release 82 9849747 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=9849747 Reactome R-MMU-450305 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-MMU-450305.1 Converted from EntitySet in Reactome p-MAP2K4/p-MAP2K7 phospho MKK4/ phospho MKK7 Reactome DB_ID: 9828570 Q8CE90 phospho-p-S271,T275-MAP2K7 Reactome DB_ID: 9828563 271 EQUAL 275 EQUAL 1 EQUAL 419 EQUAL Reactome Database ID Release 82 9828563 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=9828563 Reactome R-MMU-450353 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-MMU-450353.1 P47809 phospho-p-S257,T261-MAP2K4 Reactome DB_ID: 9828568 257 EQUAL 261 EQUAL 1 EQUAL 399 EQUAL Reactome Database ID Release 82 9828568 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=9828568 Reactome R-MMU-168170 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-MMU-168170.1 Reactome Database ID Release 82 9828570 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=9828570 Reactome R-MMU-450299 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-MMU-450299.1 2 ACTIVATION activeUnit: #Protein26 Converted from EntitySet in Reactome Activated TAK complexes Reactome DB_ID: 9849764 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 9849756 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 9849754 PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 9849752 P58801 Ub-209-RIPK2 Reactome DB_ID: 9849750 UniProt:P58801 Ripk2 Ripk2 FUNCTION Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is release from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Also plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).SUBUNIT Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1. Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with NLRP10 (By similarity). Interacts with CARD9 (PubMed:17187069). Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts (via CARD domain) with NGFR (via death domain) (By similarity).DOMAIN Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.PTM Autophosphorylated. Autophosphorylation at Tyr-473 is necessary for effective NOD2 signaling.PTM Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Also undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (By similarity). Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (PubMed:30405132). Ubiquitination at Lys-502 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions (By similarity).DISRUPTION PHENOTYPE Mice show a lack of chemokine production induced by bacterial peptidoglycans. RIPK2 deficiency affects cellular signaling and cytokine responses triggered by NOD1 and NOD2 ligands, but not TLR ligands.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. UniProt P58801 209 EQUAL 1 EQUAL 540 EQUAL Reactome Database ID Release 82 9849750 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=9849750 Reactome R-MMU-706483 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-MMU-706483.1 6 Converted from EntitySet in Reactome PAMP:NOD oligomer Reactome DB_ID: 9828629 NOD1:iE-DAP oligomer Reactome DB_ID: 9828620 NOD1:iE-DAP Reactome DB_ID: 9828616 NOD1 Q8BHB0 Reactome DB_ID: 9828614 UniProt:Q8BHB0 UniProt Q8BHB0 1 EQUAL 953 EQUAL Reactome Database ID Release 82 9828614 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=9828614 Reactome R-MMU-168407 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-MMU-168407.1 1 iE-DAP intracellular D-gamma-Glutamyl-meso-diamino-pimelic acid gamma-D-glutamyl-meso-diaminopimelic acid Reactome DB_ID: 622271 gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271] gamma-D-glutamyl-meso-diaminopimelic acid ChEBI CHEBI:59271 Reactome Database ID Release 82 622271 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=622271 Reactome R-ALL-622271 4 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-ALL-622271.4 1 Reactome Database ID Release 82 9828616 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=9828616 Reactome R-MMU-168408 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-MMU-168408.1 6 Reactome Database ID Release 82 9828620 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=9828620 Reactome R-MMU-622306 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-MMU-622306.1 MDP:NOD2 oligomer Reactome DB_ID: 9828627 MDP:NOD2 Reactome DB_ID: 9828625 MDP muramyl dipeptide Reactome DB_ID: 708341 muramyl dipeptide [ChEBI:59414] muramyl dipeptide ChEBI CHEBI:59414 Reactome Database ID Release 82 708341 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=708341 Reactome R-ALL-708341 4 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-ALL-708341.4 1 Nod2 NOD2 Q8K3Z0 Reactome DB_ID: 9828623 UniProt:Q8K3Z0 Nod2 Nod2 Card15 FUNCTION Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity (PubMed:19805227, PubMed:21715553). Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response (PubMed:22607974). Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561). Component of an autophagy-mediated antibacterial pathway together with ATG16L1. Also plays a role in sensing single-stranded RNA (ssRNA) from viruses. Interacts with mitochondrial antiviral signaling/MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon. Besides recognizing pathogens, participates in surveillance of cellular homeostasis through sensing and binding to the cytosolic metabolite sphingosine-1-phosphate and then initating inflammation process.SUBUNIT Component of a signaling complex consisting of ARHGEF2, NOD2 and RIPK2. Interacts (via CARD domain) with RIPK2 (via CARD domain). Interacts with ATG16L1. Interacts (via NACHT domain) with CARD9 (PubMed:17187069). Interacts with ANKRD17 (via N-terminus). Interacts with HSPA1A; the interaction enhances NOD2 stability. Interacts (via both CARD domains) with HSP90; the interaction enhances NOD2 stability (PubMed:23019338). Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 degradation. Interacts (via CARD domain) with ERBBI2P; the interaction inhibits activation of NOD2 (PubMed:16203728). Interacts (via CARD domain) with CASP1; this interaction leads to IL1B processing (PubMed:18511561). Also interacts with CASP4. Interacts with NLRP1; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and leads to increased IL1B release. Interacts with MAPKBP1; the interaction is enhanced in the presence of muramyl dipeptide (MDP). Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts with ANKHD1, C10ORF67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM (By similarity). Interacts with NLRP12; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (By similarity).DOMAIN The ATG16L1-binding motif mediates interaction with ATG16L1.DOMAIN Intramolecular interactions between the N-terminal moiety and the leucine-rich repeats (LRR) may be important for autoinhibition in the absence of activating signal. In the absence of LRRs, the protein becomes a constitutive activator of CASP1 cleavage and proIL1B processing.PTM Polyubiquitinated following MDP stimulation, leading to proteasome-mediated degradation.PTM Palmitoylated. Palmitoylation is required for proper recruitment to the bacterial entry site and hence for proper signaling upon cognate peptidoglycan detection.DISRUPTION PHENOTYPE Deletion mice have an altered composition of the gut microbiota with a net increase in the abundance of bacteroidetes and firmicutes phyla in the feces and terminal ileum compared to WT mice due to the fact that they are unable to kill bacteria effectively (PubMed:19805227). NOD1/NOD2 double knockout mice are protected from high-fat diet-induced inflammation, lipid accumulation, and peripheral insulin intolerance (PubMed:21715553). UniProt Q8K3Z0 1 EQUAL 1040 EQUAL Reactome Database ID Release 82 9828623 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=9828623 Reactome R-MMU-168411 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-MMU-168411.1 1 Reactome Database ID Release 82 9828625 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=9828625 Reactome R-MMU-168414 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-MMU-168414.1 6 Reactome Database ID Release 82 9828627 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=9828627 Reactome R-MMU-708350 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-MMU-708350.1 Reactome Database ID Release 82 9828629 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=9828629 Reactome R-MMU-708346 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-MMU-708346.1 1 Reactome Database ID Release 82 9849752 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=9849752 Reactome R-MMU-706482 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-MMU-706482.1 1 1 Reactome Database ID Release 82 9849754 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=9849754 Reactome R-MMU-706480 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-MMU-706480.1 1 1 Reactome Database ID Release 82 9849756 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=9849756 Reactome R-MMU-706477 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-MMU-706477.1 Reactome Database ID Release 82 9849764 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=9849764 Reactome R-MMU-772536 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-MMU-772536.1 Reactome Database ID Release 82 9849765 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=9849765 Reactome Database ID Release 82 9849767 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=9849767 Reactome R-MMU-450337 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-MMU-450337.1 In human, phosphorylation of MKK4 (MAP2K4) and MKK7 (MAP2K7) by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.<p>Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. 8533096 Pubmed 1995 Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction Yamaguchi, K Shirakabe, K Shibuya, H Irie, K Oishi, I Ueno, N Taniguchi, T Nishida, E Matsumoto, K Science 270:2008-11 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 LEFT-TO-RIGHT 2.7.11 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> 2 Converted from EntitySet in Reactome MAPK8,9,10 JNKs: MAPK8_MAPK9_MAPK10 Reactome DB_ID: 9828549 MAPK8 Q91Y86 Reactome DB_ID: 9824393 UniProt:Q91Y86 Mapk8 Mapk8 Jnk1 Prkm8 FUNCTION Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death (PubMed:9393873). Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity (PubMed:11602244). Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells (PubMed:10811224). Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy (By similarity). Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons (PubMed:21297631). In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone (PubMed:21297631). Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity (By similarity). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation (PubMed:29153991). Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (By similarity). In neurons, phosphorylates SYT4 which captures neuronal dense core vesicles at synapses (By similarity). Phosphorylates EIF4ENIF1/4-ET in response to oxidative stress, promoting P-body assembly (By similarity). Phosphorylates SIRT6 in response to oxidative stress, stimulating its mono-ADP-ribosyltransferase activity (By similarity).ACTIVITY REGULATION Inhibited by SERPINB3 (By similarity). Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1.SUBUNIT Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4 (PubMed:10523642, PubMed:12391307, PubMed:11562351). These proteins also bind other components of the JNK signaling pathway. Forms a complex with MAPK8IP1 and ARHGEF28 (PubMed:14499478). Interacts with TP53 and WWOX (By similarity). Interacts with JAMP (PubMed:16166642). Interacts with NFATC4 (By similarity). Interacts with MECOM; regulates JNK signaling (By similarity). Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates (By similarity). Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs under both normal growth conditions and immediately upon heat shock (By similarity). Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells (PubMed:19966288). Interacts with GRIPAP1 (By similarity). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-347' (PubMed:29153991). Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8IP1/JIP1 (PubMed:23963642). Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK9/JNK2 (PubMed:27084103).TISSUE SPECIFICITY Brain (at protein level).DEVELOPMENTAL STAGE At 15.5 dpc, mid to low expression throughout the midbrain, with more prominent levels in the telencephalon, especially in the intermediate zone, the midbrain roof, the olfactory epithelium, the inferior colliculus, and the medulla oblongata. telencephalon revealed concentrated (at protein level).INDUCTION In T-cells, following T-cell receptor (TCR) activation. Levels peak 48 hours after TCR and CD-28 costimulation.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Phosphorylated by TAOK2 (By similarity). Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme (PubMed:11562351). May be phosphorylated at Thr-183 and Tyr-185 by MAP3K1/MEKK1 (PubMed:17761173). Phosphorylated form is more concentrated at synapses than none-phosphorylated (By similarity).DISRUPTION PHENOTYPE At 14.5 dpc, brain intermediate zone and cortical plate are significantly thicker in mutant mice compared to wild type. The number of neuronal cells is increased in the cortical plate and intermediate zone. Cell cycle exit is decreased by 13% in the ventricular and subventricular zones. In 17.5 dpc brains, the ventricular zone was thinner in mutant mice compared to wild type animals, consistent with the increased number of neurons in the cortical plate. TUBB3 is consistently more diffuse and less structured in mutant telencephalon than in wild type.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt Q91Y86 1 EQUAL 427 EQUAL Reactome Database ID Release 82 9824393 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=9824393 Reactome R-MMU-168141 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-MMU-168141.1 MAPK9 Q9WTU6 Reactome DB_ID: 9828545 UniProt:Q9WTU6 UniProt Q9WTU6 1 EQUAL 424 EQUAL Reactome Database ID Release 82 9828545 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=9828545 Reactome R-MMU-450355 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-MMU-450355.1 MAPK10 Q61831 Reactome DB_ID: 9828547 UniProt:Q61831 UniProt Q61831 1 EQUAL 464 EQUAL Reactome Database ID Release 82 9828547 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=9828547 Reactome R-MMU-450352 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-MMU-450352.1 Reactome Database ID Release 82 9828549 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=9828549 Reactome R-MMU-450289 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-MMU-450289.1 2 Converted from EntitySet in Reactome p-MAPK8,9,10 phosphorylated JNKs: MAPK8_MAPK9_MAPK10 Reactome DB_ID: 9828557 Q91Y86 phospho-p-T,Y-MAPK8 Reactome DB_ID: 9828551 O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 427 EQUAL Reactome Database ID Release 82 9828551 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=9828551 Reactome R-MMU-194371 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-MMU-194371.1 Q9WTU6 phospho-p-T183,Y185-MAPK9 Reactome DB_ID: 9828553 183 EQUAL 185 EQUAL 1 EQUAL 424 EQUAL Reactome Database ID Release 82 9828553 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=9828553 Reactome R-MMU-450293 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-MMU-450293.1 Q61831 phospho-p-T221,Y223-MAPK10 Reactome DB_ID: 9828555 221 EQUAL 223 EQUAL 1 EQUAL 464 EQUAL Reactome Database ID Release 82 9828555 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=9828555 Reactome R-MMU-450214 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-MMU-450214.1 Reactome Database ID Release 82 9828557 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=9828557 Reactome R-MMU-450226 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-MMU-450226.1 ACTIVATION GENE ONTOLOGY GO:0008545 Reactome Database ID Release 82 9828571 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=9828571 Reactome Database ID Release 82 9828573 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=9828573 Reactome R-MMU-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-MMU-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). 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 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 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 LEFT-TO-RIGHT 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 p-MAPK8,9,10 Phosphorylated JNKs: MAPK8, MAPK9, MAPK10 Reactome DB_ID: 9828458 Q91Y86 phospho-p-T,Y-MAPK8 Reactome DB_ID: 9828444 1 EQUAL 427 EQUAL Reactome Database ID Release 82 9828444 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=9828444 Reactome R-MMU-216349 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-MMU-216349.1 Q9WTU6 phospho-p-T183,Y185-MAPK9 Reactome DB_ID: 9828450 1 EQUAL 424 EQUAL Reactome Database ID Release 82 9828450 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=9828450 Reactome R-MMU-450319 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-MMU-450319.1 Q61831 phospho-p-T221,Y223-MAPK10 Reactome DB_ID: 9828456 1 EQUAL 464 EQUAL Reactome Database ID Release 82 9828456 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=9828456 Reactome R-MMU-450311 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-MMU-450311.1 Reactome Database ID Release 82 9828458 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=9828458 Reactome R-MMU-450253 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-MMU-450253.1 Reactome Database ID Release 82 9849777 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=9849777 Reactome R-MMU-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-MMU-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 Reactome Database ID Release 82 9926112 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=9926112 Reactome R-MMU-450321 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-MMU-450321.1 GENE ONTOLOGY GO:0007254 C-Jun NH2 terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases, that belong to mitogen activated protein kinase family (MAPKs - also known as stress-activated protein kinases, SAPKs). The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. <p>The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta. The first two are ubiquitously expressed, whereas the JNK3 protein is found mainly in brain and to a lesser extent in heart and testes. As a result of alternative gene splicing all cells express distinct active forms of JNK from 46 to 55 kDa in size. Sequence alignment of these different products shows homologies of >80%. In spite of this similarity, the multiple JNK isoforms differ in their ability to bind and phosphorylate different target proteins, thus leading to the distinctive cellular processes: induction of apoptosis, or enhancment of cell survival, or proliferation.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). 9851932 Pubmed 1998 Defective T cell differentiation in the absence of Jnk1 Dong, C Yang, DD Wysk, M Whitmarsh, AJ Davis, RJ Flavell, RA Science 282:2092-5 26988982 Pubmed 2016 IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells Li, Jing-kun Nie, Lin Zhao, Yun-peng Zhang, Yuan-qiang Wang, Xiaoqing Wang, Shuai-shuai Liu, Yi Zhao, Hua Cheng, Lei J Transl Med 14:77 16937364 Pubmed 2006 The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting Bogoyevitch, MA Bioessays 28:923-34 8177321 Pubmed 1994 The stress-activated protein kinase subfamily of c-Jun kinases Kyriakis, JM Banerjee, P Nikolakaki, E Dai, T Rubie, EA Ahmad, MF Avruch, Joseph Woodgett, JR Nature 369:156-60 activated TAK1 mediates p38 MAPK activation 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> LEFT-TO-RIGHT 2.7.11.1 activated human TAK1 phosphorylates MKK3/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> 2 Converted from EntitySet in Reactome MKK3, MKK6 MAP2K3,MAP2K6 Reactome DB_ID: 9849773 MAP2K3 O09110 Reactome DB_ID: 9849769 UniProt:O09110 UniProt O09110 1 EQUAL 347 EQUAL Reactome Database ID Release 82 9849769 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=9849769 Reactome R-MMU-168051 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-MMU-168051.1 MAP2K6 P70236 Reactome DB_ID: 9849771 UniProt:P70236 Map2k6 Map2k6 Prkmk6 Sapkk3 FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.ACTIVITY REGULATION Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.SUBUNIT Dimer. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. Interacts with DCTN1. Interacts with EIF2AK2/PKR.INDUCTION MSAPK14 can negatively regulate the stability of the MAP2K6/MKK6 mRNA and thus control the steady-state concentration of one of its upstream activator.DOMAIN The DVD domain (residues 311-334) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity).DOMAIN The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.PTM Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt P70236 1 EQUAL 334 EQUAL Reactome Database ID Release 82 9849771 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=9849771 Reactome R-MMU-167998 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-MMU-167998.1 Reactome Database ID Release 82 9849773 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=9849773 Reactome R-MMU-167916 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-MMU-167916.1 2 Converted from EntitySet in Reactome p-MKK3,p-MKK6 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 Reactome DB_ID: 9849720 O09110 phospho-p-S189,T193-MAP2K3 Reactome DB_ID: 9849717 189 EQUAL 193 EQUAL 1 EQUAL 347 EQUAL Reactome Database ID Release 82 9849717 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=9849717 Reactome R-MMU-167955 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-MMU-167955.1 Phospho MKK6_MOUSE Reactome DB_ID: 532220 207 EQUAL 211 EQUAL 1 EQUAL 334 EQUAL Reactome Database ID Release 82 532220 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=532220 Reactome R-MMU-532220 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-MMU-532220.1 Reactome Database ID Release 82 9849720 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=9849720 Reactome R-MMU-167984 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-MMU-167984.1 ACTIVATION activeUnit: #Protein26 Reactome Database ID Release 82 9849775 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=9849775 Reactome R-MMU-450346 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-MMU-450346.1 Human MKK3 (MAP2K4) and MKK6 (MAP2K6) are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK.<p> Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 . 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 LEFT-TO-RIGHT 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 p-MKK3,p-MKK6 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 Reactome DB_ID: 9849726 O09110 phospho-p-S189,T193-MAP2K3 Reactome DB_ID: 9849722 1 EQUAL 347 EQUAL Reactome Database ID Release 82 9849722 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=9849722 Reactome R-MMU-450229 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-MMU-450229.1 P70236 phospho-p-S207,T211-MAP2K6 Reactome DB_ID: 9849724 1 EQUAL 334 EQUAL Reactome Database ID Release 82 9849724 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=9849724 Reactome R-MMU-450258 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-MMU-450258.1 Reactome Database ID Release 82 9849726 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=9849726 Reactome R-MMU-450343 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-MMU-450343.1 Reactome Database ID Release 82 9849728 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=9849728 Reactome R-MMU-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-MMU-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. 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 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 LEFT-TO-RIGHT 2.7.12.2 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> p38 MAPK:MAPKAPK2,3 Reactome DB_ID: 9849738 Converted from EntitySet in Reactome MAPKAP2,3 MAPKAP kinase MAPKAP2,MAPKAP3 Reactome DB_ID: 9849683 P49138 MAPKAPK2 Reactome DB_ID: 9849679 UniProt:P49138 UniProt P49138 1 EQUAL 400 EQUAL Reactome Database ID Release 82 9849679 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=9849679 Reactome R-MMU-450235 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-MMU-450235.1 Q3UMW7 MAPKAPK3 Reactome DB_ID: 9849681 UniProt:Q3UMW7 UniProt Q3UMW7 1 EQUAL 382 EQUAL Reactome Database ID Release 82 9849681 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=9849681 Reactome R-MMU-450218 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-MMU-450218.1 Reactome Database ID Release 82 9849683 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=9849683 Reactome R-MMU-450217 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-MMU-450217.1 1 Converted from EntitySet in Reactome MAPK14,MAPK11 MAP kinase p38 alpha/beta Reactome DB_ID: 9849736 MAPK11 Q9WUI1 Reactome DB_ID: 9849732 UniProt:Q9WUI1 Mapk11 Mapk11 Prkm11 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment.ACTIVITY REGULATION Activated by phosphorylation on threonine and tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by environmental stress. HDAC3 interacts directly and selectively with MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Inhibited by SB203580 and pyridinyl-imidazole related compounds.SUBUNIT Interacts with HDAC3 and DUSP16.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt Q9WUI1 1 EQUAL 364 EQUAL Reactome Database ID Release 82 9849732 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=9849732 Reactome R-MMU-203790 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-MMU-203790.1 MAPK14 P47811 Reactome DB_ID: 9849734 UniProt:P47811 Mapk14 Mapk14 Crk1 Csbp1 Csbp2 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity).ACTIVITY REGULATION Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14.SUBUNIT Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity). Interacts with DUSP2; this interaction does not lead to catalytic activation of DUSP2 and dephosphrylation of MAPK14 (PubMed:16288922).TISSUE SPECIFICITY Macrophages, monocytes, T- and B-lymphocytes. Isoform 2 is specifically expressed in kidney and liver.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).PTM Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).PTM Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P47811 2 EQUAL 360 EQUAL Reactome Database ID Release 82 9849734 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=9849734 Reactome R-MMU-446223 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-MMU-446223.1 Reactome Database ID Release 82 9849736 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=9849736 Reactome R-MMU-203795 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-MMU-203795.1 1 Reactome Database ID Release 82 9849738 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=9849738 Reactome R-MMU-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-MMU-450269.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 Reactome Database ID Release 82 29358 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=29358 Reactome R-ALL-29358 3 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-ALL-29358.3 COMPOUND C00002 2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 Reactome Database ID Release 82 113582 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=113582 Reactome R-ALL-113582 3 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-ALL-113582.3 COMPOUND C00008 2 p-p38 MAPK: MAPKAPK2,3 Reactome DB_ID: 9849685 1 Converted from EntitySet in Reactome p-MAPK11/p-MAPK14 p-p38 MAPK alpha/beta Phospho-MAP kinase p38 alpha/beta Reactome DB_ID: 9828442 p-T180,Y182-Mapk11 phospho-MAP kinase p38 beta Reactome DB_ID: 1605427 180 EQUAL 182 EQUAL 1 EQUAL 364 EQUAL Reactome Database ID Release 82 1605427 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=1605427 Reactome R-MMU-1605427 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-MMU-1605427.1 p-T180,Y182-Mapk14 phospho-MAP kinase p38 alpha Reactome DB_ID: 1605486 180 EQUAL 182 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 82 1605486 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=1605486 Reactome R-MMU-1605486 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-MMU-1605486.1 Reactome Database ID Release 82 9828442 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=9828442 Reactome R-MMU-198703 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-MMU-198703.1 1 Reactome Database ID Release 82 9849685 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=9849685 Reactome R-MMU-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-MMU-450213.1 ACTIVATION GENE ONTOLOGY GO:0004708 Reactome Database ID Release 82 9849739 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=9849739 Reactome Database ID Release 82 9849741 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=9849741 Reactome R-MMU-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-MMU-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. LEFT-TO-RIGHT 2.7.11.1 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> 3 3 p-p38 MAPK:p-MAPKAPK2/3 Reactome DB_ID: 9849693 Converted from EntitySet in Reactome Active MAPKAP kinase Reactome DB_ID: 9849691 P49138 phospho-p-T222,S272,T334-MAPKAPK2 Reactome DB_ID: 9849687 222 EQUAL 272 EQUAL 334 EQUAL 1 EQUAL 400 EQUAL Reactome Database ID Release 82 9849687 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=9849687 Reactome R-MMU-450268 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-MMU-450268.1 Q3UMW7 phospho-p-S,2T-MAPKAPK3 Reactome DB_ID: 9849689 1 EQUAL 382 EQUAL Reactome Database ID Release 82 9849689 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=9849689 Reactome R-MMU-450359 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-MMU-450359.1 Reactome Database ID Release 82 9849691 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=9849691 Reactome R-MMU-450261 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-MMU-450261.1 1 1 Reactome Database ID Release 82 9849693 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=9849693 Reactome R-MMU-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-MMU-450254.1 ACTIVATION activeUnit: #Protein117 Reactome Database ID Release 82 9849694 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=9849694 Reactome Database ID Release 82 9849696 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=9849696 Reactome R-MMU-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-MMU-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. 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 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 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 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 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 LEFT-TO-RIGHT Nuclear export of human p38 MAPK mediated by its substrate 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> p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 Reactome DB_ID: 9849698 Converted from EntitySet in Reactome Active MAPKAP kinase p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 Reactome DB_ID: 9831274 P49138 phospho-p-S272,T222,T334-MAPKAPK2 Reactome DB_ID: 9831268 1 EQUAL 400 EQUAL Reactome Database ID Release 82 9831268 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=9831268 Reactome R-MMU-187760 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-MMU-187760.1 Q3UMW7 phospho-p-S,2T-MAPKAPK3 Reactome DB_ID: 9831272 1 EQUAL 382 EQUAL Reactome Database ID Release 82 9831272 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=9831272 Reactome R-MMU-187723 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-MMU-187723.1 Reactome Database ID Release 82 9831274 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=9831274 Reactome R-MMU-187726 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-MMU-187726.1 1 Converted from EntitySet in Reactome phospho-MAPK p38 alpha/beta Reactome DB_ID: 448863 phospho-MAP kinase p38 alpha Reactome DB_ID: 448842 2 EQUAL 360 EQUAL Reactome Database ID Release 82 448842 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=448842 Reactome R-MMU-448842 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-MMU-448842.1 phospho-MAP kinase p38 beta Reactome DB_ID: 448825 1 EQUAL 364 EQUAL Reactome Database ID Release 82 448825 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=448825 Reactome R-MMU-448825 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-MMU-448825.1 Reactome Database ID Release 82 448863 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=448863 Reactome R-MMU-448863 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-MMU-448863.1 1 Reactome Database ID Release 82 9849698 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=9849698 Reactome R-MMU-450241 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-MMU-450241.1 Reactome Database ID Release 82 9849700 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=9849700 Reactome R-MMU-450257 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-MMU-450257.1 p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.<p>p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor. Reactome Database ID Release 82 9927120 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=9927120 Reactome R-MMU-450302 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-MMU-450302.1 GENE ONTOLOGY GO:0038066 p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. <p>The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases. 10878576 Pubmed 2000 p38 MAPK signalling cascades: ancient roles and new functions Martin-Blanco, E Bioessays 22:637-45 MAP3K8 (TPL2)-dependent MAPK1/3 activation 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> LEFT-TO-RIGHT NFKB p105, TPL2 (COT) and ABIN2 form a stable complex 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> MAP3K8 Q07174 Reactome DB_ID: 9843992 UniProt:Q07174 UniProt Q07174 1 EQUAL 467 EQUAL Reactome Database ID Release 82 9843992 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=9843992 Reactome R-MMU-389388 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-MMU-389388.1 Nfkb1 NFKB1(1-968) P25799 Reactome DB_ID: 9850193 1 EQUAL 968 EQUAL Reactome Database ID Release 82 9850193 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=9850193 Reactome R-MMU-451607 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-MMU-451607.1 TNIP2 Q99JG7 Reactome DB_ID: 9850197 UniProt:Q99JG7 UniProt Q99JG7 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9850197 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=9850197 Reactome R-MMU-451661 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-MMU-451661.1 NFKB1:MAP3K8:TNIP2 Reactome DB_ID: 9850199 1 1 1 Reactome Database ID Release 82 9850199 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=9850199 Reactome R-MMU-451638 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-MMU-451638.1 Reactome Database ID Release 82 9850211 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=9850211 Reactome R-MMU-451634 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-MMU-451634.1 The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). <br><br>A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.<br> 12667451 Pubmed 2003 NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase Waterfield, MR Zhang, M Norman, LP Sun, SC Mol Cell 11:685-94 15699325 Pubmed 2005 Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide Cho, J Tsichlis, PN Proc Natl Acad Sci U S A 102:2350-5 12832462 Pubmed 2003 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity Beinke, S Deka, J Lang, V Belich, MP Walker, PA Howell, S Smerdon, SJ Gamblin, SJ Ley, SC Mol Cell Biol 23:4739-52 15169888 Pubmed 2004 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability Lang, V Symons, A Watton, SJ Janzen, J Soneji, Y Beinke, S Howell, S Ley, SC Mol Cell Biol 24:5235-48 9950430 Pubmed 1999 TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105 Belich, MP Salmeron, A Johnston, LH Ley, SC Nature 397:363-8 INHIBITION Reactome Database ID Release 82 9850213 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=9850213 3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 9850209 P25799 phospho-Nfkb1 3xUb-p-S927,S932-NFKB1(1-968) Reactome DB_ID: 9850204 927 EQUAL 932 EQUAL 1 EQUAL 968 EQUAL Reactome Database ID Release 82 9850204 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=9850204 Reactome R-MMU-451619 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-MMU-451619.1 1 Q07174 phospho-p-S400,T290-MAP3K8 Reactome DB_ID: 9850207 290 EQUAL 400 EQUAL 1 EQUAL 467 EQUAL Reactome Database ID Release 82 9850207 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=9850207 Reactome R-MMU-5684259 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-MMU-5684259.1 1 1 Reactome Database ID Release 82 9850209 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=9850209 Reactome R-MMU-5684242 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-MMU-5684242.1 INHIBITION Reactome Database ID Release 82 9850212 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=9850212 LEFT-TO-RIGHT 2.7.11.10 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 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> NFKB1:p-S400-MAP3K8:TNIP2 Reactome DB_ID: 9893494 Q07174 phospho-p-S400-MAP3K8 Reactome DB_ID: 9843995 1 EQUAL 467 EQUAL Reactome Database ID Release 82 9843995 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=9843995 Reactome R-MMU-389738 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-MMU-389738.1 1 1 1 Reactome Database ID Release 82 9893494 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=9893494 Reactome R-MMU-5687880 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-MMU-5687880.1 ACTIVATION activeUnit: #Protein40 GENE ONTOLOGY GO:0008384 Reactome Database ID Release 82 9893488 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=9893488 Reactome Database ID Release 82 9893496 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=9893496 Reactome R-MMU-5684275 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-MMU-5684275.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages). 19754427 Pubmed 2009 IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2 Handoyo, Hosea Stafford, Margaret J McManus, Eamon Baltzis, Dionissios Peggie, Mark Cohen, P Biochem. J. 424:109-18 16806191 Pubmed 2006 Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62 Stafford, Margaret J Morrice, Nick A Peggie, Mark W Cohen, P FEBS Lett. 580:4010-4 22988300 Pubmed 2012 I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400 Roget, Karine Ben-Addi, Abduelhakem Mambole-Dema, Agnes Gantke, Thorsten Yang, Huei-Ting Janzen, Julia Morrice, N Abbott, Derek W Ley, Steven C Mol. Cell. Biol. 32:4684-90 LEFT-TO-RIGHT MAP3K8 is phosphorylated TPL2 (MAP3K8) is phosphorylated at T290 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> NFKB1:p-T290-MAP3K8:TNIP2 Reactome DB_ID: 9893483 1 1 1 Reactome Database ID Release 82 9893483 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=9893483 Reactome R-MMU-5684265 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-MMU-5684265.1 Reactome Database ID Release 82 9893485 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=9893485 Reactome R-MMU-5684261 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-MMU-5684261.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).<p>The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.<p> Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012). 21135874 Pubmed 2011 Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinase Gantke, Thorsten Sriskantharajah, Srividya Ley, Steven C Cell Res. 21:131-45 15466476 Pubmed 2004 Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity Luciano, Brenda S Hsu, Sang Channavajhala, Padma L Lin, Lih-Ling Cuozzo, John W J. Biol. Chem. 279:52117-23 15778223 Pubmed 2005 Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals Cho, Jeonghee Melnick, Michael Solidakis, Georgios P Tsichlis, Philip N J. Biol. Chem. 280:20442-8 LEFT-TO-RIGHT 2.7.11.10 IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex 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 2 p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 Reactome DB_ID: 9893487 P25799 phospho-Nfkb1 p-S927,S932-NFKB1(1-968) Reactome DB_ID: 9893472 1 EQUAL 968 EQUAL Reactome Database ID Release 82 9893472 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=9893472 Reactome R-MMU-451611 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-MMU-451611.1 1 1 1 Reactome Database ID Release 82 9893487 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=9893487 Reactome R-MMU-5687885 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-MMU-5687885.1 ACTIVATION activeUnit: #Protein40 Reactome Database ID Release 82 9893490 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=9893490 Reactome R-MMU-5684267 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-MMU-5684267.1 NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro. 12482991 Pubmed 2003 betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932 Lang, V Janzen, J Fischer, GZ Soneji, Y Beinke, S Salmeron, A Allen, H Hay, RT Ben-Neriah, Y Ley, SC Mol Cell Biol 23:402-13 LEFT-TO-RIGHT SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2 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>