BioPAX pathway converted from "Toll Like Receptor 9 (TLR9) Cascade" in the Reactome database.

Toll Like Receptor 9 (TLR9) Cascade

CpG DNA is an unusual Pathogen-Associated Molecular Pattern (PAMP). Cytosine methylation exists in mammalian but not bacterial cells, and most (but not all) CpG in the mammalian genome is methylated. Therefore, unmethylated CpG DNA may signal the presence of microbial infection. Evidence of CpG recognition by TLR9 was demonstrated both in human and mouse, and this type of signaling requires its internalization into late endosomal/lysosomal compartments. TLR9 has been reported to be able to discern different types of CpG motifs, and therefore that it presumably recognizes CpG DNA directly. It appears that over evolutionary periods, TLR9 molecules expressed by different species have diverged. This has led to differences in the precise sequence motif (CpG dinucleotide plus flanking regions) that optimally stimulate the innate immune system of different animals.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gale M, Jr, 2006-10-31 16:45:01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Engulfed CpG DNA binds to endosomal full-length TLR9

Both the full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008,).

Authored: Shamovsky, V, 2011-09-21Reviewed: Gillespie, ME, 2012-02-09Edited: Shamovsky, V, 2012-02-19

Reactome DB_ID: 187882

endosome membraneGO0010008

UniProt:Q9NR96 TLR9

TLR9

TLR9UNQ5798/PRO19605FUNCTION Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:11564765, PubMed:17932028). Controls lymphocyte response to Helicobacter infection (By similarity). Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (PubMed:23857366).SUBUNIT Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (By similarity). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (PubMed:17932028). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses (By similarity). Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum (PubMed:20865800). Interacts with SMPDL3B (By similarity).TISSUE SPECIFICITY Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.PTM Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling.SIMILARITY Belongs to the Toll-like receptor family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtQ9NR96

Chain Coordinates

EQUAL

1032

EQUAL

Reactome DB_ID: 167913

Unmethylated CpG DNA [endosome membrane]

Unmethylated CpG DNA

Reactome DB_ID: 187884

fl-TLR9:unmethylated CpG DNA [endosome membrane]

fl-TLR9:unmethylated CpG DNA

Reactome DB_ID: 187882

EQUAL

1032

EQUAL

Reactome DB_ID: 167913

Reactome Database ID Release 75187884Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187884ReactomeR-HSA-187884

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-187884.1Reactome Database ID Release 751679589Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679589ReactomeR-HSA-1679589

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679589.115207506Pubmed2004The immunobiology of the TLR9 subfamilyWagner, HTrends Immunol 25:381-621604257Pubmed2011Negative regulation of signaling by a soluble form of toll-like receptor 9Chockalingam, ACameron, JLBrooks, JCLeifer, CAEur J Immunol 41:2176-8418820679Pubmed2008The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptorEwald, SELee, BLLau, LWickliffe, KEShi, GPChapman, HABarton, GMNature 456:658-62

Engulfed CpG DNA binds to endosomal N-ter TLR9 dimer

TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011).

Authored: Shamovsky, V, 2011-09-21Reviewed: Gillespie, ME, 2012-02-09Edited: Shamovsky, V, 2012-02-19

Reactome DB_ID: 1679574

N-ter TLR9 dimer [endosome membrane]

N-ter TLR9 dimer

Reactome DB_ID: 1679573

Reactome Database ID Release 751679574Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679574ReactomeR-HSA-1679574

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679574.1

Reactome DB_ID: 167913

Reactome DB_ID: 1679094

N-ter TLR9 dimer:unmethylated CpG DNA [endosome membrane]

N-ter TLR9 dimer:unmethylated CpG DNA

Reactome DB_ID: 1679574

Reactome DB_ID: 167913

Reactome Database ID Release 751679094Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679094ReactomeR-HSA-1679094

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679094.1Reactome Database ID Release 751679098Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679098ReactomeR-HSA-1679098

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679098.2

ACTIVATION

Reactome Database ID Release 751679582Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679582ReactomeR-HSA-1679582

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679582.1

Reactome DB_ID: 187897

EEA1:EEA1 [endosome membrane]

EEA1:EEA1

Reactome DB_ID: 187893

UniProt:Q15075 EEA1

EEA1

EEA1ZFYVE2FUNCTION Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.SUBUNIT Homodimer. Binds STX6. Binds RAB5A, RAB5B, RAB5C and RAB22A that have been activated by GTP-binding. Interacts with RAB31. Interacts with ERBB2. Interacts with SAMD9 AND SAMD9L (PubMed:24029230). May interact with PLEKHF2.DOMAIN The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.MISCELLANEOUS Antibodies against EEA1 are found in sera from patients with subacute cutaneous lupus erythematosus and other autoimmune diseases.

UniProtQ15075

EQUAL

1411

EQUAL

Reactome Database ID Release 75187897Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187897ReactomeR-HSA-187897

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-187897.1

Engulfed CpG DNA binds to endosomal C-ter TLR9

Synthetic oligodeoxynucleotides (ODN) expressing non-methylated CpG motifs patterned after those present in bacterial DNA have characteristic immunomodulatory effects. CpG DNA is recognized as a pathogen-associated molecular pattern by TLR9, and triggers a rapid innate immune response.

Edited: Shamovsky, V, 2011-08-12

Reactome DB_ID: 1679581

C-ter-TLR9 dimer [endosome membrane]

C-ter-TLR9 dimer

C-terminus Toll like receptor 9 (TLR9) dimer

Reactome DB_ID: 1679580

EQUAL

1032

EQUAL

Reactome Database ID Release 751679581Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679581ReactomeR-HSA-1679581

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679581.1

Reactome DB_ID: 167913

Reactome DB_ID: 1679087

C-ter TLR9 dimer:unmethylated CpG DNA [endosome membrane]

C-ter TLR9 dimer:unmethylated CpG DNA

Reactome DB_ID: 1679581

Reactome DB_ID: 167913

Reactome Database ID Release 751679087Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1679087ReactomeR-HSA-1679087

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1679087.1Reactome Database ID Release 75187895Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187895ReactomeR-HSA-187895

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-187895.5

ACTIVATION

Reactome Database ID Release 75187892Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187892ReactomeR-HSA-187892

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-187892.1

Reactome DB_ID: 187897

INHIBITION

Reactome Database ID Release 759691209Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9691209

Reactome DB_ID: 9678655

C-ter TLR9 dimer:HCQ [endosome membrane]

C-ter TLR9 dimer:HCQ

Reactome DB_ID: 9678628

cytosolGO0005829

hydroxychloroquine [IUPHAR:7198]

hydroxychloroquine

Dolquine®Plaquenil®

IUPHAR7198

Reactome DB_ID: 1679581

Reactome Database ID Release 759678655Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9678655ReactomeR-HSA-9678655

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9678655.2

C-ter TLR9 dimer binds HCQ

Toll-like receptor 9 (TLR9) is a key component of innate and adaptive immunity. It controls the host immune response against pathogens by stimulating dendritic cells and macrophages to secrete interferon alpha and other proinflammatory and regulatory cytokines (Lenert 2010). Hydroxychloroquine (HCQ) binds and antagonises TLR9 (Lamphier et al. 2014), and thus inhibits interferon alpha production. HCQ is used clinically to treat systemic lupus erythromatosis and other autoimmune disorders (Costedoat Chalumeau et al. 2014). HCQ’s immunomodulatory properties may be useful for treatment of patients with COVID-19 (Sinha & Balayla 2020, Colson et al. 2020, Gautret et al. 2020).

Authored: Jassal, Bijay, 2020-03-23Reviewed: Shoichet, Brian, 2020-05-14Edited: Jassal, Bijay, 2020-03-23

Reactome DB_ID: 9678628

Reactome DB_ID: 1679581

Reactome DB_ID: 9678655

Reactome Database ID Release 759679045Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679045ReactomeR-HSA-9679045

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9679045.232145363Pubmed2020Chloroquine and hydroxychloroquine as available weapons to fight COVID-19Colson, PhilippeRolain, Jean-MarcLagier, Jean-ChristopheBrouqui, PhilippeRaoult, DidierInt. J. Antimicrob. Agents10593220490286Pubmed2010Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9Lenert, Petar SMediators Inflamm. 2010:98659624855048Pubmed2014Hydroxychloroquine: a multifaceted treatment in lupusCostedoat-Chalumeau, NathalieDunogué, BertrandMorel, NathalieLe Guern, VéroniqueGuettrot-Imbert, GaëllePresse Med 43:e167-8032205204Pubmed2020Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trialGautret, PhilippeLagier, Jean-ChristopheParola, PhilippeHoang, Van ThuanMeddeb, LineMailhe, MorganeDoudier, BarbaraCourjon, JohanGiordanengo, ValérieVieira, Vera EstevesDupont, Hervé TissotHonoré, StéphaneColson, PhilippeChabrière, EricLa Scola, BernardRolain, Jean-MarcBrouqui, PhilippeRaoult, DidierInt. J. Antimicrob. Agents10594932295814Pubmed2020Hydroxychloroquine and covid-19Sinha, NeerajBalayla, GalitPostgrad Med J24342772Pubmed2014Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivoLamphier, MarcZheng, WanjunLatz, EickeSpyvee, MarkHansen, HansRose, JeffreyGenest, MelindaYang, HuaShaffer, ChristinaZhao, YanShen, YongchunLiu, CarrieLiu, DianaMempel, Thorsten RRowbottom, ChristopherChow, JesseTwine, Natalie CYu, MelvinGusovsky, FabianIshizaka, Sally TMol. Pharmacol. 85:429-40

Rab5-mediated recruitment of class III PI3K to TLR9

TLR9 signaling has the uncommon property of triggering PI3K-mediated cascades via Rab5.

Reactome DB_ID: 188015

PI3K class III [cytosol]

PI3K class III

Reactome DB_ID: 188010

UniProt:Q99570 PIK3R4

PIK3R4

PIK3R4VPS15FUNCTION Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123).SUBUNIT Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG (PubMed:8999962, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:25490155). Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1, AMBRA1 and NRBF2 (PubMed:19270696, PubMed:20643123, PubMed:24785657). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3C3/VPS34 (PubMed:14617358). Interacts with NRBF2 (PubMed:24785657).TISSUE SPECIFICITY Ubiquitously expressed.PTM Myristoylated.PTM Probably autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.

UniProtQ99570

EQUAL

1358

EQUAL

Reactome DB_ID: 188011

UniProt:Q8NEB9 PIK3C3

PIK3C3

PIK3C3VPS34FUNCTION Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123, PubMed:20208530). Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for transport from early to late endosomes (By similarity).SUBUNIT Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are: the PI3K complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:7628435, PubMed:19050071, PubMed:20643123, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3R4 (PubMed:14617358). Interacts with AMBRA1 (By similarity). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts with SLAMF1(PubMed:22493499). May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with NCKAP1L (PubMed:16417406). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350).TISSUE SPECIFICITY Ubiquitously expressed, with a highest expression in skeletal muscle.SIMILARITY Belongs to the PI3/PI4-kinase family.

UniProtQ8NEB9

EQUAL

887

EQUAL

Reactome Database ID Release 75188015Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188015ReactomeR-HSA-188015

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188015.1

Reactome DB_ID: 1679087

Reactome DB_ID: 188017

activated TLR9:PI3K class III [cytosol]

activated TLR9:PI3K class III

Reactome DB_ID: 188015

Reactome DB_ID: 187884

Reactome Database ID Release 75188017Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188017ReactomeR-HSA-188017

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188017.2Reactome Database ID Release 75188002Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188002ReactomeR-HSA-188002

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188002.317878374Pubmed2007TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathwayHoarau, CyrilleGérard, BénédicteLescanne, EmmanuelHenry, DominiqueFrançois, StéphanieLacapère, Jean-JacquesEl Benna, JamelDang, Pham My-ChanGrandchamp, BernardLebranchu, YvonGougerot-Pocidalo, Marie-AnneElbim, CaroleJ. Immunol. 179:4754-6514751759Pubmed2004Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9Takeshita, FGursel, IIshii, KJSuzuki, KGursel, MKlinman, DMSemin Immunol 16:17-22

ACTIVATION

Reactome Database ID Release 75188013Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188013ReactomeR-HSA-188013

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188013.1

Reactome DB_ID: 188000

UniProt:Q9H1K0 RBSN

RBSN

ZFYVE20RBSNFUNCTION Rab4/Rab5 effector protein acting in early endocytic membrane fusion and membrane trafficking of recycling endosomes. Required for endosome fusion either homotypically or with clathrin coated vesicles. Plays a role in the lysosomal trafficking of CTSD/cathepsin D from the Golgi to lysosomes. Also promotes the recycling of transferrin directly from early endosomes to the plasma membrane. Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate (PtdInsP3) (PubMed:11062261, PubMed:11788822, PubMed:15020713). Plays a role in the recycling of transferrin receptor to the plasma membrane (PubMed:22308388).SUBUNIT Interacts with EHD1, RAB4A, RAB5A, RAB14, RAB22A, RAB24 and VPS45 (PubMed:11062261, PubMed:15020713, PubMed:16034420). Binds simultaneously to RAB4A and RAB5A in vitro (PubMed:16034420). Interacts with RAB4A and RAB5A that has been activated by GTP binding (PubMed:11062261, PubMed:16034420, PubMed:20098723, PubMed:11788822).

UniProtQ9H1K0

EQUAL

784

EQUAL

MyD88 dependent cascade initiated on endosome

Upon binding of their ligands, TLR7/8 and TLR9 recruit a cytoplasmic adaptor MyD88 and IRAKs, downstream of which the signaling pathways are divided to induce either inflammatory cytokines or type I IFNs.

Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

MyD88 interacts with the activated TLR receptor 7, 8 or 9

MyD88 binds to IRAK (IL-1 receptor-associated kinase) and the receptor heterocomplex (the signaling complex) and thereby mediates the association of IRAK with the receptor. MyD88 therefore couples a serine/threonine protein kinase to the receptor complex.

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 166059

UniProt:Q99836 MYD88

MYD88

MYD88FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).SUBUNIT Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; 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. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.TISSUE SPECIFICITY Ubiquitous.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.DISEASE Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), Waldenstroem macroglobulinemia, cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL).

UniProtQ99836

EQUAL

296

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 975158

Activated TLR7-9 homodimers [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 975124

MyD88 complexed with the activated TLR receptor [endosome membrane]

MyD88 complexed with the activated TLR receptor

Reactome DB_ID: 975152

MYD88 homodimer [endosome membrane]

MYD88 homodimer

Reactome DB_ID: 975123

EQUAL

296

EQUAL

Reactome Database ID Release 75975152Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975152ReactomeR-HSA-975152

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975152.1Converted from EntitySet in Reactome

Reactome DB_ID: 975158

Reactome Database ID Release 75975124Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975124ReactomeR-HSA-975124

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975124.2Reactome Database ID Release 75975175Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975175ReactomeR-HSA-975175

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975175.215361868Pubmed2004Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6Kawai, TSato, SIshii, KJCoban, CHemmi, HYamamoto, MTerai, KMatsuda, MInoue, JUematsu, STakeuchi, OAkira, ShizuoNat Immunol 5:1061-815492225Pubmed2004Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signalingHonda, KYanai, HMizutani, TNegishi, HShimada, NSuzuki, NOhba, YTakaoka, AYeh, WCTaniguchi, TProc Natl Acad Sci U S A 101:15416-219430229Pubmed1997MyD88: an adapter that recruits IRAK to the IL-1 receptor complexWesche, HHenzel, WJShillinglaw, WLi, SCao, ZImmunity 7:837-4712447442Pubmed2002The adaptor molecule TIRAP provides signalling specificity for Toll-like receptorsHorng, TBarton, GMFlavell, RAMedzhitov, RNature 420:329-33

MyD88 oligomerization within the complex of activated TLR 7/8 or 9 : MyD88

Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010).

Authored: Shamovsky, V, 2010-09-22Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 166059

EQUAL

296

EQUAL

Reactome DB_ID: 975124

Reactome DB_ID: 975114

oligo-MyD88:activated TLR7-9 [endosome membrane]

oligo-MyD88:activated TLR7-9

Reactome DB_ID: 975141

MyD88 oligomer [endosome membrane]

MyD88 oligomer

Reactome DB_ID: 975123

EQUAL

296

EQUAL

Reactome Database ID Release 75975141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975141ReactomeR-HSA-975141

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975141.1Converted from EntitySet in Reactome

Reactome DB_ID: 975158

Reactome Database ID Release 75975114Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975114ReactomeR-HSA-975114

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975114.2Reactome Database ID Release 75975098Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975098ReactomeR-HSA-975098

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975098.219592493Pubmed2009An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4Motshwene, PGMoncrieffe, MCGrossmann, JGKao, CAyaluru, MSandercock, AMRobinson, CVLatz, EGay, Nicholas JJ Biol Chem 284:25404-1120485341Pubmed2010Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signallingLin, SCLo, YCWu, HNature 465:885-9020966070Pubmed2011Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assemblyGeorge, JulieMotshwene, Precious GWang, HuiKubarenko, Andriy VRautanen, AnnaMills, Tara CHill, Adrian V SGay, Nicholas JWeber, Alexander N RJ. Biol. Chem. 286:1341-53

IRAK4 binds to the activated TLR7/8 or 9 receptor:MyD88 complex

IRAK4 is the mammalian homolog of Drosophila melanogaster Tube [Towb P et al 2009; Moncrieffe MC et al 2008]. Like Tube, IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other, thereby bridging MyD88 and IRAK1/2 association [Towb P et al 2009; Lin SC e al 2010]. IRAK-4 plays a critical role in Toll receptor signaling - any interference with IRAK-4's kinase activity virtually abolishes downstream events. This is not the case with other members of the IRAK family [Suzuki N et al 2002; Li S et al 2002].

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 166081

UniProt:Q9NWZ3 IRAK4

IRAK4

IRAK4FUNCTION 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 (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. 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 NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.SUBUNIT Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Interacts with IL1RL1.PTM Phosphorylated.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

UniProtQ9NWZ3

EQUAL

460

EQUAL

Reactome DB_ID: 975114

Reactome DB_ID: 975183

IRAK4:oligo-MyD88:activated TLR 7/8 or 9 [endosome membrane]

IRAK4:oligo-MyD88:activated TLR 7/8 or 9

Reactome DB_ID: 975114

Reactome DB_ID: 975167

EQUAL

460

EQUAL

Reactome Database ID Release 75975183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975183ReactomeR-HSA-975183

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975183.2Reactome Database ID Release 75975156Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975156ReactomeR-HSA-975156

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975156.211960013Pubmed2002IRAK-4: a novel member of the IRAK family with the properties of anLi, SStrelow, AFontana, EJWesche, HProc Natl Acad Sci U S A 99:5567-7218794297Pubmed2008The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activationFraczek, JerzyKim, Tae WhanXiao, HYao, JianhongWen, QianLi, YaliCasanova, JLPryjma, JuliuszLi, XJ. Biol. Chem. 283:31697-70516286015Pubmed2005Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to virusesYang, KPuel, AZhang, ShenyingEidenschenk, CKu, Cheng-LungCasrouge, ArmandaPicard, Cvon Bernuth, HorstSénéchal, BPlancoulaine, SAl-Hajjar, SamiAl-Ghonaium, AbdulazizMaródi, LászlóDavidson, DonaldSpeert, DavidRoifman, ChaimGarty, Ben-ZionOzinsky, AdrianBarrat, Franck JCoffman, Robert LMiller, RLLi, XLebon, PierreRodriguez-Gallego, CarlosChapel, HelenGeissmann, FJouanguy, ECasanova, JLImmunity 23:465-7812297423Pubmed2002IRAK-4 as the central TIR signaling mediator in innate immunitySuzuki, NSuzuki, SYeh, WCTrends Immunol 23:503-6

2.7.11

IRAK4 autophosphorylation in the complex with MyD88:activated TLR 7/8 or 9

IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975183

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216

Reactome DB_ID: 975159

p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptor [endosome membrane]

p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptor

Reactome DB_ID: 975149

O-phospho-L-threonine at 342

342

EQUAL

O-phospho-L-threonine [MOD:00047]

O-phospho-L-threonine at 345

345

EQUAL

O-phospho-L-serine at 346

346

EQUAL

O-phospho-L-serine [MOD:00046]

EQUAL

460

EQUAL

Reactome DB_ID: 975114

Reactome Database ID Release 75975159Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975159ReactomeR-HSA-975159

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975159.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975183

GO0004674

GO molecular function

Reactome Database ID Release 75975169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975169Reactome Database ID Release 75975170Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975170ReactomeR-HSA-975170

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975170.317141195Pubmed2007Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loopCheng, HAddona, TKeshishian, HDahlstrand, ELu, CDorsch, MLi, ZWang, AOcain, TDLi, PParsons, TFJaffee, BXu, YBiochem Biophys Res Commun 352:609-1617485511Pubmed2007Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signalingKawagoe, TSato, SJung, AYamamoto, MMatsui, KunikoKato, HUematsu, STakeuchi, OAkira, ShizuoJ Exp Med 204:1013-24

IRAK1/or IRAK2 binds to the activated IRAK4 :MyD88:activated TLR 7/8 or 9.

MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex.IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4.

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Converted from EntitySet in Reactome

Reactome DB_ID: 937023

IRAK1, IRAK2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityIRAK2 [cytosol]IRAK1 [cytosol]

UniProtO43187UniProtP51617

Reactome DB_ID: 975159

Reactome DB_ID: 975113

IRAK1/or IRAK2 :p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 [endosome membrane]

IRAK1/or IRAK2 :p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9

Converted from EntitySet in Reactome

Reactome DB_ID: 975179

IRAK1/ IRAK2 [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityIRAK2 [endosome membrane]IRAK1 [endosome membrane]

Reactome DB_ID: 975159

Reactome Database ID Release 75975113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975113ReactomeR-HSA-975113

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975113.2Reactome Database ID Release 75975115Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975115ReactomeR-HSA-975115

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975115.216024789Pubmed2005A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in toll/IL-1R-induced inflammatoryRao, NNguyen, SNgo, KFung-Leung, WPMol Cell Biol 25:6521-3217878161Pubmed2007IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitinationKeating, SEMaloney, GMMoran, EMBowie, AGJ Biol Chem 282:33435-4312150927Pubmed2002IRAK-M is a negative regulator of Toll-like receptor signalingKobayashi, KHernandez, LDGalan, JEJaneway CA, JrMedzhitov, RFlavell, RACell 110:191-20219224918Pubmed2009Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional controlWan, YXiao, HAffolter, JKim, TWBulek, KChaudhuri, SCarlson, DHamilton, TMazumder, BStark, GRThomas, JLi, XJ Biol Chem 284:10367-7517890055Pubmed2008IRAK1: a critical signaling mediator of innate immunityGottipati, SRao, NLFung-Leung, WPCell Signal 20:269-7618438411Pubmed2008Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2Kawagoe, TSato, SMatsushita, KKato, HMatsui, KunikoKumagai, YSaitoh, TKawai, TTakeuchi, OAkira, ShizuoNat Immunol 9:684-919374458Pubmed1997IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signalingMuzio, MNi, JFeng, PDixit, VMScience 278:1612-515767370Pubmed2005Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} inductionUematsu, SSato, SYamamoto, MHirotani, TKato, HTakeshita, FMatsuda, MCoban, CIshii, KJKawai, TTakeuchi, OAkira, ShizuoJ Exp Med 201:915-23

2.7.11

Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:activated TLR 7/8 or 9

IRAK4 deficient macrophages fail to induce IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1.Phosphorylation sites of IRAK2 remain to be characterized.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975146

IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9 [endosome membrane]

IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9

Reactome DB_ID: 975159

Reactome DB_ID: 975116

UniProt:O43187 IRAK2

IRAK2

IRAK2FUNCTION Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.SUBUNIT Interacts with MYD88. IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1.TISSUE SPECIFICITY Expressed in spleen, thymus, prostate, lung, liver, skeletal muscle, kidney, pancreas and peripheral blood leukocytes.DOMAIN The protein kinase domain is predicted to be catalytically inactive.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.CAUTION Asn-335 is present instead of the conserved Asp which is expected to be an active site residue. This enzyme has been shown to be catalytically inactive.

EQUAL

625

EQUAL

Reactome Database ID Release 75975146Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975146ReactomeR-HSA-975146

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975146.2

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 975133

p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9 [endosome membrane]

p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9

Reactome DB_ID: 975187

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

625

EQUAL

Reactome DB_ID: 975159

Reactome Database ID Release 75975133Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975133ReactomeR-HSA-975133

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975133.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975146

Reactome Database ID Release 75975177Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975177Reactome Database ID Release 75975160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975160ReactomeR-HSA-975160

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975160.3

2.7.11

First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR 7/8 or 9

First, IRAK1 is phosphorylated at Thr209 by IRAK4. This results in a conformational change of the kinase domain, permitting further phosphorylations to take place. Substitution of Thr209 by alanine results in a kinase-inactive IRAK1.

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975132

IRAK1:p-S,2T-IRAK4 :oligo-MyD88:activated TLR 7/8 or 9 [endosome membrane]

IRAK1:p-S,2T-IRAK4 :oligo-MyD88:activated TLR 7/8 or 9

Reactome DB_ID: 975159

Reactome DB_ID: 975127

UniProt:P51617 IRAK1

IRAK1

IRAKIRAK1FUNCTION 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.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 (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts with PELI1 and TRAF6 (PubMed:12496252). Interacts (when polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via C-terminus) with NFATC4 (via N-terminus) (PubMed:18691762).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.TISSUE SPECIFICITY Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.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.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.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.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

EQUAL

712

EQUAL

Reactome Database ID Release 75975132Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975132ReactomeR-HSA-975132

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975132.2

Reactome DB_ID: 113592

Reactome DB_ID: 975130

p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complex [endosome membrane]

p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complex

Reactome DB_ID: 975189

O-phospho-L-threonine at 209

209

EQUAL

712

EQUAL

Reactome DB_ID: 975159

Reactome Database ID Release 75975130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975130ReactomeR-HSA-975130

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975130.2

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975132

Reactome Database ID Release 75975140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975140Reactome Database ID Release 75975180Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975180ReactomeR-HSA-975180

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975180.314625308Pubmed2004Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 SignalingKollewe, CMackensen, ACNeumann, DKnop, JCao, PLi, SWesche, HMartin, MUJ Biol Chem 279:5227-36

2.7.11

Second phosphorylation of IRAK1 by IRAK4 bound to MyD88: activated TLR 7/8 or 9

Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975130

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 975161

pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complex [endosome membrane]

pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complex

Reactome DB_ID: 975117

O-phospho-L-threonine at 209

209

EQUAL

O-phospho-L-threonine at 387

387

EQUAL

712

EQUAL

Reactome DB_ID: 975159

Reactome Database ID Release 75975161Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975161ReactomeR-HSA-975161

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975161.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975130

Reactome Database ID Release 751014248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1014248Reactome Database ID Release 75975134Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975134ReactomeR-HSA-975134

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975134.2

2.7.11

Multiple IRAK1 autophosphorylation steps within the complex pIRAK4:MyD88:activated TLR7/8 or 9

A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008).

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975161

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 975107

p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 [endosome membrane]

p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9

Reactome DB_ID: 975157

O-phospho-L-threonine at 387

387

EQUAL

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 209

209

EQUAL

O-phospho-L-serine at unknown position

O-phospho-L-threonine at unknown position

EQUAL

712

EQUAL

Reactome DB_ID: 975159

Reactome Database ID Release 75975107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975107ReactomeR-HSA-975107

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975107.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975161

Reactome Database ID Release 75975129Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975129Reactome Database ID Release 75975125Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975125ReactomeR-HSA-975125

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975125.318347055Pubmed2008Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activationConze, DBWu, CJThomas, JALandstrom, AAshwell, JDMol Cell Biol 28:3538-4717337443Pubmed2007IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expressionKoziczak-Holbro, MJoyce, CGlück, AKinzel, BMuller, MTschopp, CMathison, JCDavis, CNGram, HJ Biol Chem 282:13552-6011923871Pubmed2002Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4Suzuki, NSuzuki, SDuncan, GSMillar, DGWada, TMirtsos, CTakada, HWakeham, AItie, ALi, SPenninger, JMWesche, HOhashi, PSMak, TWYeh, WCNature 416:750-610217414Pubmed1999Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activityKnop, JMartin, MUFEBS Lett 448:81-5

TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9

Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002).IRAK-2 has two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). IRAK2 point mutants with mutated TRAF6-binding motifs abrogate NFkB activation and are incapable to stimulate TRAF6 ubiquitination (Keating SE et al 2007).

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 166366

UniProt:Q9Y4K3 TRAF6

TRAF6

TRAF6RNF85FUNCTION 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. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. 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.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. 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. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. 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). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.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-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; 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-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.

UniProtQ9Y4K3

EQUAL

522

EQUAL

Reactome DB_ID: 975178

hp-IRAK1 or p-IRAK2 bound to the pIRAK4:MyD88:activated TLR7/8 or 9 complex [endosome membrane]

hp-IRAK1 or p-IRAK2 bound to the pIRAK4:MyD88:activated TLR7/8 or 9 complex

Converted from EntitySet in Reactome

Reactome DB_ID: 1014260

hp-IRAK1/p-IRAK2 [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-2S,S376,T,T209,T387-IRAK1 [endosome membrane]p-IRAK2 [endosome membrane]

Reactome DB_ID: 975159

Reactome Database ID Release 75975178Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975178ReactomeR-HSA-975178

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975178.2

Reactome DB_ID: 975182

TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 [endosome membrane]

TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9

Reactome DB_ID: 975178

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome Database ID Release 75975182Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975182ReactomeR-HSA-975182

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975182.2Reactome Database ID Release 75975111Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975111ReactomeR-HSA-975111

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975111.211287640Pubmed2001IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)Li, XCommane, MJiang, ZStark, GRProc Natl Acad Sci U S A 98:4461-58837778Pubmed1996TRAF6 is a signal transducer for interleukin-1Cao, ZXiong, JTakeuchi, MKurama, TGoeddel, DVNature 383:443-612138165Pubmed2002Identification of threonine 66 as a functionally critical residue of theRoss, KYang, LDower, SVolpe, FGuesdon, FJ Biol Chem 277:37414-2118070982Pubmed2008TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaBMuroi, MTanamoto, KJ Leukoc Biol 83:702-712140561Pubmed2002Distinct molecular mechanism for initiating TRAF6 signallingYe, HArron, JRLamothe, BCirilli, MKobayashi, TShevde, NKSegal, DDzivenu, OKVologodskaia, MYim, MDu, KSingh, SPike, JWDarnay, BGChoi, YWu, HNature 418:443-7

TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation

TRAF6 mediates NFkB activation via canonical phosphorylation of IKK complex by TAK1. TRAF6 and TAK1 also regulate MAPK cascades leading to the activation of AP-1.

Authored: Shamovsky, V, 2010-08-25Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated TLR7/8 or 9 complex

Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006). Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered.

Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975182

Reactome DB_ID: 975126

hp-IRAK1/or p-IRAK2 :TRAF6 [endosome membrane]

hp-IRAK1/or p-IRAK2 :TRAF6

Converted from EntitySet in Reactome

Reactome DB_ID: 1014260

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome Database ID Release 75975126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975126ReactomeR-HSA-975126

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975126.1

Reactome DB_ID: 975159

Reactome Database ID Release 75975100Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975100ReactomeR-HSA-975100

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975100.216831874Pubmed2006The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4Dong, WLiu, YPeng, JChen, LZou, TXiao, HLiu, ZLi, WBu, YQi, YJ Biol Chem 281:26029-40

IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation

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]. 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. 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].

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation

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. 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.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975150

TRAF6:hp-IRAK1 [endosome membrane]

TRAF6:hp-IRAK1

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome DB_ID: 975157

O-phospho-L-threonine at 387

387

EQUAL

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 209

209

EQUAL

O-phospho-L-serine at unknown position

O-phospho-L-threonine at unknown position

EQUAL

712

EQUAL

Reactome Database ID Release 75975150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975150ReactomeR-HSA-975150

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975150.1Converted from EntitySet in Reactome

Reactome DB_ID: 450819

p-Pellino-1,2,(3) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-PELI2 [cytosol]p-PELI1 [cytosol]

UniProtQ9HAT8UniProtQ96FA3

Reactome DB_ID: 975143

TRAF6:hp-IRAK1:Pellino [endosome membrane]

TRAF6:hp-IRAK1:Pellino

Reactome DB_ID: 975150

Converted from EntitySet in Reactome

Reactome DB_ID: 450819

Reactome Database ID Release 75975143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975143ReactomeR-HSA-975143

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975143.1Reactome Database ID Release 75975142Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975142ReactomeR-HSA-975142

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975142.112496252Pubmed2003Pellino 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) complexJiang, ZJohnson, HJNie, HQin, JBird, TALi, XJ Biol Chem 278:10952-615917247Pubmed2005Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent mannerButler, MPHanly, JAMoynagh, PNJ Biol Chem 280:27759-6817997719Pubmed2008The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1Ordureau, ASmith, HWindheim, MPeggie, MCarrick, EMorrice, NCohen, PBiochem J 409:43-5218326498Pubmed2008Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activationXiao, HQian, WStaschke, KQian, YCui, GDeng, LEhsani, MWang, XQian, YWChen, ZJGilmour, RJiang, ZLi, XJ Biol Chem 283:14654-6416884718Pubmed2006Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligasesSchauvliege, RJanssens, SBeyaert, RFEBS Lett 580:4697-70212860405Pubmed2003Characterization of Pellino2, a substrate of IRAK1 and IRAK4Strelow, AKollewe, CWesche, HFEBS Lett 547:157-6119022706Pubmed2009The Pellino family: IRAK E3 ligases with emerging roles in innate immune signallingMoynagh, PNTrends Immunol 30:33-4217675297Pubmed2007Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligasesButler, MPHanly, JAMoynagh, PNJ Biol Chem 282:29729-37

IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation

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.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975143

Reactome DB_ID: 113592

Reactome DB_ID: 975166

p-Pellino:hp-IRAK1:TRAF6 [endosome membrane]

p-Pellino:hp-IRAK1:TRAF6

Reactome DB_ID: 975150

Converted from EntitySet in Reactome

Reactome DB_ID: 450819

Reactome Database ID Release 75975166Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975166ReactomeR-HSA-975166

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975166.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975143

GO0004672

GO molecular function

Reactome Database ID Release 75975181Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975181Reactome Database ID Release 75975139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975139ReactomeR-HSA-975139

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975139.119264966Pubmed2009Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4Smith, HPeggie, MCampbell, DGVandermoere, FCarrick, ECohen, PProc Natl Acad Sci U S A 106:4584-90

Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation

IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; 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 stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. 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 K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975166

Reactome DB_ID: 450152

K63polyUb [cytosol]

K63polyUb

K63-polyubiquitinLys-63 polyubiquitin

Reactome DB_ID: 202463

UBE2N:UBE2V1 [cytosol]

UBE2N:UBE2V1

Ubc13:UBE2V1TRIKA1TRAF6-regulated IKK activator 1

Reactome DB_ID: 206072

UniProt:P61088 UBE2N

UBE2N

UBE2NBLUFUNCTION The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UB2V1, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175, PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.ACTIVITY REGULATION Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (PubMed:20725033, PubMed:22325355, PubMed:22367539). Activity is inhibited by GPS2, leading to prevent 'Lys-63'-linked polyubiquitination (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with UBE2V2 (PubMed:10089880, PubMed:11473255, PubMed:14562038, PubMed:16307917, PubMed:16307917). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with RNF8 and RNF168 (PubMed:16215985, PubMed:19203578). Interacts with RNF11 (PubMed:18615712). Interacts with the E3 ligases, HLTF and SHPRH; the interactions promote the 'Lys-63'-linked polyubiquitination of PCNA upon genotoxic stress and lead to DNA repair (PubMed:17108083, PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with ARIH2 (via RING-type 2) (PubMed:19340006). Interacts with OTUB1; leading to inhibit E2-conjugating activity (PubMed:20725033, PubMed:22325355, PubMed:22367539). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with DDX58 and RNF135; involved in DDX58 ubiquitination and activation (PubMed:28469175).PTM Conjugation to ISG15 impairs formation of the thioester bond with ubiquitin but not interaction with UBE2V2.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtP61088

EQUAL

152

EQUAL

Reactome DB_ID: 205753

UniProt:Q13404 UBE2V1

UBE2V1

UBE2VP/OKcl.19CROC1UBE2V1UEV1FUNCTION Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UBE2N, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.SUBUNIT Heterodimer with UBE2N (PubMed:11057907, PubMed:16307917, PubMed:16893187). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with TRAF6 (PubMed:11057907, PubMed:16307917).TISSUE SPECIFICITY Highly expressed in thyroid, pancreas, spinal cord, lymph node, trachea, adrenal gland, bone marrow and pancreas. Detected at low levels in heart, breast, placenta, brain, liver, kidney, stomach and lung.INDUCTION Down-regulated during differentiation of cultured colon adenocarcinoma cells.MISCELLANEOUS In human, PESD1/KUA and UBE2V1/UEV1 are adjacent genes which can produce independent proteins and can also be fused to form a PESD1-UBE2V1 hybrid protein.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtQ13404

EQUAL

147

EQUAL

Reactome Database ID Release 75202463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202463ReactomeR-HSA-202463

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202463.2

Reactome DB_ID: 202463

Reactome DB_ID: 975172

K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6 [endosome membrane]

K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome DB_ID: 975112

O-phospho-L-threonine at 209

209

EQUAL

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 387

387

EQUAL

O-phospho-L-threonine at unknown position

O-phospho-L-serine at unknown position

ubiquitinylated lysine (K63polyUb [endosome membrane]) at 134

134

EQUAL

ubiquitinylated lysine [MOD:01148]

ubiquitinylated lysine (K63polyUb [endosome membrane]) at 180

180

EQUAL

O-phospho-L-serine at unknown position

EQUAL

712

EQUAL

Reactome Database ID Release 75975172Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975172ReactomeR-HSA-975172

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975172.1Converted from EntitySet in Reactome

Reactome DB_ID: 450819

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975166

GO0034450

GO molecular function

Reactome Database ID Release 751014250Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1014250Reactome Database ID Release 75975122Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975122ReactomeR-HSA-975122

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975122.118180283Pubmed2008Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinaseWindheim, MStafford, MPeggie, MCohen, PMol Cell Biol 28:1783-91

NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9.

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).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975172

Reactome DB_ID: 168113

CHUK:IKBKB:IKBKG [cytosol]

CHUK:IKBKB:IKBKG

IKKA:IKBKB:IKBKGIKK complexInhibitor of KappaB kinase (IKK) Complex

Reactome DB_ID: 168114

UniProt:O14920 IKBKB

IKBKB

IKBKBIKKBFUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418).SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658).SUBUNIT (Microbial infection) Interacts with Yersinia yopJ.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein B14.TISSUE SPECIFICITY Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B.PTM (Microbial infection) Acetylation of Thr-180 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.PTM Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.PTM (Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia yopJ.PTM Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

UniProtO14920

EQUAL

756

EQUAL

Reactome DB_ID: 168108

UniProt:Q9Y6K9 IKBKG

IKBKG

FIP3IKBKGNEMOFUNCTION Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either 'Lys-63'-linked or linear polyubiquitin) and its functional importance is reported conflictingly. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.SUBUNIT Homodimer; disulfide-linked. Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1. Interacts with ATM; the complex is exported from the nucleus. Interacts with TRAF6. Interacts with IKBKE. Interacts with TANK; the interaction is enhanced by IKBKE and TBK1. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with ZFAND5. Interacts with RIPK2. Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG. Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin. Binds polyubiquitin; the interaction is mediated by two domains; reports about the binding to 'Lys-63'-linked and/or linear polyubiquitin, respective binding affinities and stoichiometry are conflicting. Interacts with NLRP10. Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (PubMed:27695001). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (PubMed:25152375). Interacts with ARFIP2 (PubMed:26296658). Interacts with RIPK1 (By similarity).SUBUNIT (Microbial infection) Interacts with Molluscum contagiosum virus protein MC005; this interaction inhibits NF-kappa-B activation.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG.SUBUNIT (Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG which perturbs NF-kappa-B activation during bacterial infection.TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The leucine-zipper domain and the CCHC NOA-type zinc-finger are essential for polyubiquitin binding and for the activation of IRF3.PTM Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.PTM Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989).PTM Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.PTM Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.PTM (Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.PTM (Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome.

UniProtQ9Y6K9

EQUAL

419

EQUAL

Reactome DB_ID: 168104

UniProt:O15111 CHUK

CHUK

TCF16CHUKIKKAFUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:12789342, PubMed:15084260, PubMed:17434128, PubMed:20434986, PubMed:20501937, PubMed:21765415). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

UniProtO15111

EQUAL

745

EQUAL

Reactome Database ID Release 75168113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168113ReactomeR-HSA-168113

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168113.3

Reactome DB_ID: 975121

TRAF6:K63-linked polyUb p-IRAK1:IKK complex [endosome membrane]

TRAF6:K63-linked polyUb p-IRAK1:IKK complex

Reactome DB_ID: 975172

Reactome DB_ID: 168113

Reactome Database ID Release 75975121Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975121ReactomeR-HSA-975121

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975121.1Reactome Database ID Release 75975119Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975119ReactomeR-HSA-975119

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975119.116603398Pubmed2006Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMOEa, CKDeng, LXia, ZPPineda, GChen, ZJMol Cell 22:245-5716547522Pubmed2006Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]Wu, CJConze, DBLi, TSrinivasula, SMAshwell, JDNat Cell Biol 8:398-406

Reactome Database ID Release 75975144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975144ReactomeR-HSA-975144

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975144.118276832Pubmed2008Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activityLiu, GPark, YJAbraham, EFASEB J 22:2285-9616477006Pubmed2006IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activationSong, YJJen, KYSoni, VKieff, ECahir-McFarland, EProc Natl Acad Sci U S A 103:2689-9415695821Pubmed2005The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signalingSchoenemeyer, ABarnes, BJMancl, MELatz, EGoutagny, NPitha-Rowe, Paula MFitzgerald, Katherine AGolenbock, DTJ Biol Chem 280:17005-1212856330Pubmed2003IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expressionNguyen, HChatterjee-Kishore, MJiang, ZQing, YRamana, CVBayes, JCommane, MLi, XStark, GRJ Interferon Cytokine Res 23:183-9214661019Pubmed2004Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3Huang, QYang, JLin, YWalker, Graham CCheng, JLiu, ZGSu, BNat Immunol 5:98-103

IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation

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.IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

IRAK2 induces TRAF6 oligomerization initiated from endosomal compartments

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.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 166366

EQUAL

522

EQUAL

Reactome DB_ID: 975108

TRAF6:p-IRAK2 [endosome membrane]

TRAF6:p-IRAK2

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome DB_ID: 975187

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 75975108Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975108ReactomeR-HSA-975108

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975108.1

Reactome DB_ID: 975137

p-IRAK2:oligo-TRAF6 [endosome membrane]

p-IRAK2:oligo-TRAF6

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome DB_ID: 975108

Reactome Database ID Release 75975137Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975137ReactomeR-HSA-975137

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975137.1Reactome Database ID Release 75975185Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975185ReactomeR-HSA-975185

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975185.1

6.3.2.19

Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 at endosome membrane

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.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975137

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(77-152) [cytosol]UBB(153-228) [cytosol]UBC(305-380) [cytosol]UBB(1-76) [cytosol]UBB(77-152) [cytosol]UBA52(1-76) [cytosol]UBC(533-608) [cytosol]UBC(381-456) [cytosol]UBC(457-532) [cytosol]UBC(609-684) [cytosol]UBC(153-228) [cytosol]RPS27A(1-76) [cytosol]UBC(1-76) [cytosol]UBC(229-304) [cytosol]

UniProtP0CG48UniProtP0CG47UniProtP62987UniProtP62979

Reactome DB_ID: 975164

p-IRAK2:K63-linked pUb oligo-TRAF6 [endosome membrane]

p-IRAK2:K63-linked pUb oligo-TRAF6

Reactome DB_ID: 450227

ubiquitinylated lysine (K63polyUb [endosome membrane]) at 124

124

EQUAL

522

EQUAL

Reactome DB_ID: 975187

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 75975164Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975164ReactomeR-HSA-975164

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975164.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 975137

GO0004842

GO molecular function

Reactome Database ID Release 751014251Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1014251Reactome Database ID Release 75975147Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975147ReactomeR-HSA-975147

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975147.117135271Pubmed2007Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activationLamothe, BBesse, ACampos, ADWebster, WKWu, HDarnay, BGJ Biol Chem 282:4102-12

6.3.2.19

Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR stimulation

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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-03-02Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 450152

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 975153

K63-linked polyUb TRAF6 complexes [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 75450295Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450295Reactome Database ID Release 75450358Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450358ReactomeR-HSA-450358

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450358.219675569Pubmed2009Direct activation of protein kinases by unanchored polyubiquitin chainsXia, ZPSun, LChen, XPineda, GJiang, XAdhikari, AZeng, WChen, ZJNature

Activated TRAF6:p-IRAK2 interacts with TAK1 complex upon TLR7/8 or 9 stimulation

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.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 450152

Reactome DB_ID: 975164

Reactome DB_ID: 446878

TAK1 complex [cytosol]

TAK1 complex

TAK1:TAB1:TAB2/3

Reactome DB_ID: 168156

UniProt:O43318 MAP3K7

MAP3K7

TAK1MAP3K7FUNCTION 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). 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. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. 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. 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 (By similarity).ACTIVITY REGULATION Activated by proinflammatory 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 (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.TISSUE SPECIFICITY Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 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 Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.PTM (Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

UniProtO43318

EQUAL

606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 446874

TAB2,TAB3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTAB2 [cytosol]TAB3 [cytosol]

UniProtQ9NYJ8UniProtQ8N5C8

Reactome DB_ID: 167923

UniProt:Q15750 TAB1

TAB1

MAP3K7IP1TAB1FUNCTION 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 (PubMed:17560374, PubMed:11865055). Interacts with TRAF6 and MAP3K7; during IL-1 signaling (PubMed:8638164, PubMed:10094049, PubMed:11323434). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167).TISSUE SPECIFICITY Ubiquitous.PTM Monoubiquitinated. Deubiquitinated by Y.enterocolitica YopP.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity.

UniProtQ15750

EQUAL

504

EQUAL

Reactome Database ID Release 75446878Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=446878ReactomeR-HSA-446878

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-446878.3

Reactome DB_ID: 975099

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex [endosome membrane]

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex

Reactome DB_ID: 450152

Reactome DB_ID: 975164

Reactome DB_ID: 975128

TAK1 complex [endosome membrane]

TAK1 complex

TAK1:TAB1:TAB2/3

Reactome DB_ID: 450238

EQUAL

504

EQUAL

Reactome DB_ID: 450315

EQUAL

606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 975101

TAB2/3 [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTAB2 [endosome membrane]TAB3 [endosome membrane]

Reactome Database ID Release 75975128Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975128ReactomeR-HSA-975128

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975128.1Reactome Database ID Release 75975099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975099ReactomeR-HSA-975099

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975099.1Reactome Database ID Release 75975097Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975097ReactomeR-HSA-975097

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975097.115327770Pubmed2004TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chainsKanayama, ASeth, RBSun, LEa, CKHong, MShaito, AChiu, YHDeng, LChen, ZJMol Cell 15:535-4810882101Pubmed2000TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathwayTakaesu, GKishida, SHiyama, AYamaguchi, KShibuya, HIrie, KNinomiya-Tsuji, JMatsumoto, KMol Cell 5:649-58

Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 upon TLR7/8 or 9 activation

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).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-10-29Edited: Shamovsky, V, 2010-11-15

Reactome DB_ID: 975099

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 975171

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex [endosome membrane]

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex

Reactome DB_ID: 450152

Reactome DB_ID: 450238

EQUAL

504

EQUAL

Reactome DB_ID: 975164

Reactome DB_ID: 450332

O-phospho-L-threonine at 184

184

EQUAL

O-phospho-L-threonine at 187

187

EQUAL

606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 975101

Reactome Database ID Release 75975171Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975171ReactomeR-HSA-975171

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975171.1Reactome Database ID Release 75975103Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975103ReactomeR-HSA-975103

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975103.110702308Pubmed2000TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loopKishimoto, KMatsumoto, KNinomiya-Tsuji, JJ Biol Chem 275:7359-6416186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-9514633987Pubmed2003Role of the TAB2-related protein TAB3 in IL-1 and TNF signalingIshitani, TTakaesu, GNinomiya-Tsuji, JShibuya, HGaynor, RBMatsumoto, KEMBO J 22:6277-8816260493Pubmed2005TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivoShim, JHXiao, CPaschal, AEBailey, STRao, PHayden, MSLee, KYBussey, CSteckel, MTanaka, NYamada, GAkira, ShizuoMatsumoto, KGhosh, SGenes Dev 19:2668-81

Reactome Database ID Release 75975163Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975163ReactomeR-HSA-975163

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975163.1

TAK1 activates NFkB by phosphorylation and activation of IKKs complex

NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

IKBKA, IKBKB and IKBKG form IKK complex

The multimeric I kappa B kinase (IKK) complex is a key regulator of NFkB signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading 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) and IKKB (IKBKB) kinases, and a regulatory subunit, NFkB essential modulator (IKBKG/NEMO/IKKG). IKBKG (NEMO) associates with the unphosphorylated IKK kinase C-termini and activates the IKK complex’s catalytic activity (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).

Authored: Shamovsky, Veronica, 2015-02-15Reviewed: D'Eustachio, Peter, 2014-09-06Reviewed: McDonald, Douglas R, 2015-02-15Edited: Shamovsky, Veronica, 2015-02-15

Reactome DB_ID: 168114

EQUAL

756

EQUAL

Reactome DB_ID: 168108

EQUAL

419

EQUAL

Reactome DB_ID: 168104

EQUAL

745

EQUAL

Reactome DB_ID: 168113

Reactome Database ID Release 755609665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5609665ReactomeR-HSA-5609665

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5609665.17479848Pubmed1995Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathwayAlkalay, IYaron, AHatzubai, AOrian, ACiechanover, ABen-Neriah, YProc Natl Acad Sci U S A 92:10599-6039751060Pubmed1998IKK-gamma is an essential regulatory subunit of the IkappaB kinase complexRothwarf, D MZandi, ENatoli, GKarin, MNature 395:297-30020066092Pubmed2009The NF-kappaB family of transcription factors and its regulationOeckinghaus, AndreaGhosh, SankarCold Spring Harb Perspect Biol 1:a00003418462684Pubmed2008Structure of a NEMO/IKK-associating domain reveals architecture of the interaction siteRushe, MiaSilvian, LauraBixler, SarahChen, Ling LingCheung, AnneBowes, ScottCuervo, HernanBerkowitz, StevenZheng, TimothyGuckian, KevinPellegrini, MariaLugovskoy, AlexeyStructure 16:798-80817000764Pubmed2006Dimerization of the I kappa B kinase-binding domain of NEMO is required for tumor necrosis factor alpha-induced NF-kappa B activityMarienfeld, Ralf BPalkowitsch, LysannGhosh, SankarMol. Cell. Biol. 26:9209-19

2.7.11.25

Activated TAK1 mediates phosphorylation of the IKK Complex

In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 168113

Reactome DB_ID: 113592

Reactome DB_ID: 177663

IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB [cytosol]

IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB

Activated IKK Complex

Reactome DB_ID: 168108

EQUAL

419

EQUAL

Reactome DB_ID: 202506

O-phospho-L-serine at 177

177

EQUAL

O-phospho-L-serine at 181

181

EQUAL

756

EQUAL

Reactome DB_ID: 177667

O-phospho-L-serine at 176

176

EQUAL

O-phospho-L-serine at 180

180

EQUAL

745

EQUAL

Reactome Database ID Release 75177663Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177663ReactomeR-HSA-177663

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177663.3

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Activated TAK complexes [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

GO0004709

GO molecular function

Reactome Database ID Release 75177696Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177696Reactome Database ID Release 75168184Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168184ReactomeR-HSA-168184

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168184.412221085Pubmed2002IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response programLi, XMassa, PEHanidu, APeet, GWAro, PSavitt, AMische, SLi, JMarcu, KBJ Biol Chem 277:45129-4017496917Pubmed2007Ubiquitin-mediated activation of TAK1 and IKKAdhikari, AXu, MChen, ZJOncogene 26:3214-269744859Pubmed1998Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and deathArch, RHGedrich, RWThompson, CBGenes Dev 12:2821-3019666475Pubmed2009The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activationSolt, LAMadge, LAMay, MJJ Biol Chem11460167Pubmed2001TAK1 is a ubiquitin-dependent kinase of MKK and IKKWang, CDeng, LHong, MAkkaraju, GRInoue, JChen, ZJNature 412:346-51

NFkB inhibitor binds NFkB complex

NFkB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NFkB inhibitors (IkBs). IkBs proteins such as NFKBIA or NFKBIB 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). NFkB inhibitors (IkBs) mask the nuclear localization signal (NLS) of NFKB preventing its nuclear translocation (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NFkB 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 and targeted for ubiquitin-mediated proteasomal degradation, releasing the NFkB dimer p50/p65 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 NFkB inhibitors:NFkB complexes revealed that an NFkB dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012).

Authored: Shamovsky, Veronica, 2018-11-30Reviewed: D'Eustachio, Peter, 2018-12-04Edited: Shamovsky, Veronica, 2018-12-05

Reactome DB_ID: 168155

NFKB1(1-433), NFKB2(1-454):RELA [cytosol]

NFKB1(1-433), NFKB2(1-454):RELA

NFkB Complex

Reactome DB_ID: 168172

UniProt:Q04206 RELA

RELA

NFKB3RELAFUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (By similarity). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070). Directly interacts with DDX3X; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.DOMAIN The transcriptional activation domain 3/TA3 does not participate in the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).PTM Ubiquitinated by RNF182, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.PTM Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes (By similarity).PTM Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.PTM Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.PTM S-nitrosylation of Cys-38 inactivates the enzyme activity.PTM Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.PTM Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.PTM Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).DISEASE A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141).

UniProtQ04206

EQUAL

551

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 177656

NFKB1(1-433), NFKB2(1-454) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKB1(1-433) [cytosol]NFKB2(1-454) [cytosol]

UniProtP19838UniProtQ00653Reactome Database ID Release 75168155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168155ReactomeR-HSA-168155

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168155.3Converted from EntitySet in Reactome

Reactome DB_ID: 168143

NFkB inhibitor [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKBIB [cytosol]NFKBIA [cytosol]

UniProtQ15653UniProtP25963

Reactome DB_ID: 168130

NFkB inhibitor:NFkB complex [cytosol]

NFkB inhibitor:NFkB complex

IkBs:NFkB

Reactome DB_ID: 168155

Converted from EntitySet in Reactome

Reactome DB_ID: 168143

Reactome Database ID Release 75168130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168130ReactomeR-HSA-168130

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168130.2Reactome Database ID Release 759630923Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9630923ReactomeR-HSA-9630923

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630923.115145317Pubmed2004The two NF-kappaB activation pathways and their role in innate and adaptive immunityBonizzi, GKarin, MTrends Immunol 25:280-810837071Pubmed2000Phosphorylation meets ubiquitination: the control of NF-[kappa]B activityKarin, MBen-Neriah, YAnnu. Rev. Immunol. 18:621-6322435548Pubmed2012Regulation of NF-κB by ubiquitination and degradation of the IκBsKanarek, NaamaBen-Neriah, YinonImmunol. Rev. 246:77-9422435546Pubmed2012NF-κB regulation: lessons from structuresGhosh, GourisankarWang, Vivien Ya-FanHuang, De-BinFusco, AmandaImmunol. Rev. 246:36-5821203422Pubmed2010Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysisManavalan, BalachandranBasith, ShaherinChoi, Yong-MinLee, GwangChoi, SangdunPLoS ONE 5:e157829865693Pubmed1998Structure of an IkappaBalpha/NF-kappaB complexJacobs, M DHarrison, S CCell 95:749-5821094161Pubmed2011The RelA nuclear localization signal folds upon binding to IκBαCervantes, Carla FBergqvist, SimonKjaergaard, MagnusKroon, GerardSue, Shih-CheDyson, H JaneKomives, Elizabeth AJ. Mol. Biol. 405:754-6417072323Pubmed2006Transcriptional regulation via the NF-kappaB signaling moduleHoffmann, ANatoli, GGhosh, GOncogene 25:6706-16

2.7.11

Phospho-IKK Complex phosphorylates NFkB inhibitor within the NFkB inhibitor:NFkB complex

In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB 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-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.

Reviewed: D'Eustachio, P, 2011-12-07Reviewed: Upton, JW, Mocarski, ES, 2012-02-19Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 168130

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 177678

Phospho-NF-kappaB Inhibitor [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S32,S36-NFKBIA [cytosol]p-S19,S23-NFKBIB [cytosol]

Reactome DB_ID: 29370

Reactome DB_ID: 168155

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

Reactome Database ID Release 75450351Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450351Reactome Database ID Release 75168140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168140ReactomeR-HSA-168140

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168140.427701768Pubmed2017Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κBYazdi, SamiraNaumann, MichaelStein, MatthiasProteins 85:17-2910723127Pubmed2000Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complexGil, JAlcami, JEsteban, MOncogene 19:1369-7817047224Pubmed2006Regulation and function of IKK and IKK-related kinasesHacker, HKarin, MSci STKE 2006:re13

INHIBITION

Reactome Database ID Release 758952695Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8952695ReactomeR-HSA-8952695

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8952695.1Converted from EntitySet in Reactome

Reactome DB_ID: 8952687

NKIRAS [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNKIRAS1 [cytosol]NKIRAS2 [cytosol]

UniProtQ9NYS0UniProtQ9NYR9

NFkB complex is transported from cytosol to nucleus

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 (NFkappa-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. Therefor, 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.

Authored: Shamovsky, V, 2009-12-16Reviewed: D'Eustachio, P, 2011-12-07Reviewed: Upton, JW, Mocarski, ES, 2012-02-19Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Jin, Lei, 2013-05-21Reviewed: Wu, Jiaxi, 2013-05-21Edited: Shamovsky, V, 2013-05-17

Reactome DB_ID: 168155

Reactome DB_ID: 177673

nucleoplasmGO0005654NFkB Complex [nucleoplasm]

NFkB Complex

Converted from EntitySet in Reactome

Reactome DB_ID: 177662

Nuclear factor NF-kappa-B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKB2(1-454) [nucleoplasm]NFKB1(1-433) [nucleoplasm]

Reactome DB_ID: 177676

EQUAL

551

EQUAL

Reactome Database ID Release 75177673Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177673ReactomeR-HSA-177673

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177673.1Reactome Database ID Release 75168166Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168166ReactomeR-HSA-168166

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168166.416056267Pubmed2005Ubiquitin signalling in the NF-kappaB pathwayChen, ZJNat Cell Biol 7:758-65

ACTIVATION

Though the signaling cascade is unclear, several pieces of experimental data suggest that activation of AGER leads to sustained activation and upregulation of NFkappaB, measured as NFkappaB translocation to the nucleus, and increased levels of de novo synthesized NFkappaB.

Reactome Database ID Release 75879381Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879381ReactomeR-HSA-879381

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-879381.2

Reactome DB_ID: 879365

plasma membraneGO0005886AGER ligands:AGER [plasma membrane]

AGER ligands:AGER

Converted from EntitySet in Reactome

Reactome DB_ID: 879455

extracellular regionGO0005576

AGER ligands [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySAA1(19-122) [extracellular region]APP(672-713) [extracellular region]HMGB1 [extracellular region]APP(672-711) [extracellular region]

UniProtP0DJI8UniProtP05067UniProtP09429

Reactome DB_ID: 197639

UniProt:Q15109 AGER

AGER

RAGEAGERFUNCTION Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Can also bind oligonucleotides.SUBUNIT Interacts with S100A1 and APP (By similarity). Interacts with S100B, S100A12 and S100A14. Constitutive homodimer; disulfide-linked.TISSUE SPECIFICITY Endothelial cells.

UniProtQ15109

EQUAL

404

EQUAL

Reactome Database ID Release 75879365Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879365ReactomeR-HSA-879365

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-879365.1

Reactome Database ID Release 75445989Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445989ReactomeR-HSA-445989

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445989.315837794Pubmed2005Simultaneous 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 genesThiefes, AWolter, SMushinski, JFHoffmann, EDittrich-Breiholz, OGraue, NDörrie, ASchneider, HWirth, DLuckow, BResch, KKracht, MJ Biol Chem 280:27728-41GO0051092

GO biological process

TRAF6 binds MEKK1

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].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.

Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Napetschnig, Johanna, 2012-11-16Edited: de Bono, B, 2005-08-16 10:54:15

Reactome DB_ID: 166366

EQUAL

522

EQUAL

Reactome DB_ID: 166866

UniProt:Q13233 MAP3K1

MAP3K1

MAP3K1MEKK1MAPKKK1MEKKFUNCTION Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:9808624).ACTIVITY REGULATION Activated by autophosphorylation on Thr-1400 and Thr-1412 following oligomerization.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus (PubMed:9808624). Oligomerizes after binding MAP2K4 or TRAF2 (PubMed:9808624). Interacts with AXIN1 (PubMed:12223491, PubMed:15262978). Interacts (via the kinase catalytic domain) with STK38 (PubMed:17906693). Interacts with GRIPAP1 (PubMed:17761173).PTM Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

UniProtQ13233

EQUAL

1512

EQUAL

Reactome DB_ID: 166867

MEKK1:activated TRAF6 [cytosol]

MEKK1:activated TRAF6

Reactome DB_ID: 166366

EQUAL

522

EQUAL

Reactome DB_ID: 166866

EQUAL

1512

EQUAL

Reactome Database ID Release 75166867Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166867ReactomeR-HSA-166867

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166867.1Reactome Database ID Release 75166869Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166869ReactomeR-HSA-166869

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166869.39836645Pubmed1998Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruptionYujiri, TSather, SFanger, GRJohnson, GLScience 282:1911-49689078Pubmed1998MEKK1 activates both IkappaB kinase alpha and IkappaB kinase betaLee, FSPeters, RTDang, LCManiatis, TProc Natl Acad Sci U S A 95:9319-2410465784Pubmed1999ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathwayKopp, EMedzhitov, RCarothers, JXiao, CDouglas, IJaneway, CAGhosh, SGenes Dev 13:2059-719008162Pubmed1997Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathwayLee, FSHagler, JChen, ZJManiatis, TCell 88:213-22

ACTIVATION

Reactome Database ID Release 75181968Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181968ReactomeR-HSA-181968

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181968.2

Reactome DB_ID: 168064

UniProt:Q9BQ95 ECSIT

ECSIT

ECSITFUNCTION Adapter protein of the Toll-like and IL-1 receptor signaling pathway that is involved in the activation of NF-kappa-B via MAP3K1. Promotes proteolytic activation of MAP3K1. Involved in the BMP signaling pathway. Required for normal embryonic development (By similarity).FUNCTION Required for efficient assembly of mitochondrial NADH:ubiquinone oxidoreductase.SUBUNIT Interacts with MAP3K1, SMAD4 and TRAF6. Interacts with SMAD1 only after BMP4-treatment (By similarity). Part of the mitochondrial complex I assembly (MCIA) complex. The complex comprises at least TMEM126B, NDUFAF1, ECSIT, and ACAD9 (By similarity). Interacts with NDUFAF1 (PubMed:17344420). Interacts with ACAD9 (PubMed:20816094). Interacts with TRIM59 (By similarity).SIMILARITY Belongs to the ECSIT family.

UniProtQ9BQ95

EQUAL

431

EQUAL

MAP kinase activation

The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1

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. 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.Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7).

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11.25

Activated TAK1 phosphorylates MKK4/MKK7

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.Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 450305

MAP2K7,MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K7 [cytosol]MAP2K4 [cytosol]

UniProtO14733UniProtP45985

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Converted from EntitySet in Reactome

Reactome DB_ID: 450299

p-MAP2K4/p-MAP2K7 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S271,T275-MAP2K7 [cytosol]p-S257,T261-MAP2K4 [cytosol]

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Reactome Database ID Release 75450337Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450337ReactomeR-HSA-450337

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450337.18533096Pubmed1995Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transductionYamaguchi, KShirakabe, KShibuya, HIrie, KOishi, IUeno, NTaniguchi, TNishida, EMatsumoto, KScience 270:2008-1117875933Pubmed2007Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature deathWang, XNadarajah, BRobinson, ACMcColl, BWJin, JWDajas-Bailador, FBoot-Handford, RPTournier, CMol Cell Biol 27:7935-46

2.7.11

Phosphorylation of human JNKs by activated MKK4/MKK7

Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. 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).

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Converted from EntitySet in Reactome

Reactome DB_ID: 450289

MAPK8,9,10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK10 [cytosol]MAPK8 [cytosol]MAPK9 [cytosol]

UniProtP53779UniProtP45983UniProtP45984

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 450226

p-MAPK8,9,10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T,Y-MAPK8 [cytosol]p-T183,Y185-MAPK9 [cytosol]p-T221,Y223-MAPK10 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450299

GO0008545

GO molecular function

Reactome Database ID Release 75450334Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450334Reactome Database ID Release 75168162Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168162ReactomeR-HSA-168162

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168162.218713996Pubmed2008Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinasesYoshizawa, THammaker, DSweeney, SEBoyle, DLFirestein, GSJ Immunol 181:3252-813130464Pubmed2003Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNKSundarrajan, MBoyle, DLChabaud-Riou, MHammaker, DFirestein, GSArthritis Rheum 48:2450-6011062067Pubmed2000Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7Fleming, YArmstrong, CGMorrice, NPaterson, AGoedert, MCohen, PBiochem J 352:145-549162092Pubmed1997Characterization 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, KBlank, JLJ Biol Chem 272:14489-96

Activated human JNKs migrate to nucleoplasm

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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 450226

Converted from EntitySet in Reactome

Reactome DB_ID: 450253

p-MAPK8,9,10 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T221,Y223-MAPK10 [nucleoplasm]p-T,Y-MAPK8 [nucleoplasm]p-T183,Y185-MAPK9 [nucleoplasm]

Reactome Database ID Release 75450348Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450348ReactomeR-HSA-450348

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450348.112193592Pubmed2002Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP)Lutz, CNimpf, JJenny, MBoecklinger, KEnzinger, CUtermann, GBaier-Bitterlich, GBaier, GJ Biol Chem 277:43143-519195981Pubmed1997A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.Mizukami, YYoshioka, KMorimoto, SYoshida, KJ Biol Chem 272:16657-62

Reactome Database ID Release 75450321Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450321ReactomeR-HSA-450321

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450321.226988982Pubmed2016IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cellsLi, Jing-kunNie, LinZhao, Yun-pengZhang, Yuan-qiangWang, XiaoqingWang, Shuai-shuaiLiu, YiZhao, HuaCheng, LeiJ Transl Med 14:7716937364Pubmed2006The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targetingBogoyevitch, MABioessays 28:923-349851932Pubmed1998Defective T cell differentiation in the absence of Jnk1Dong, CYang, DDWysk, MWhitmarsh, AJDavis, RJFlavell, RAScience 282:2092-58177321Pubmed1994The stress-activated protein kinase subfamily of c-Jun kinasesKyriakis, JMBanerjee, PNikolakaki, EDai, TRubie, EAAhmad, MFAvruch, JosephWoodgett, JRNature 369:156-60GO0007254

GO biological process

activated TAK1 mediates p38 MAPK activation

p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. 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.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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11.25

activated human TAK1 phosphorylates MKK3/MKK6

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. 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 .

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2011-08-12

Converted from EntitySet in Reactome

Reactome DB_ID: 167916

MAP2K3,MAP2K6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K6 [cytosol]MAP2K3 [cytosol]

UniProtP52564UniProtP46734

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 167984

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S189,T193-MAP2K3 [cytosol]p-S207,T211-MAP2K6 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Reactome Database ID Release 75450346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450346ReactomeR-HSA-450346

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450346.18622669Pubmed1996MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathwayRaingeaud, JWhitmarsh, AJBarrett, TDerijard, BDavis, RJMol Cell Biol 16:1247-55

Phosphorylated MKK3/MKK6 migrates to nucleus

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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 167984

Converted from EntitySet in Reactome

Reactome DB_ID: 450343

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S207,T211-MAP2K6 [nucleoplasm]p-S189,T193-MAP2K3 [nucleoplasm]

Reactome Database ID Release 75450296Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450296ReactomeR-HSA-450296

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450296.27535770Pubmed1995Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonineRaingeaud, JGupta, SRogers, JSDickens, MHan, JUlevitch, RJDavis, RJJ Biol Chem 270:7420-69768359Pubmed1998Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2Ben-Levy, RHooper, SWilson, RPaterson, HFMarshall, CJCurr Biol 8:1049-57

2.7.12.2

Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3

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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 29358

Reactome DB_ID: 450269

p38 MAPK:MAPKAPK2,3 [nucleoplasm]

p38 MAPK:MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 450217

MAPKAP2,3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPKAPK3 [nucleoplasm]MAPKAPK2 [nucleoplasm]

UniProtQ16644UniProtP49137Converted from EntitySet in Reactome

Reactome DB_ID: 203795

MAP kinase p38 alpha/beta [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK14 [nucleoplasm]MAPK11 [nucleoplasm]

UniProtQ16539UniProtQ15759Reactome Database ID Release 75450269Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450269ReactomeR-HSA-450269

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450269.2

Reactome DB_ID: 450213

p-p38 MAPK: MAPKAPK2,3 [nucleoplasm]

p-p38 MAPK: MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 450217

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

p-p38 MAPK alpha/beta [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T180,Y182-MAPK11 [nucleoplasm]p-T180,Y182-MAPK14 [nucleoplasm]

Reactome Database ID Release 75450213Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450213ReactomeR-HSA-450213

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450213.2

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450343

GO0004708

GO molecular function

Reactome Database ID Release 75450239Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450239Reactome Database ID Release 75450333Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450333ReactomeR-HSA-450333

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450333.1

2.7.11

Active p38 MAPK phosphorylates MAPKAPK2 or 3

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).Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). 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).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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 450213

Reactome DB_ID: 29358

Reactome DB_ID: 450254

p-p38 MAPK:p-MAPKAPK2/3 [nucleoplasm]

p-p38 MAPK:p-MAPKAPK2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

Converted from EntitySet in Reactome

Reactome DB_ID: 450261

Active MAPKAP kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T222,S272,T334-MAPKAPK2 [nucleoplasm]p-S,2T-MAPKAPK3 [nucleoplasm]

Reactome Database ID Release 75450254Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450254ReactomeR-HSA-450254

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450254.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 450213

Reactome Database ID Release 75450303Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450303Reactome Database ID Release 75450222Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450222ReactomeR-HSA-450222

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450222.115287722Pubmed2004Catalysis and function of the p38 alpha.MK2a signaling complexLukas, SMKroe, RRWildeson, JPeet, GWFrego, LDavidson, WIngraham, RHPargellis, CALabadia, MEWerneburg, BGBiochemistry 43:9950-6012171911Pubmed2002Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear exportMeng, WSwenson, LLFitzgibbon, MJHayakawa, KTer Haar, EBehrens, AEFulghum, JRLippke, JAJ Biol Chem 277:37401-58622688Pubmed19963pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene regionSithanandam, GLatif, FDuh, F MBernal, RSmola, ULi, HKuzmin, IWixler, VGeil, LShrestha, SMol. Cell. Biol. 16:868-768774846Pubmed1996A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stressClifton, A DYoung, P RCohen, PFEBS Lett. 392:209-1417255097Pubmed2007Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimerTer Haar, EPrabhakar, PLiu, XLepre, CJ Biol Chem 282:9733-917395714Pubmed2007Molecular basis of MAPK-activated protein kinase 2:p38 assemblyWhite, APargellis, CAStudts, JMWerneburg, BGFarmer BT, 2ndProc Natl Acad Sci U S A 104:6353-88626550Pubmed1996Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinaseMcLaughlin, M MKumar, SMcDonnell, P CVan Horn, SLee, J CLivi, G PYoung, P RJ. Biol. Chem. 271:8488-928846784Pubmed1995Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2Ben-Levy, RLeighton, IADoza, YNAttwood, PMorrice, NMarshall, CJCohen, PEMBO J 14:5920-30

Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3

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.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.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 450254

Reactome DB_ID: 450241

p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol]

p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3

Converted from EntitySet in Reactome

Reactome DB_ID: 187726

p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S272,T222,T334-MAPKAPK2 [cytosol]p-S,2T-MAPKAPK3 [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 170997

p-p38 MAPK alpha/beta [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T180,Y182-MAPK11 [cytosol]p-T180,Y182-MAPK14 [cytosol]

Reactome Database ID Release 75450241Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450241ReactomeR-HSA-450241

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450241.2Reactome Database ID Release 75450257Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450257ReactomeR-HSA-450257

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450257.1

Reactome Database ID Release 75450302Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450302ReactomeR-HSA-450302

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450302.210878576Pubmed2000p38 MAPK signalling cascades: ancient roles and new functionsMartin-Blanco, EBioessays 22:637-45GO0000187

GO biological process

MAP3K8 (TPL2)-dependent MAPK1/3 activation

Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

NFKB p105, TPL2 (COT) and ABIN2 form a stable complex

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). 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.

Authored: Ray, KP, 2010-05-17Reviewed: Pinteaux, E, 2010-05-17Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Jupe, S, 2010-05-17

Reactome DB_ID: 451607

UniProt:P19838 NFKB1

NFKB1

NFKB1FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-p50 complex. Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. Component of the NF-kappa-B p50-c-Rel complex. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Also interacts with MAP3K8. NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity. Interacts with DSIPI; this interaction prevents nuclear translocation and DNA-binding. Interacts with SPAG9 and UNC5CL. NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50. NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2. Interacts with GSK3B; the interaction prevents processing of p105 to p50. NFKB1/p50 interacts with NFKBIE. NFKB1/p50 interacts with NFKBIZ. Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1. Interacts with HIF1AN.INDUCTION By phorbol ester and TNF.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.DOMAIN Glycine-rich region (GRR) appears to be a critical element in the generation of p50.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.PTM Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.PTM Polyubiquitination seems to allow p105 processing.PTM S-nitrosylation of Cys-61 affects DNA binding.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.

EQUAL

968

EQUAL

Reactome DB_ID: 451661

UniProt:Q8NFZ5 TNIP2

TNIP2

TNIP2FLIP1ABIN2FUNCTION Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.SUBUNIT Interacts with STK11/LKB1, TNFAIP3, IKBKG, NFKB1, MAP3K8, TEK, RIPK1, CHUK, IKBKB and SMARCD1. Interacts with polyubiquitin.TISSUE SPECIFICITY Ubiquitously expressed in all tissues examined.PTM In vitro phosphorylated by CHUK.PTM Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination probably leading to constitutive proteasomal degradation which can be impaired by IKK-A/CHUK or IKBKB probably involving deubiquitination.

UniProtQ8NFZ5

EQUAL

429

EQUAL

Reactome DB_ID: 389388

UniProt:P41279 MAP3K8

MAP3K8

ESTFCOTMAP3K8FUNCTION Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.SUBUNIT Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.TISSUE SPECIFICITY Expressed in several normal tissues and human tumor-derived cell lines.DEVELOPMENTAL STAGE Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.INDUCTION Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.PTM Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).MISCELLANEOUS Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.CAUTION A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced.

UniProtP41279

EQUAL

467

EQUAL

Reactome DB_ID: 451638

NFKB1:MAP3K8:TNIP2 [cytosol]

NFKB1:MAP3K8:TNIP2

NFKB p105:TPL2:ABIN2

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 389388

EQUAL

467

EQUAL

Reactome Database ID Release 75451638Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451638ReactomeR-HSA-451638

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451638.1Reactome Database ID Release 75451634Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451634ReactomeR-HSA-451634

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451634.312832462Pubmed2003NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activityBeinke, SDeka, JLang, VBelich, MPWalker, PAHowell, SSmerdon, SJGamblin, SJLey, SCMol Cell Biol 23:4739-5215169888Pubmed2004ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stabilityLang, VSymons, AWatton, SJJanzen, JSoneji, YBeinke, SHowell, SLey, SCMol Cell Biol 24:5235-489950430Pubmed1999TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105Belich, MPSalmeron, AJohnston, LHLey, SCNature 397:363-812667451Pubmed2003NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinaseWaterfield, MRZhang, MNorman, LPSun, SCMol Cell 11:685-9415699325Pubmed2005Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharideCho, JTsichlis, PNProc Natl Acad Sci U S A 102:2350-5

INHIBITION

Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1.

Reactome Database ID Release 75451645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451645ReactomeR-HSA-451645

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451645.1

Reactome DB_ID: 451619

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

INHIBITION

Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1.

Reactome Database ID Release 755692833Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5692833ReactomeR-HSA-5692833

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5692833.1

Reactome DB_ID: 5684242

3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol]

3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 451619

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

Reactome Database ID Release 755684242Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684242ReactomeR-HSA-5684242

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684242.2

2.7.11.10

IKBKB phosphorylates TPL2 (MAP3K8) at Ser400

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).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 451638

Reactome DB_ID: 113592

Reactome DB_ID: 5687880

NFKB1:p-S400-MAP3K8:TNIP2 [cytosol]

NFKB1:p-S400-MAP3K8:TNIP2

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 5684308

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome Database ID Release 755687880Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687880ReactomeR-HSA-5687880

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5687880.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

GO0008384

GO molecular function

Reactome Database ID Release 75451612Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451612Reactome Database ID Release 755684275Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684275ReactomeR-HSA-5684275

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684275.119754427Pubmed2009IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2Handoyo, HoseaStafford, Margaret JMcManus, EamonBaltzis, DionissiosPeggie, MarkCohen, PBiochem. J. 424:109-1822988300Pubmed2012I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400Roget, KarineBen-Addi, AbduelhakemMambole-Dema, AgnesGantke, ThorstenYang, Huei-TingJanzen, JuliaMorrice, NAbbott, Derek WLey, Steven CMol. Cell. Biol. 32:4684-9016806191Pubmed2006Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62Stafford, Margaret JMorrice, Nick APeggie, Mark WCohen, PFEBS Lett. 580:4010-4

MAP3K8 is phosphorylated

TPL2 (MAP3K8) is phosphorylated at T290The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).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. Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 451638

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 5684265

NFKB1:p-T290-MAP3K8:TNIP2 [cytosol]

NFKB1:p-T290-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 755684265Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684265ReactomeR-HSA-5684265

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684265.1Reactome Database ID Release 755684261Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684261ReactomeR-HSA-5684261

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684261.221135874Pubmed2011Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinaseGantke, ThorstenSriskantharajah, SrividyaLey, Steven CCell Res. 21:131-4515778223Pubmed2005Tpl2 (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 signalsCho, JeongheeMelnick, MichaelSolidakis, Georgios PTsichlis, Philip NJ. Biol. Chem. 280:20442-815466476Pubmed2004Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activityLuciano, Brenda SHsu, SangChannavajhala, Padma LLin, Lih-LingCuozzo, John WJ. Biol. Chem. 279:52117-23

2.7.11.10

IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex

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.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 451638

Reactome DB_ID: 113592

Reactome DB_ID: 5687885

p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 [cytosol]

p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 451611

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

968

EQUAL

Reactome DB_ID: 389388

EQUAL

467

EQUAL

Reactome Database ID Release 755687885Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687885ReactomeR-HSA-5687885

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5687885.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

Reactome Database ID Release 755684267Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684267ReactomeR-HSA-5684267

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684267.112482991Pubmed2003betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932Lang, VJanzen, JFischer, GZSoneji, YBeinke, SSalmeron, AAllen, HHay, RTBen-Neriah, YLey, SCMol Cell Biol 23:402-13

SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2

IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Converted from EntitySet in Reactome

Reactome DB_ID: 1168601

(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 5684268

p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol]

p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 451611

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

968

EQUAL

Reactome Database ID Release 755684268Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684268ReactomeR-HSA-5684268

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684268.1

Reactome DB_ID: 5684270

SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2 [cytosol]

SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2

Converted from EntitySet in Reactome

Reactome DB_ID: 1168601

Reactome DB_ID: 5684268

Reactome Database ID Release 755684270Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684270ReactomeR-HSA-5684270

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684270.1Reactome Database ID Release 755684248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684248ReactomeR-HSA-5684248

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684248.114673179Pubmed2004Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processingCohen, SAchbert-Weiner, HCiechanover, AMol Cell Biol 24:475-8611158290Pubmed2001Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalphaHeissmeyer, VKrappmann, DHatada, E NScheidereit, CMol. Cell. Biol. 21:1024-35

6.3.2.19

SCF betaTrCP ubiquitinates NFKB p105 within p-S927, S932-NFkB p105:TPL2:ABIN2

Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 5684270

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 5684242

Converted from EntitySet in Reactome

Reactome DB_ID: 1168601

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5684270

Reactome Database ID Release 755687862Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687862Reactome Database ID Release 755684250Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684250ReactomeR-HSA-5684250

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684250.3

3xUb,p-S-NFkB p105:TPL2:ABIN2 dissociates due to degradation of p105

IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 5684242

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 755684273Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684273ReactomeR-HSA-5684273

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684273.1

2.7.11.25

TPL2 phosphorylates MEK1, SEK1

Tpl2 (also known as Cot, officially known as MAP3K8) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1 (MAP2K4). Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007). Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994).

Authored: Ray, KP, 2010-05-17Reviewed: Pinteaux, E, 2010-05-17Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Jupe, S, 2010-05-17

Converted from EntitySet in Reactome

Reactome DB_ID: 451647

MAP2K1,MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K1 [cytosol]MAP2K4 [cytosol]

UniProtQ02750

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 451654

p-S218,S222-MAP2K1,p-S257,T261-MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S218,S222-MAP2K1 [cytosol]p-S257,T261-MAP2K4 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome Database ID Release 75451651Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451651Reactome Database ID Release 75451649Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451649ReactomeR-HSA-451649

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451649.317709378Pubmed2007Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophagesRobinson, MJBeinke, SKouroumalis, ATsichlis, PNLey, SCMol Cell Biol 27:7355-648131746Pubmed1994Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residuesZheng, CFGuan, KLEMBO J 13:1123-31

Reactome Database ID Release 755684264Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684264ReactomeR-HSA-5684264

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684264.215485931Pubmed2004Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105Beinke, SRobinson, M JHugunin, MLey, S CMol. Cell. Biol. 24:9658-6722733995Pubmed2012Coordinate regulation of TPL-2 and NF-?B signaling in macrophages by NF-?B1 p105Yang, Huei-TingPapoutsopoulou, StamatiaBelich, MonicaBrender, ChristineJanzen, JuliaGantke, ThorstenHandley, MattLey, Steven CMol. Cell. Biol. 32:3438-5110072079Pubmed1999The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinasesLin, XCunningham, E TMu, YGeleziunas, RGreene, W CImmunity 10:271-8019414798Pubmed2009Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expressionZacharioudaki, VassilikiAndroulidaki, AriadneArranz, AliciaVrentzos, GeorgeMargioris, Andrew NTsatsanis, ChristosJ. Immunol. 182:6444-5112234923Pubmed2002Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signalsEliopoulos, Aristides GDumitru, Calin DWang, Chun-ChiCho, JeongheeTsichlis, Philip NEMBO J. 21:4831-4011163183Pubmed2000TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathwayDumitru, C DCeci, J DTsatsanis, CKontoyiannis, DStamatakis, KLin, J HPatriotis, CJenkins, N ACopeland, N GKollias, GTsichlis, P NCell 103:1071-8321377269Pubmed2011Tpl2 kinase signal transduction in inflammation and cancerVougioukalaki, MariaKanellis, Dimitris CGkouskou, KalliopiEliopoulos, Aristides GCancer Lett. 304:80-921469113Pubmed2011Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expressionLópez-Peláez, MartaSoria-Castro, IreneBoscá, LisardoFernández, MargaritaAlemany, SusanaEur. J. Immunol. 41:1733-4117848581Pubmed2007Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and bloodHall, J PerryKurdi, YahyaHsu, SangCuozzo, JohnLiu, JulieTelliez, Jean-BaptisteSeidl, Katherine JWinkler, AaronHu, YonghanGreen, NealAskew, G RogerTam, SteveClark, James DLin, Lih-LingJ. Biol. Chem. 282:33295-304978-953-51-0633-3ISBN2012The Role of Tpl2 Protein Kinase in Carcinogenesis and InflammationDeCicco-Skinner, Kathleen L.Deshpande, MonikaWiest, JonathanAdvances in Protein Kinases (Book)20606319Pubmed2010Inhibition of tumor progression locus 2 protein kinase decreases lipopolysaccharide-induced tumor necrosis factor alpha production due to the inhibition of the tip-associated protein induction in RAW264.7 cellsHirata, KazuyaMiyashiro, MasahikoOgawa, HirofumiTaki, HirofumiTobe, KazuyukiSugita, TakahisaBiol. Pharm. Bull. 33:1233-719933865Pubmed2009Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta productionMielke, Lisa AElkins, Karen LWei, LaiStarr, RobynTsichlis, Philip NO'Shea, John JWatford, Wendy TJ. Immunol. 183:7984-93

MAPK targets/ Nuclear events mediated by MAP kinases

MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

ERK/MAPK targets

ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

2.7.11

ERK1/2 activates ELK1

Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon stimulation with growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like FOS (c-fos) (Marais et al, 1993; Gille et al, 1995; Duan et al, 1998; reviewed in Treisman, 1995).

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 3009346

UniProt:P19419 ELK1

ELK1

ELK1FUNCTION Transcription factor that binds to purine-rich DNA sequences. Forms a ternary complex with SRF and the ETS and SRF motifs of the serum response element (SRE) on the promoter region of immediate early genes such as FOS and IER2. Induces target gene transcription upon JNK-signaling pathway stimulation (By similarity).SUBUNIT Interacts in its sumoylated form with PIAS2/PIASX which enhances its transcriptional activator activity (PubMed:15920481). Interacts with MAD2L2; the interaction is direct and promotes phosphorylation by the kinases MAPK8 and/or MAPK9 (PubMed:17296730). Interacts with POU1F1 (PubMed:26612202).TISSUE SPECIFICITY Lung and testis.PTM Sumoylation represses transcriptional activator activity as it results in recruitment of HDAC2 to target gene promoters which leads to decreased histone acetylation and reduced transactivator activity. It also regulates nuclear retention.PTM On mitogenic stimulation, phosphorylated on C-terminal serine and threonine residues by MAPK1. Ser-383 and Ser-389 are the preferred sites for MAPK1. In vitro, phosphorylation by MAPK1 potentiates ternary complex formation with the serum responses factors, SRE and SRF. Also phosphorylated on Ser-383 by MAPK8 and/or MAKP9. Phosphorylation leads to loss of sumoylation and restores transcriptional activator activity. Phosphorylated and activated by CAMK4, MAPK11, MAPK12 and MAPK14. Upon bFGF stimulus, phosphorylated by PAK1 (By similarity).SIMILARITY Belongs to the ETS family.

UniProtP19419

EQUAL

428

EQUAL

Reactome DB_ID: 3009350

O-phospho-L-serine at 324

324

EQUAL

O-phospho-L-serine at 383

383

EQUAL

O-phospho-L-serine at 389

389

EQUAL

O-phospho-L-serine at 422

422

EQUAL

O-phospho-L-threonine at 336

336

EQUAL

428

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198701

p-T,Y MAPK dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 75198713Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198713Reactome Database ID Release 75198731Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198731ReactomeR-HSA-198731

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198731.37889942Pubmed1995ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivationGille, HKortenjann, MThomae, OMoomaw, CSlaughter, CCobb, MHShaw, PEEMBO J 14:951-628386592Pubmed1993The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domainMarais, RWynne, JudyTreisman, RichardCell 73:381-9311145955Pubmed2001Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1Duan, RenqinXie, WenBurghardt, Robert CSafe, StephenJ. Biol. Chem. 276:11590-87588619Pubmed1995Journey to the surface of the cell: Fos regulation and the SRETreisman, RichardEMBO J. 14:4905-13

2.7.11

ERK1/2 phosphorylates MSK1

MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 198657

UniProt:O75582 RPS6KA5

RPS6KA5

RPS6KA5MSK1FUNCTION Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes (PubMed:11909979, PubMed:12569367, PubMed:12763138, PubMed:9687510, PubMed:18511904, PubMed:9873047). Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin (PubMed:11909979, PubMed:9873047). Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression (PubMed:12628924, PubMed:18511904). In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress (PubMed:12628924). In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential (PubMed:12763138). Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation (PubMed:12569367). Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A (PubMed:15010469). Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN (PubMed:12773393). May also phosphorylate 'Ser-28' of histone H3 (PubMed:12773393). Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) (PubMed:12773393). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines (By similarity). Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors (By similarity). Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury (By similarity). Phosphorylates TRIM7 at 'Ser-107' in response to growth factor signaling via the MEK/ERK pathway, thereby stimulating its ubiquitin ligase activity (PubMed:25851810).ACTIVITY REGULATION Activated by phosphorylation at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-212, Ser-376 and Ser-381 by the activated C-terminal kinase domain. The active N-terminal kinase domain finally phosphorylates downstream substrates, as well as Ser-750, Ser-752 and Ser-758 in its own C-terminal region.SUBUNIT Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA5 associates with and phosphorylates the NF-kappa-B p65 subunit RELA. Interacts with CREBBP and EP300.TISSUE SPECIFICITY Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver.PTM Ser-376 and Thr-581 phosphorylation is required for kinase activity. Ser-376 and Ser-212 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-750, Ser-752 and Ser-758 by the N-terminal kinase domain.PTM Ubiquitinated.MISCELLANEOUS Enzyme activity requires the presence of both kinase domains.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.

UniProtO75582

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198701

Reactome Database ID Release 75198756Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198756ReactomeR-HSA-198756

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198756.39687510Pubmed1998Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREBDeak, MClifton, ADLucocq, LMAlessi, DREMBO J 17:4426-41

2.7.11

p38MAPK phosphorylates MSK1

MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 198657

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

Reactome Database ID Release 75198647Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198647Reactome Database ID Release 75198669Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198669ReactomeR-HSA-198669

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198669.1

2.7.11

ERK1/2/5 activate RSK1/2/3

The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK. RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398. Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15

Converted from EntitySet in Reactome

Reactome DB_ID: 199858

Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS6KA2 [nucleoplasm]RPS6KA3 [nucleoplasm]RPS6KA1 [nucleoplasm]

UniProtQ15349UniProtP51812UniProtQ15418

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 199849

Phospho-Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-4S,T359,T573-RPS6KA1 [nucleoplasm]p-4S,T231,T365-RPS6KA3 [nucleoplasm]p-4S,T356,T570-RPS6KA2 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 199878

p-MAPK3/MAPK1/MAPK7 dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 75199864Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199864Reactome Database ID Release 75198746Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198746ReactomeR-HSA-198746

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198746.312832467Pubmed2003Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activityRoux, PPRichards, SABlenis, JMol Cell Biol 23:4796-80416626623Pubmed2006The MAP kinase ERK5 binds to and phosphorylates p90 RSKRanganathan, APearson, GWChrestensen, CASturgill, TWCobb, MHArch Biochem Biophys 449:8-16

2.7.11

ERK5 activates the transcription factor MEF2

The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 199911

MEF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMEF2C [nucleoplasm]MEF2A [nucleoplasm]

UniProtQ06413UniProtQ02078Converted from EntitySet in Reactome

Reactome DB_ID: 199933

p-MEF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S408-MEF2A [nucleoplasm]p-S396-MEF2C [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198738

UniProt:Q13164 MAPK7

MAPK7

MAPK7ERK5BMK1PRKM7FUNCTION Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.ACTIVITY REGULATION Activated by tyrosine and threonine phosphorylation (By similarity). Activated in response to hyperosmolarity, hydrogen peroxide, and epidermal growth factor (EGF).SUBUNIT Interacts with MAP2K5. Forms oligomers (By similarity). Interacts with MEF2A, MEF2C and MEF2D; the interaction phosphorylates the MEF2s and enhances transcriptional activity of MEF2A, MEF2C but not MEF2D (By similarity). Interacts with SGK1. Preferentially interacts with PML isoform PML-4 but shows interaction also with its other isoforms: isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6. Interacts (via N-terminal half) with HSP90AB1-CDC37 chaperone complex in resting cells; the interaction is MAP2K5-independent and prevents MAPK7 from ubiquitination and proteasomal degradation (PubMed:23428871).TISSUE SPECIFICITY Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver.DOMAIN The second proline-rich region may interact with actin targeting the kinase to a specific location in the cell.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-219 and Tyr-221, which activates the enzyme (By similarity). Autophosphorylated in vitro on threonine and tyrosine residues when the C-terminal part of the kinase, which could have a regulatory role, is absent.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

UniProtQ13164

O-phospho-L-threonine at 218

218

EQUAL

O4'-phospho-L-tyrosine at 220

220

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

EQUAL

816

EQUAL

Reactome Database ID Release 75199939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199939Reactome Database ID Release 75199929Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199929ReactomeR-HSA-199929

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199929.1

ERKs are inactivated by protein phosphatase 2A

ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK. Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted from EntitySet in Reactome

Reactome DB_ID: 199878

Converted from EntitySet in Reactome

Reactome DB_ID: 199955

MAPK3/MAPK1/MAPK7 dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 113550

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

[PO3(OH)](2-)HYDROGENPHOSPHATE IONhydrogen phosphate[P(OH)O3](2-)HPO4(2-)phosphateINORGANIC PHOSPHATE GROUP

ChEBI43474PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 165970

PP2A-ABdeltaC complex [nucleoplasm]

PP2A-ABdeltaC complex

Reactome DB_ID: 3008956

UniProt:Q14738 PPP2R5D

PPP2R5D

PPP2R5DFUNCTION The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.SUBUNIT PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with SGO1. Interacts with ADCY8 (PubMed:22976297).TISSUE SPECIFICITY Isoform Delta-2 is widely expressed. Isoform Delta-1 is highly expressed in brain.INDUCTION By retinoic acid; in neuroblastoma cell lines.SIMILARITY Belongs to the phosphatase 2A regulatory subunit B56 family.

UniProtQ14738

EQUAL

602

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 165997

PP2A-subunit A [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 165974

PP2A-catalytic subunit C [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 75165970Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165970ReactomeR-HSA-165970

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165970.1GO0004722

GO molecular function

Reactome Database ID Release 75199956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199956Reactome Database ID Release 75199959Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199959ReactomeR-HSA-199959

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199959.116456541Pubmed2006B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERKLetourneux, CRocher, GPorteu, FEMBO J 25:727-38

ERKs are inactivated

MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK.

Reviewed: Greene, LA, 2007-11-08 15:39:37

3.1.3.48

ERKs are inactivated by dual-specific phosphatases (DUSPs)

Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Edited: Jassal, B, 2010-11-17

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 199878

Converted from EntitySet in Reactome

Reactome DB_ID: 199955

Reactome DB_ID: 113550

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 203792

ERK-specific DUSP [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDUSP3 [nucleoplasm]DUSP6 [nucleoplasm]DUSP4 [nucleoplasm]DUSP7 [nucleoplasm]

UniProtP51452UniProtQ16828UniProtQ13115UniProtQ16829GO0004725

GO molecular function

Reactome Database ID Release 75203785Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203785Reactome Database ID Release 75203797Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203797ReactomeR-HSA-203797

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203797.217322878Pubmed2007A module of negative feedback regulators defines growth factor signalingAmit, ICitri, AShay, TLu, YKatz, MZhang, FTarcic, GSiwak, DLahad, JJacob-Hirsch, JAmariglio, NVaisman, NSegal, ERechavi, GAlon, UMills, GBDomany, EYarden, YNat Genet 39:503-12

INHIBITION

Reactome Database ID Release 758942517Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942517ReactomeR-HSA-8942517

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942517.1

Reactome DB_ID: 8942511

VRK3:DUSP3 [nucleoplasm]

VRK3:DUSP3

Reactome DB_ID: 203798

UniProt:P51452 DUSP3

DUSP3

VHRDUSP3FUNCTION Shows activity both for tyrosine-protein phosphate and serine-protein phosphate, but displays a strong preference toward phosphotyrosines. Specifically dephosphorylates and inactivates ERK1 and ERK2.SUBUNIT Interacts with VRK3, which seems to activate it's phosphatase activity.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.

EQUAL

185

EQUAL

Reactome DB_ID: 8942507

UniProt:Q8IV63 VRK3

VRK3

VRK3FUNCTION Inactive kinase that suppresses ERK activity by promoting phosphatase activity of DUSP3 which specifically dephosphorylates and inactivates ERK in the nucleus.SUBUNIT Interacts with DUSP3 (By similarity). Interacts with RAN.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily.CAUTION Inactive as a kinase due to its inability to bind ATP.

UniProtQ8IV63

EQUAL

474

EQUAL

Reactome Database ID Release 758942511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942511ReactomeR-HSA-8942511

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942511.1

Reactome Database ID Release 75202670Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202670ReactomeR-HSA-202670

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202670.215115656Pubmed2004Structure and regulation of MAPK phosphatasesFarooq, AZhou, MMCell Signal 16:769-79

Reactome Database ID Release 75198753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198753ReactomeR-HSA-198753

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198753.1

CREB phosphorylation

Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

2.7.11

MSK1 activates CREB

MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 52777

UniProt:P16220 CREB1

CREB1

CREB1FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family.

UniProtP16220

EQUAL

341

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

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341

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Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome Database ID Release 75199934Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199934Reactome Database ID Release 75199935Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199935ReactomeR-HSA-199935

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199935.1

2.7.11

MSK1 activates ATF1

Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 199900

UniProt:P18846 ATF1

ATF1

ATF1FUNCTION This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Binds to the Tax-responsive element (TRE) of HTLV-I. Mediates PKA-induced stimulation of CRE-reporter genes. Represses the expression of FTH1 and other antioxidant detoxification genes. Triggers cell proliferation and transformation.SUBUNIT Binds DNA as a dimer. Interacts with HIPK2 and CDK3.PTM Phosphorylated at Ser-198 by HIPK2 in response to genotoxic stress. This phosphorylation promotes transcription repression of FTH1 and other antioxidant detoxification genes. The CDK3-mediated phosphorylation at Ser-63 promotes its transactivation and transcriptional activities. Phosphorylated at Ser-63 by RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli.SIMILARITY Belongs to the bZIP family. ATF subfamily.

UniProtP18846

EQUAL

271

EQUAL

Reactome DB_ID: 199897

O-phospho-L-serine at 63

EQUAL

271

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome Database ID Release 75199910Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199910ReactomeR-HSA-199910

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199910.212414794Pubmed2002ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expressionGupta, PankajPrywes, RonJ. Biol. Chem. 277:50550-6

2.7.11

RSK1/2/3 phosphorylates CREB at Serine 133

CREB is phosphorylated at Serine 133 by RSK1/2/3.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 52777

EQUAL

341

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

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341

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Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 199849

Reactome Database ID Release 75199892Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199892Reactome Database ID Release 75199895Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199895ReactomeR-HSA-199895

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199895.19770464Pubmed1998Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos geneDe Cesare, DJacquot, SHanauer, ASassone-Corsi, PProc Natl Acad Sci U S A 95:12202-7

2.7.11

MAPKAPK2 phosphorylates CREB at Serine 133

p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 52777

EQUAL

341

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

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Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

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Reactome DB_ID: 199936

UniProt:P49137 MAPKAPK2

MAPKAPK2

MAPKAPK2FUNCTION Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.ACTIVITY REGULATION Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.SUBUNIT Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).TISSUE SPECIFICITY Expressed in all tissues examined.PTM Sumoylation inhibits the protein kinase activity.PTM Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

O-phospho-L-threonine at 222

222

EQUAL

O-phospho-L-serine at 272

272

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400

EQUAL

Reactome Database ID Release 75199915Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199915Reactome Database ID Release 75199917Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199917ReactomeR-HSA-199917

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199917.27551568Pubmed1995Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signalsBonni, AGinty, D DDudek, HGreenberg, M EMol. Cell. Neurosci. 6:168-83

Reactome Database ID Release 75199920Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199920ReactomeR-HSA-199920

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199920.1

Activation of the AP-1 family of transcription factors

Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through:<ol><li>effects on jun, fos, atf gene transcription and mRNA turnover.<li> AP-1 protein members turnover. <li>post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases).<li>interactions with other transcription factors that can either induce or interfere with AP-1 activity.</ol>

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11

Phosphorylated MAPKs phosphorylate ATF-2

At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'ATF-2' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'ATF-2-P' are present. This reaction is mediated by the 'protein kinase activity' of 'MAPK1-P'. the Raf–MEK–ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral–RalGDS–Src–p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 450336

UniProt:P15336 ATF2

ATF2

CREB2ATF2CREBP1FUNCTION Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro (PubMed:10821277). In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.SUBUNIT Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.TISSUE SPECIFICITY Ubiquitously expressed, with more abundant expression in the brain.DOMAIN The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.PTM Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity (PubMed:9430721, PubMed:12110590). Phosphorylated by PLK3 following hyperosmotic stress (PubMed:21098032). Also phosphorylated and activated by JNK and CaMK4 (PubMed:8855261). ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response (PubMed:15916964). Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity (PubMed:15105425). Phosphorylation at Thr-69 or Thr-71 enhances acetylation of histones H2B and H4 (PubMed:10821277).SIMILARITY Belongs to the bZIP family. ATF subfamily.CAUTION Appears to have histone acetyltransferase (HAT) activity, specifically towards histones H2B and H4 in vitro (PubMed:10821277). However, it is not clear if this activity is genuine or caused by contamination with other histone acetyltransferases in the assay.

UniProtP15336

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Reactome DB_ID: 29358

Reactome DB_ID: 450243

O-phospho-L-threonine at 71

EQUAL

O-phospho-L-threonine at 69

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505

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450307

Activated MAPK kinases ERK1/2, JNK, p38 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T221,Y223-MAPK10 [nucleoplasm]p-T,Y-MAPK8 [nucleoplasm]p-T183,Y185-MAPK9 [nucleoplasm]p-T180,Y182-MAPK11 [nucleoplasm]p-T180,Y182-MAPK14 [nucleoplasm]

Reactome Database ID Release 75167971Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167971Reactome Database ID Release 75168053Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168053ReactomeR-HSA-168053

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168053.119647037Pubmed2009The nuclear appearance of ERK1/2 and p38 determines the sequential induction of ATF2-Thr71 and ATF2-Thr69 phosphorylation by serum in JNK-deficient cellsBaan, Bvan der Zon, GCMaassen, JAOuwens, DMMol Cell Endocrinol 311:94-10012110590Pubmed2002Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-ME