BioPAX pathway converted from "Toll Like Receptor 2 (TLR2) Cascade" in the Reactome database.

Toll Like Receptor 2 (TLR2) Cascade

This event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>

Toll Like Receptor TLR1:TLR2 Cascade

MyD88:MAL(TIRAP) cascade initiated on plasma membrane

TIRAP binds PIP2-rich regions in the plasma membrane

MAL binds PIP2-rich regions in the plasma membraneThis event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>

Reactome DB_ID: 10145509

cytosolGO0005829

UniProt:A0A287A8A9TIRAP

Reactomehttp://www.reactome.orgSus scrofa

NCBI Taxonomy9823UniProtA0A287A8A9

Chain Coordinates

EQUAL

221

EQUAL

Reactome DB_ID: 179856

plasma membraneGO0005886

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate

PIP2

ChEBI18348

Reactome DB_ID: 10145511

TIRAP:PI(4,5)P2 [plasma membrane]

TIRAP:PI(4,5)P2

Reactome DB_ID: 10145509

EQUAL

221

EQUAL

Reactome DB_ID: 179856

Reactome Database ID Release 7510145511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10145511ReactomeR-SSC-2559415

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2559415.1Reactome Database ID Release 7510145513Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10145513ReactomeR-SSC-2559456

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2559456.1Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain [Kagan JC and Medzithov R 2007]. TLR2 or 4 associates with Mal(TIRAP) on the cell surface, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel R et al 2007, Nagpal K et al 2009].

11544529Pubmed2001Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transductionFitzgerald, K APalsson-McDermott, E MBowie, A GJefferies, C AMansell, A SBrady, GBrint, EDunne, AGray, PHarte, MTMcMurray, DSmith, D ESims, J EBird, T AO'Neill, L ANature 413:78-8319509286Pubmed2009A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signalingNagpal, KamalpreetPlantinga, Theo SWong, JoyceMonks, BGGay, Nicholas JNetea, Mihai GFitzgerald, Katherine AGolenbock, DTJ. Biol. Chem. 284:25742-816751103Pubmed2006Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signalingKagan, JCMedzhitov, RCell 125:943-5515585605Pubmed2005TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIRTakeda, KAkira, ShizuoInt Immunol 17:1-14inferred by electronic annotationIEAGOIEA

IRAK2 mediated activation of TAK1 complex

IRAK2 induces TRAF6 oligomerization

Reactome DB_ID: 10102867

UniProt:A7XUJ6TRAF6

UniProtA7XUJ6

EQUAL

522

EQUAL

Reactome DB_ID: 10127105

TRAF6:p-IRAK2 [plasma membrane]

TRAF6:p-IRAK2

Reactome DB_ID: 10127101

EQUAL

522

EQUAL

Reactome DB_ID: 10127103

UniProt:A0A287AF06IRAK2

UniProtA0A287AF06

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

625

EQUAL

Reactome Database ID Release 7510127105Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127105ReactomeR-SSC-936961

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936961.1

Reactome DB_ID: 10127107

p-IRAK2:oligo-TRAF6 [plasma membrane]

p-IRAK2:oligo-TRAF6

Reactome DB_ID: 10127101

EQUAL

522

EQUAL

Reactome DB_ID: 10127105

Reactome Database ID Release 7510127107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127107ReactomeR-SSC-936990

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936990.1Reactome Database ID Release 7510127134Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127134ReactomeR-SSC-936963

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936963.1The 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.

17878161Pubmed2007IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitinationKeating, SEMaloney, GMMoran, EMBowie, AGJ Biol Chem 282:33435-43inferred by electronic annotationIEAGOIEA

6.3.2.19

Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2

Reactome DB_ID: 10127107

Converted from EntitySet in Reactome

Reactome DB_ID: 10091209

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBB [cytosol]RPS27A [cytosol]UBA52(1-76) [cytosol]

UniProtA7U5U2UniProtA0A287AZA7UniProtP63053

Reactome DB_ID: 10127112

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

p-IRAK2:K63-linked pUb oligo-TRAF6

Reactome DB_ID: 10127110

ubiquitinylated lysine (K63polyUb [plasma membrane]) at 124 (in Homo sapiens)

124

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

522

EQUAL

Reactome DB_ID: 10127103

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 7510127112Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127112ReactomeR-SSC-936988

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936988.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10127107

GO0004842

GO molecular function

Reactome Database ID Release 7510127113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127113Reactome Database ID Release 7510127115Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127115ReactomeR-SSC-936942

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936942.1TRAF6 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.

17135271Pubmed2007Site-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 282:4102-12inferred by electronic annotationIEAGOIEA

6.3.2.19

Activated TRAF6 synthesizes unanchored polyubiquitin chains

Converted from EntitySet in Reactome

Reactome DB_ID: 10091209

Reactome DB_ID: 10103167

K63polyUb [cytosol]

K63polyUb

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10127112

Reactome Database ID Release 7510127137Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127137Reactome Database ID Release 7510127139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127139ReactomeR-SSC-936986

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936986.1Polyubiquitinated 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.

19675569Pubmed2009Direct activation of protein kinases by unanchored polyubiquitin chainsXia, ZPSun, LChen, XPineda, GJiang, XAdhikari, AZeng, WChen, ZJNatureinferred by electronic annotationIEAGOIEA

Activated TRAF6:p-IRAK2 interacts with TAK1 complex

Reactome DB_ID: 10103146

TAK1 complex [cytosol]

TAK1 complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10103144

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]

UniProtF1S7S1UniProtK7GRR6

Reactome DB_ID: 10103130

UniProt:B0LXP5MAP3K7

UniProtB0LXP5

EQUAL

606

EQUAL

Reactome DB_ID: 10103134

UniProt:K7GLB8TAB1

UniProtK7GLB8

EQUAL

504

EQUAL

Reactome Database ID Release 7510103146Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103146ReactomeR-SSC-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-SSC-446878.1

Reactome DB_ID: 10103167

Reactome DB_ID: 10127112

Reactome DB_ID: 10127130

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

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

Reactome DB_ID: 10103146

Reactome DB_ID: 10103167

Reactome DB_ID: 10127112

Reactome Database ID Release 7510127130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127130ReactomeR-SSC-936953

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936953.1Reactome Database ID Release 7510127132Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127132ReactomeR-SSC-936960

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936960.1TAK1-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.

19935683Pubmed2009Two-sided ubiquitin binding explains specificity of the TAB2 NZF domainKulathu, YogeshAkutsu, MasatoBremm, AnjaHofmann, KKomander, DavidNat. Struct. Mol. Biol. 16:1328-3015327770Pubmed2004TAB2 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 5:649-58inferred by electronic annotationIEAGOIEA

2.7.11

Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3

Reactome DB_ID: 10127130

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 10127141

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

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10103144

Reactome DB_ID: 10103167

Reactome DB_ID: 10127112

Reactome DB_ID: 10103134

EQUAL

504

EQUAL

Reactome DB_ID: 10103187

O-phospho-L-threonine at 184 (in Homo sapiens)

184

EQUAL

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

O-phospho-L-threonine at 187 (in Homo sapiens)

187

EQUAL

606

EQUAL

Reactome Database ID Release 7510127141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127141ReactomeR-SSC-937008

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937008.1

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10127130

GO0008349

GO molecular function

Reactome Database ID Release 7510127142Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127142Reactome Database ID Release 7510127144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127144ReactomeR-SSC-936991

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936991.1The 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).

10838074Pubmed2000Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1Sakurai, HMiyoshi, HMizukami, JSugita, TFEBS Lett. 474:141-510702308Pubmed2000TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loopKishimoto, KMatsumoto, KNinomiya-Tsuji, JJ Biol Chem 275:7359-6416289117Pubmed2005Structural basis for the interaction of TAK1 kinase with its activating protein TAB1Brown, KieronVial, Sarah C MDedi, NeeshaLong, Joanna MDunster, Nicholas JCheetham, Graham M TJ. Mol. Biol. 354:1013-2016186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-9511323434Pubmed2001An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKKOno, KOhtomo, TSato, SSugamata, YSuzuki, MHisamoto, NNinomiya-Tsuji, JTsuchiya, MMatsumoto, KJ. Biol. Chem. 276:24396-4008638164Pubmed1996TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transductionShibuya, HYamaguchi, KShirakabe, KTonegawa, AGotoh, YUeno, NIrie, KNishida, EMatsumoto, KScience 272:1179-8214633987Pubmed2003Role 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 19:2668-81inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510186571Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10186571ReactomeR-SSC-937042

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937042.1Although 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).

21606490Pubmed2011Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alphaFlannery, Sinead MKeating, Sinead ESzymak, JoannaBowie, Andrew GJ. Biol. Chem. 286:23688-9712140561Pubmed2002Distinct molecular mechanism for initiating TRAF6 signallingYe, HArron, JRLamothe, BCirilli, MKobayashi, TShevde, NKSegal, DDzivenu, OKVologodskaia, MYim, MDu, KSingh, SPike, JWDarnay, BGChoi, YWu, HNature 418:443-716831874Pubmed2006The 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 281:26029-40inferred by electronic annotationIEAGOIEA

IRAK1 recruits IKK complex

Pellino binds hp-IRAK1:TRAF6

Reactome DB_ID: 10127158

TRAF6:hp-IRAK1 [plasma membrane]

TRAF6:hp-IRAK1

Reactome DB_ID: 10127101

EQUAL

522

EQUAL

Reactome DB_ID: 10127156

UniProt:F1RZU1

UniProtF1RZU1

O-phospho-L-threonine at 387 (in Homo sapiens)

387

EQUAL

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

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

O-phospho-L-threonine at 209 (in Homo sapiens)

209

EQUAL

O-phospho-L-serine at unknown position

O-phospho-L-threonine at unknown position

EQUAL

712

EQUAL

Reactome Database ID Release 7510127158Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127158ReactomeR-SSC-937036

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937036.1Converted from EntitySet in Reactome

Reactome DB_ID: 10123891

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 PhysicalEntityphospho-p-PELI2 [cytosol]phospho-PELI1 [cytosol]

UniProtA0A287A3S0UniProtI3LPL3

Reactome DB_ID: 10127160

TRAF6:hp-IRAK1:Pellino [plasma membrane]

TRAF6:hp-IRAK1:Pellino

Reactome DB_ID: 10127158

Converted from EntitySet in Reactome

Reactome DB_ID: 10123891

Reactome Database ID Release 7510127160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127160ReactomeR-SSC-937020

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937020.1Reactome Database ID Release 7510127165Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127165ReactomeR-SSC-937044

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937044.1Pellino 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.

12496252Pubmed2003Pellino 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 282:29729-37inferred by electronic annotationIEAGOIEA

IRAK1 phosphorylates Pellino

Reactome DB_ID: 10127160

Reactome DB_ID: 113592

Reactome DB_ID: 10127160

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10127160

GO0004672

GO molecular function

Reactome Database ID Release 7510127161Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127161Reactome Database ID Release 7510127163Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127163ReactomeR-SSC-937034

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937034.1Both 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.

19264966Pubmed2009Identification 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 106:4584-90inferred by electronic annotationIEAGOIEA

Pellino ubiquitinates hp-IRAK1

Reactome DB_ID: 10127160

Reactome DB_ID: 10103167

Reactome DB_ID: 10103124

UBE2N:UBE2V1 [cytosol]

UBE2N:UBE2V1

Reactome DB_ID: 10103122

UniProt:A0A287BSL7UBE2V1

UniProtA0A287BSL7

EQUAL

147

EQUAL

Reactome DB_ID: 10103118

UniProt:F1SQ14UBE2N

UniProtF1SQ14

EQUAL

152

EQUAL

Reactome Database ID Release 7510103124Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103124ReactomeR-SSC-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-SSC-202463.1Converted from EntitySet in Reactome

Reactome DB_ID: 10123891

Reactome DB_ID: 10103124

Reactome DB_ID: 10127150

K63-linked polyUb p-IRAK1:TRAF6 [cytosol]

K63-linked polyUb p-IRAK1:TRAF6

Reactome DB_ID: 10124020

O-phospho-L-threonine at 209 (in Homo sapiens)

209

EQUAL

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 387 (in Homo sapiens)

387

EQUAL

O-phospho-L-threonine at unknown position

O-phospho-L-serine at unknown position

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 134 (in Homo sapiens)

134

EQUAL

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 160 (in Homo sapiens)

160

EQUAL

712

EQUAL

Reactome DB_ID: 10102867

EQUAL

522

EQUAL

Reactome Database ID Release 7510127150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127150ReactomeR-SSC-937043

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937043.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10127160

GO0034450

GO molecular function

Reactome Database ID Release 7510127166Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127166Reactome Database ID Release 7510127168Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127168ReactomeR-SSC-937050

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937050.1IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.IRAK1 is ubiquitinated on Lys134 and Lys180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is a stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al 2008; Butler et al 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008).

18347055Pubmed2008Lys63-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 28:3538-4718180283Pubmed2008Interleukin-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 28:1783-9118724939Pubmed2008Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodiesNewton, KimMatsumoto, Marissa LWertz, Ingrid EKirkpatrick, Donald SLill, Jennie RTan, JenilleDugger, DebraGordon, NathanielSidhu, SSFellouse, FAKomuves, LaszloFrench, Dorothy MFerrando, Ronald ELam, CynthiaCompaan, DeanneYu, ChristineBosanac, IvanHymowitz, Sarah GKelley, Robert FDixit, Vishva MCell 134:668-78inferred by electronic annotationIEAGOIEA

NEMO subunit of IKK complex binds to activated IRAK1

Reactome DB_ID: 10127150

Reactome DB_ID: 10103102

CHUK:IKBKB:IKBKG [cytosol]

CHUK:IKBKB:IKBKG

Reactome DB_ID: 10103100

UniProt:A5A757IKBKB

UniProtA5A757

EQUAL

756

EQUAL

Reactome DB_ID: 10103098

UniProt:F1S8V5CHUK

UniProtF1S8V5

EQUAL

745

EQUAL

Reactome DB_ID: 10103000

UniProt:A9QT41IKBKG

UniProtA9QT41

EQUAL

419

EQUAL

Reactome Database ID Release 7510103102Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103102ReactomeR-SSC-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-SSC-168113.1

Reactome DB_ID: 10127152

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

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

Reactome DB_ID: 10127150

Reactome DB_ID: 10103102

Reactome Database ID Release 7510127152Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127152ReactomeR-SSC-937038

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937038.1Reactome Database ID Release 7510127154Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10127154ReactomeR-SSC-937032

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937032.1NF-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).

16603398Pubmed2006Activation 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 8:398-406inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510186573Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10186573ReactomeR-SSC-937039

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937039.1GO0043123

GO biological process

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].

14625308Pubmed2004Sequential 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 279:5227-3618276832Pubmed2008Interleukin-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 5:98-10315767370Pubmed2005Interleukin-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 201:915-23inferred by electronic annotationIEAGOIEA

TRAF6 binds MEKK1

Reactome DB_ID: 10102867

EQUAL

522

EQUAL

Reactome DB_ID: 10102863

UniProt:F1SLK9

UniProtF1SLK9

EQUAL

1512

EQUAL

Reactome DB_ID: 10102869

MEKK1:activated TRAF6 [cytosol]

MEKK1:activated TRAF6

Reactome DB_ID: 10102867

EQUAL

522

EQUAL

Reactome DB_ID: 10102863

EQUAL

1512

EQUAL

Reactome Database ID Release 7510102869Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102869ReactomeR-SSC-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-SSC-166867.1Reactome Database ID Release 7510102875Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102875ReactomeR-SSC-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-SSC-166869.1TRAF6 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.

9836645Pubmed1998Role 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 88:213-22inferred by electronic annotationIEAGOIEA

ACTIVATION

Reactome Database ID Release 7510102876Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102876

Reactome DB_ID: 10102873

UniProt:F1SA17ECSIT

UniProtF1SA17

EQUAL

431

EQUAL

TAK1 activates NFkB by phosphorylation and activation of IKKs complex

IKBKA, IKBKB and IKBKG form IKK complex

Reactome DB_ID: 10103100

EQUAL

756

EQUAL

Reactome DB_ID: 10103098

EQUAL

745

EQUAL

Reactome DB_ID: 10103000

EQUAL

419

EQUAL

Reactome DB_ID: 10103102

Reactome Database ID Release 7510156154Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10156154ReactomeR-SSC-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-SSC-5609665.1The 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).

7479848Pubmed1995Stimulation-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. 26:9209-19inferred by electronic annotationIEAGOIEA

2.7.11.25

Activated TAK1 mediates phosphorylation of the IKK Complex

Reactome DB_ID: 10103102

Reactome DB_ID: 113592

Reactome DB_ID: 10103014

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

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

Reactome DB_ID: 10103012

O-phospho-L-serine at 177 (in Homo sapiens)

177

EQUAL

O-phospho-L-serine at 181 (in Homo sapiens)

181

EQUAL

756

EQUAL

Reactome DB_ID: 10103000

EQUAL

419

EQUAL

Reactome DB_ID: 10103006

O-phospho-L-serine at 176 (in Homo sapiens)

176

EQUAL

O-phospho-L-serine at 180 (in Homo sapiens)

180

EQUAL

745

EQUAL

Reactome Database ID Release 7510103014Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103014ReactomeR-SSC-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-SSC-177663.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10103200

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 7510103201Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103201Reactome Database ID Release 7510103203Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103203ReactomeR-SSC-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-SSC-168184.1In 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.

12221085Pubmed2002IKKalpha, 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 412:346-51inferred by electronic annotationIEAGOIEA

NFkB inhibitor binds NFkB complex

Reactome DB_ID: 10102974

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

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10102972

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 PhysicalEntityNFKB2 [cytosol]NFKB1(1-433) [cytosol]

UniProtK7GMC4UniProtK7GNS9

Reactome DB_ID: 10102962

UniProt:B0LXP3RELA

UniProtB0LXP3

EQUAL

551

EQUAL

Reactome Database ID Release 7510102974Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102974ReactomeR-SSC-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-SSC-168155.1Converted from EntitySet in Reactome

Reactome DB_ID: 10102984

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]

UniProtI3LLS5UniProtQ08353

Reactome DB_ID: 10102986

NFkB inhibitor:NFkB complex [cytosol]

NFkB inhibitor:NFkB complex

Reactome DB_ID: 10102974

Converted from EntitySet in Reactome

Reactome DB_ID: 10102984

Reactome Database ID Release 7510102986Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102986ReactomeR-SSC-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-SSC-168130.1Reactome Database ID Release 7510183361Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10183361ReactomeR-SSC-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-SSC-9630923.1NFkB 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).

15145317Pubmed2004The 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 25:6706-16inferred by electronic annotationIEAGOIEA

2.7.11

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

Reactome DB_ID: 10102986

Reactome DB_ID: 113592

Reactome DB_ID: 10102974

Converted from EntitySet in Reactome

Reactome DB_ID: 10102996

Phospho-NF-kappaB Inhibitor [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-NFKBIA [cytosol]phospho-NFKBIB [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10103014

GO0004674

GO molecular function

Reactome Database ID Release 7510103015Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103015Reactome Database ID Release 7510103027Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103027ReactomeR-SSC-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-SSC-168140.1In 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.

27701768Pubmed2017Double 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:re13inferred by electronic annotationIEAGOIEA

INHIBITION

Reactome Database ID Release 7510103028Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103028Converted from EntitySet in Reactome

Reactome DB_ID: 10103025

NKIRAS [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNKIRAS2 [cytosol]NKIRAS1 [cytosol]

UniProtF2Z555UniProtI3L911

NFkB complex is transported from cytosol to nucleus

Reactome DB_ID: 10102974

Reactome DB_ID: 10103069

nucleoplasmGO0005654NFkB Complex [nucleoplasm]

NFkB Complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10103065

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 PhysicalEntityNFKB1(1-433) [nucleoplasm]NFKB2 [nucleoplasm]

Reactome DB_ID: 10103067

EQUAL

551

EQUAL

Reactome Database ID Release 7510103069Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103069ReactomeR-SSC-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-SSC-177673.1Reactome Database ID Release 7510103095Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103095ReactomeR-SSC-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-SSC-168166.1NFkB 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.

16056267Pubmed2005Ubiquitin signalling in the NF-kappaB pathwayChen, ZJNat Cell Biol 7:758-65inferred by electronic annotationIEAGOIEA

ACTIVATION

Reactome Database ID Release 7510103096Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103096

Reactome DB_ID: 10103093

AGER ligands:AGER [plasma membrane]

AGER ligands:AGER

Reactome DB_ID: 10103073

UniProt:A5A8Y1AGER

UniProtA5A8Y1

EQUAL

404

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10103091

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 PhysicalEntityHMGB1 [extracellular region]

UniProtF2Z594Reactome Database ID Release 7510103093Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103093ReactomeR-SSC-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-SSC-879365.1

Reactome Database ID Release 7510185501Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185501ReactomeR-SSC-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-SSC-445989.1GO0051092

GO biological process

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.

15837794Pubmed2005Simultaneous 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 280:27728-41inferred by electronic annotationIEAGOIEA

MAP kinase activation

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

2.7.11.25

Activated TAK1 phosphorylates MKK4/MKK7

Converted from EntitySet in Reactome

Reactome DB_ID: 10123648

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]

UniProtA0A286ZVB5UniProtF1SS51

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 10103056

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

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10103200

Reactome Database ID Release 7510123650Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123650ReactomeR-SSC-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-SSC-450337.1In 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.

8533096Pubmed1995Identification 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 27:7935-46inferred by electronic annotationIEAGOIEA

2.7.11

Phosphorylation of human JNKs by activated MKK4/MKK7

Converted from EntitySet in Reactome

Reactome DB_ID: 10103034

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]

UniProtK7GP94UniProtK7GRS5UniProtA0A287APM5

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 10103042

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

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10103056

GO0008545

GO molecular function

Reactome Database ID Release 7510103057Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103057Reactome Database ID Release 7510103059Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10103059ReactomeR-SSC-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-SSC-168162.1Activated 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).

18713996Pubmed2008Synoviocyte 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 272:14489-96inferred by electronic annotationIEAGOIEA

Activated human JNKs migrate to nucleoplasm

Converted from EntitySet in Reactome

Reactome DB_ID: 10103042

Converted from EntitySet in Reactome

Reactome DB_ID: 10102951

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

Reactome Database ID Release 7510123656Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123656ReactomeR-SSC-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-SSC-450348.1c-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.

12193592Pubmed2002Evidence 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 272:16657-62inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185517Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185517ReactomeR-SSC-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-SSC-450321.1GO0007254

GO biological process

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).

26988982Pubmed2016IL-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 369:156-60inferred by electronic annotationIEAGOIEA

activated TAK1 mediates p38 MAPK activation

2.7.11.25

activated human TAK1 phosphorylates MKK3/MKK6

Reactome DB_ID: 10123652

UniProt:F1RV28MAP2K6

UniProtF1RV28

EQUAL

334

EQUAL

Reactome DB_ID: 113592

Reactome DB_ID: 10123623

O-phospho-L-serine at 207 (in Homo sapiens)

207

EQUAL

O-phospho-L-threonine at 211 (in Homo sapiens)

211

EQUAL

334

EQUAL

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10103200

Reactome Database ID Release 7510123654Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123654ReactomeR-SSC-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-SSC-450346.1Human 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 .

8622669Pubmed1996MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathwayRaingeaud, JWhitmarsh, AJBarrett, TDerijard, BDavis, RJMol Cell Biol 16:1247-55inferred by electronic annotationIEAGOIEA

Phosphorylated MKK3/MKK6 migrates to nucleus

Reactome DB_ID: 10123623

O-phospho-L-serine at 207 (in Homo sapiens)

207

EQUAL

O-phospho-L-threonine at 211 (in Homo sapiens)

211

EQUAL

334

EQUAL

Reactome DB_ID: 10123625

O-phospho-L-serine at 207 (in Homo sapiens)

207

EQUAL

O-phospho-L-threonine at 211 (in Homo sapiens)

211

EQUAL

334

EQUAL

Reactome Database ID Release 7510123627Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123627ReactomeR-SSC-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-SSC-450296.1The 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.

7535770Pubmed1995Pro-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 8:1049-57inferred by electronic annotationIEAGOIEA

2.7.12.2

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

Reactome DB_ID: 10123639

p38 MAPK:MAPKAPK2,3 [nucleoplasm]

p38 MAPK:MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 10123592

MAPKAP2,3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPKAPK2 [nucleoplasm]MAPKAPK3 [nucleoplasm]

UniProtF1SEZ4UniProtB8XSJ7Converted from EntitySet in Reactome

Reactome DB_ID: 10123637

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 PhysicalEntityMAPK11 [nucleoplasm]MAPK14 [nucleoplasm]

UniProtA0A286ZJZ3UniProtA0A287BHS8Reactome Database ID Release 7510123639Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123639ReactomeR-SSC-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-SSC-450269.1

Reactome DB_ID: 29358

Reactome DB_ID: 10123594

p-p38 MAPK: MAPKAPK2,3 [nucleoplasm]

p-p38 MAPK: MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 10102933

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 PhysicalEntityphospho-MAPK14 [nucleoplasm]phospho-MAPK11 [nucleoplasm]

Converted from EntitySet in Reactome

Reactome DB_ID: 10123592

Reactome Database ID Release 7510123594Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123594ReactomeR-SSC-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-SSC-450213.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10123625

O-phospho-L-serine at 207 (in Homo sapiens)

207

EQUAL

O-phospho-L-threonine at 211 (in Homo sapiens)

211

EQUAL

334

EQUAL

GO0004708

GO molecular function

Reactome Database ID Release 7510123640Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123640Reactome Database ID Release 7510123642Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123642ReactomeR-SSC-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-SSC-450333.1The 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.

inferred by electronic annotationIEAGOIEA

2.7.11

Active p38 MAPK phosphorylates MAPKAPK2 or 3

Reactome DB_ID: 10123594

Reactome DB_ID: 29358

Reactome DB_ID: 10123602

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

p-p38 MAPK:p-MAPKAPK2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 10102933

Converted from EntitySet in Reactome

Reactome DB_ID: 10123600

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

Reactome Database ID Release 7510123602Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123602ReactomeR-SSC-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-SSC-450254.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10123594

Reactome Database ID Release 7510123603Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123603Reactome Database ID Release 7510123605Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123605ReactomeR-SSC-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-SSC-450222.1Human 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.

15287722Pubmed2004Catalysis 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 14:5920-30inferred by electronic annotationIEAGOIEA

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

Reactome DB_ID: 10123602

Reactome DB_ID: 10123607

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: 10105265

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 PhysicalEntityphospho-MAPKAPK3 [cytosol]phospho-p-S272,T222,T334-MAPKAPK2 [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 10105271

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 PhysicalEntityphospho-MAPK11 [cytosol]phospho-MAPK14 [cytosol]

Reactome Database ID Release 7510123607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123607ReactomeR-SSC-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-SSC-450241.1Reactome Database ID Release 7510123609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123609ReactomeR-SSC-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-SSC-450257.1p38 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.

inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510186427Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10186427ReactomeR-SSC-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-SSC-450302.1GO0000187

GO biological process

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.

10878576Pubmed2000p38 MAPK signalling cascades: ancient roles and new functionsMartin-Blanco, EBioessays 22:637-45inferred by electronic annotationIEAGOIEA

MAP3K8 (TPL2)-dependent MAPK1/3 activation

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

Reactome DB_ID: 10124033

UniProt:K7GNS9

EQUAL

968

EQUAL

Reactome DB_ID: 10124037

UniProt:F1S8Q0TNIP2

UniProtF1S8Q0

EQUAL

429

EQUAL

Reactome DB_ID: 10118407

UniProt:K7GKL4MAP3K8

UniProtK7GKL4

EQUAL

467

EQUAL

Reactome DB_ID: 10124039

NFKB1:MAP3K8:TNIP2 [cytosol]

NFKB1:MAP3K8:TNIP2

Reactome DB_ID: 10124033

EQUAL

968

EQUAL

Reactome DB_ID: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10118407

EQUAL

467

EQUAL

Reactome Database ID Release 7510124039Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10124039ReactomeR-SSC-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-SSC-451638.1Reactome Database ID Release 7510124051Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10124051ReactomeR-SSC-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-SSC-451634.1The 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.

12832462Pubmed2003NF-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 102:2350-5inferred by electronic annotationIEAGOIEA

INHIBITION

Reactome Database ID Release 7510124052Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10124052

Reactome DB_ID: 10124044

O-phospho-L-serine at 927 (in Homo sapiens)

927

EQUAL

O-phospho-L-serine at 932 (in Homo sapiens)

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

INHIBITION

Reactome Database ID Release 7510124053Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10124053

Reactome DB_ID: 10124049

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: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10124044

O-phospho-L-serine at 927 (in Homo sapiens)

927

EQUAL

O-phospho-L-serine at 932 (in Homo sapiens)

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

Reactome DB_ID: 10124047

O-phospho-L-threonine at 290 (in Homo sapiens)

290

EQUAL

O-phospho-L-serine at 400 (in Homo sapiens)

400

EQUAL

467

EQUAL

Reactome Database ID Release 7510124049Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10124049ReactomeR-SSC-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-SSC-5684242.1

2.7.11.10

IKBKB phosphorylates TPL2 (MAP3K8) at Ser400

Reactome DB_ID: 10124039

Reactome DB_ID: 113592

Reactome DB_ID: 10160848

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

NFKB1:p-S400-MAP3K8:TNIP2

Reactome DB_ID: 10124033

EQUAL

968

EQUAL

Reactome DB_ID: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10118410

O-phospho-L-serine at 400 (in Homo sapiens)

400

EQUAL

467

EQUAL

Reactome Database ID Release 7510160848Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160848ReactomeR-SSC-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-SSC-5687880.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10103014

GO0008384

GO molecular function

Reactome Database ID Release 7510160842Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160842Reactome Database ID Release 7510160850Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160850ReactomeR-SSC-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-SSC-5684275.1The 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).

19754427Pubmed2009IRAK1-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. 580:4010-4inferred by electronic annotationIEAGOIEA

MAP3K8 is phosphorylated

TPL2 (MAP3K8) is phosphorylated at T290This event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>

Reactome DB_ID: 10124039

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10160837

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

NFKB1:p-T290-MAP3K8:TNIP2

Reactome DB_ID: 10124033

EQUAL

968

EQUAL

Reactome DB_ID: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10124047

O-phospho-L-threonine at 290 (in Homo sapiens)

290

EQUAL

O-phospho-L-serine at 400 (in Homo sapiens)

400

EQUAL

467

EQUAL

Reactome Database ID Release 7510160837Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160837ReactomeR-SSC-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-SSC-5684265.1Reactome Database ID Release 7510160839Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160839ReactomeR-SSC-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-SSC-5684261.1The 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).

21135874Pubmed2011Regulation 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. 279:52117-23inferred by electronic annotationIEAGOIEA

2.7.11.10

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

Reactome DB_ID: 10124039

Reactome DB_ID: 113592

Reactome DB_ID: 10160841

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

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

Reactome DB_ID: 10160831

O-phospho-L-serine at 927 (in Homo sapiens)

927

EQUAL

O-phospho-L-serine at 932 (in Homo sapiens)

932

EQUAL

968

EQUAL

Reactome DB_ID: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10118407

EQUAL

467

EQUAL

Reactome Database ID Release 7510160841Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160841ReactomeR-SSC-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-SSC-5687885.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10103014

Reactome Database ID Release 7510160844Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160844ReactomeR-SSC-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-SSC-5684267.1NFkappaB 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.

12482991Pubmed2003betaTrCP-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 23:402-13inferred by electronic annotationIEAGOIEA

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

Reactome DB_ID: 10124049

Reactome DB_ID: 10124037

EQUAL

429

EQUAL

Reactome DB_ID: 10124047

O-phospho-L-threonine at 290 (in Homo sapiens)

290

EQUAL

O-phospho-L-serine at 400 (in Homo sapiens)

400

EQUAL

467

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10091209

Reactome Database ID Release 7510160846Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10160846ReactomeR-SSC-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-SSC-5684273.1IKBKB-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).

inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510186453Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10186453ReactomeR-SSC-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-SSC-5684264.1Tumor 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).

15485931Pubmed2004Lipopolysaccharide 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. 183:7984-93inferred by electronic annotationIEAGOIEA

MAPK targets/ Nuclear events mediated by MAP kinases

ERK/MAPK targets

2.7.11

ERK1/2 phosphorylates MSK1

Reactome DB_ID: 29358

Reactome DB_ID: 10107584

UniProt:I3LQZ5RPS6KA5

UniProtI3LQZ5

EQUAL

802

EQUAL

Reactome DB_ID: 10107590

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10107654

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 7510107655Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107655Reactome Database ID Release 7510107657Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107657ReactomeR-SSC-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-SSC-198756.1MSK1 (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.

9687510Pubmed1998Mitogen- 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 17:4426-41inferred by electronic annotationIEAGOIEA

2.7.11

p38MAPK phosphorylates MSK1

Reactome DB_ID: 29358

Reactome DB_ID: 10107584

EQUAL

802

EQUAL

Reactome DB_ID: 10107590

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10102933

Reactome Database ID Release 7510107591Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107591Reactome Database ID Release 7510107593Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107593ReactomeR-SSC-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-SSC-198669.1MSK1 (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.

inferred by electronic annotationIEAGOIEA

2.7.11

ERK1/2/5 activate RSK1/2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 10107617

Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS6KA1 [nucleoplasm]RPS6KA2 [nucleoplasm]RPS6KA3 [nucleoplasm]

UniProtA0A287BHE2UniProtA0A287A8Q2UniProtA0A287A3K5

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 10107643

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 PhysicalEntityphospho-RPS6KA3 [nucleoplasm]phospho-RPS6KA2 [nucleoplasm]phospho-RPS6KA1 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10107649

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 7510107650Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107650Reactome Database ID Release 7510107652Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107652ReactomeR-SSC-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-SSC-198746.1The 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.

12832467Pubmed2003Phosphorylation 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 449:8-16inferred by electronic annotationIEAGOIEA

ERKs are inactivated

3.1.3.48

ERKs are inactivated by dual-specific phosphatases (DUSPs)

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted from EntitySet in Reactome

Reactome DB_ID: 10107649

Converted from EntitySet in Reactome

Reactome DB_ID: 10108487

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10109745

ERK-specific DUSP [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPOC1A [nucleoplasm]DUSP3 [nucleoplasm]DUSP4 [nucleoplasm]DUSP6 [nucleoplasm]

UniProtF1SIY1UniProtI3LCX3UniProtA0A286ZK12UniProtA0A287AJD2GO0004725

GO molecular function

Reactome Database ID Release 7510109746Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109746Reactome Database ID Release 7510109754Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109754ReactomeR-SSC-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-SSC-203797.1Over 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.

17322878Pubmed2007A 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 39:503-12inferred by electronic annotationIEAGOIEA

INHIBITION

Reactome Database ID Release 7510109755Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109755

Reactome DB_ID: 10109752

VRK3:DUSP3 [nucleoplasm]

VRK3:DUSP3

Reactome DB_ID: 10109750

UniProt:F1RH55VRK3

UniProtF1RH55

EQUAL

474

EQUAL

Reactome DB_ID: 10109731

UniProt:I3LCX3

EQUAL

185

EQUAL

Reactome Database ID Release 7510109752Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109752ReactomeR-SSC-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-SSC-8942511.1

Reactome Database ID Release 7510185907Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185907ReactomeR-SSC-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-SSC-202670.1MAP 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.

15115656Pubmed2004Structure and regulation of MAPK phosphatasesFarooq, AZhou, MMCell Signal 16:769-79inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185823Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185823ReactomeR-SSC-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-SSC-198753.1ERK/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.

inferred by electronic annotationIEAGOIEA

CREB phosphorylation

2.7.11

MSK1 activates CREB

Reactome DB_ID: 29358

Reactome DB_ID: 10108332

UniProt:A0A287AVH0CREB1

UniProtA0A287AVH0

EQUAL

341

EQUAL

Reactome DB_ID: 10108335

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10107590

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome Database ID Release 7510108464Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108464Reactome Database ID Release 7510108473Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108473ReactomeR-SSC-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-SSC-199935.1MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).

inferred by electronic annotationIEAGOIEA

2.7.11

MSK1 activates ATF1

Reactome DB_ID: 10108460

UniProt:F1SHC5ATF1

UniProtF1SHC5

EQUAL

271

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10108463

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

271

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10107590

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome Database ID Release 7510108466Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108466ReactomeR-SSC-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-SSC-199910.1Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.

12414794Pubmed2002ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expressionGupta, PankajPrywes, RonJ. Biol. Chem. 277:50550-6inferred by electronic annotationIEAGOIEA

2.7.11

RSK1/2/3 phosphorylates CREB at Serine 133

Reactome DB_ID: 29358

Reactome DB_ID: 10108332

EQUAL

341

EQUAL

Reactome DB_ID: 10108335

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10107643

Reactome Database ID Release 7510108454Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108454Reactome Database ID Release 7510108456Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108456ReactomeR-SSC-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-SSC-199895.1CREB is phosphorylated at Serine 133 by RSK1/2/3.

9770464Pubmed1998Rsk-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 95:12202-7inferred by electronic annotationIEAGOIEA

2.7.11

MAPKAPK2 phosphorylates CREB at Serine 133

Reactome DB_ID: 29358

Reactome DB_ID: 10108332

EQUAL

341

EQUAL

Reactome DB_ID: 10108335

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10108468

UniProt:F1SEZ4

O-phospho-L-threonine at 222 (in Homo sapiens)

222

EQUAL

O-phospho-L-serine at 272 (in Homo sapiens)

272

EQUAL

400

EQUAL

Reactome Database ID Release 7510108469Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108469Reactome Database ID Release 7510108471Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10108471ReactomeR-SSC-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-SSC-199917.1p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.

7551568Pubmed1995Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signalsBonni, AGinty, D DDudek, HGreenberg, M EMol. Cell. Neurosci. 6:168-83inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185859Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185859ReactomeR-SSC-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-SSC-199920.1Nerve 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.

inferred by electronic annotationIEAGOIEA

Activation of the AP-1 family of transcription factors

2.7.11

Phosphorylated MAPKs phosphorylate ATF-2

Reactome DB_ID: 10102915

UniProt:A0A287BS39ATF2

UniProtA0A287BS39

EQUAL

505

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10102919

O-phospho-L-threonine at 71 (in Homo sapiens)

EQUAL

O-phospho-L-threonine at 69 (in Homo sapiens)

EQUAL

505

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10102955

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 PhysicalEntityphospho-MAPK14 [nucleoplasm]phospho-p-T221,Y223-MAPK10 [nucleoplasm]phospho-MAPK11 [nucleoplasm]phospho-MAPK8 [nucleoplasm]phospho-MAPK9 [nucleoplasm]

Reactome Database ID Release 7510102956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102956Reactome Database ID Release 7510102958Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10102958ReactomeR-SSC-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-SSC-168053.1At 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'.

inferred by electronic annotationIEAGOIEA

2.7.11

c-FOS activation by phospho ERK1/2

Reactome DB_ID: 10123629

UniProt:A0A140TAJ8FOS

UniProtA0A140TAJ8

EQUAL

380

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10123617

O-phospho-L-serine at 362 (in Homo sapiens)

362

EQUAL

O-phospho-L-serine at 374 (in Homo sapiens)

374

EQUAL

O-phospho-L-threonine at 325 (in Homo sapiens)

325

EQUAL

O-phospho-L-threonine at 331 (in Homo sapiens)

331

EQUAL

380

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10107654

Reactome Database ID Release 7510123631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10123631ReactomeR-SSC-450325

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450325.1The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.

12134156Pubmed2002Molecular interpretation of ERK signal duration by immediate early gene productsMurphy, LOSmith, StuartChen, RHFingar, DCBlenis, JNat Cell Biol 4:556-647588633Pubmed1995The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cellsOkazaki, KSagata, NEMBO J 14:5048-59inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185483Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185483ReactomeR-SSC-450341

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450341.1GO0051090

GO biological process

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>

19167516Pubmed2009Translational regulation mechanisms of AP-1 proteinsVesely, PWStaber, PBHoefler, GKenner, LMutat Res 682:7-129069263Pubmed1997AP-1 function and regulationKarin, MLiu, ZZandi, ECurr Opin Cell Biol 9:240-67622446Pubmed1995The regulation of AP-1 activity by mitogen-activated protein kinasesKarin, MJ Biol Chem 270:16483-615564374Pubmed2004AP-1 subunits: quarrel and harmony among siblingsHess, JAngel, PSchorpp-Kistner, MJ Cell Sci 117:5965-73inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185485Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185485ReactomeR-SSC-450282

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450282.1MAPKs 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.

19767751Pubmed2009Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transportKosako, HYamaguchi, NAranami, CUshiyama, MKose, SImamoto, NTaniguchi, HNishida, EHattori, SNat Struct Mol Biol 16:1026-3512471242Pubmed2002Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinasesJohnson, GLLapadat, RScience 298:1911-216393692Pubmed2006The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functionsYoon, SSeger, RGrowth Factors 24:21-4417637696Pubmed2007Coordinating TLR-activated signaling pathways in cells of the immune systemBanerjee, AGerondakis, SImmunol Cell Biol 85:420-417158707Pubmed2006Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinasesBogoyevitch, MAKobe, BMicrobiol Mol Biol Rev 70:1061-95inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185487Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185487ReactomeR-SSC-450294

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450294.1GO0051403

GO biological process

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.

11861597Pubmed2002MAP kinases in the immune responseDong, CDavis, RJFlavell, RAAnnu Rev Immunol 20:55-7211242034Pubmed2001Mammalian MAP kinase signalling cascadesChang, LKarin, MNature 410:37-4019196711Pubmed2009Selectivity of docking sites in MAPK kinasesBardwell, AJFrankson, EBardwell, LJ Biol Chem 284:13165-73inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185461Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185461ReactomeR-SSC-166058

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-166058.1GO0002755

GO biological process

The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects.

15276183Pubmed2004MD-2: the Toll 'gatekeeper' in endotoxin signallingGangloff, MGay, Nicholas JTrends Biochem Sci 29:294-300inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185463ReactomeR-SSC-168179

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168179.1GO0038123

GO biological process

TLR1 is expressed by monocytes. TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others, triggering up-regulation of nuclear factor-kappaB production and apoptotic cascades. Such cooperation between TLR1 and TLR2 on the cell surface of normal human peripheral blood mononuclear cells, for instance, leads to the activation of pro-inflammatory cytokine secretion (Sandor et al. 2003).

12975352Pubmed2003Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signalingSandor, FLatz, ERe, FMandell, LRepik, GGolenbock, DTEspevik, TKurt-Jones, EAFinberg, RWJ Cell Biol 162:1099-110inferred by electronic annotationIEAGOIEA

Toll Like Receptor TLR6:TLR2 Cascade

Reactome Database ID Release 7510185467Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185467ReactomeR-SSC-168188

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168188.1GO0038124

GO biological process

TLR2 and TLR4 recognize different bacterial cell wall components. While TLR4 is trained onto Gram-negative lipopolysaccharide components, TLR2 - in combination with TLR6 - plays a major role in recognizing peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides. In particular, TLR6 appears to participate in discriminating the subtle differences between dipalmitoyl and tripalmitoyl cysteinyl residues (Okusawa et al. 2004).

14977973Pubmed2004Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6Okusawa, TFujita, MNakamura, JInto, TYasuda, MYoshimura, AHara, YHasebe, AGolenbock, DTMorita, MKuroki, YOgawa, TShibata, KInfect Immun 72:1657-65inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510185465Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10185465ReactomeR-SSC-181438

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-181438.1GO0034134

GO biological process

TLR2 is involved in recognition of peptidoglycan from gram-positive bacteria, bacterial lipoproteins, mycoplasma lipoprotein and mycobacterial products. It is quite possible that recognition of at least some other TLR2 ligands may be assisted by additional accessory proteins, particularly in association with TLR1 or TLR6. TLR2 is expressed constitutively on macrophages, dendritic cells, and B cells, and can be induced in some other cell types, including epithelial cells. TLR1 and TLR6, on the other hand, are expressed almost ubiquitously (Muzio et al. 2000). TLR2 may be a sensor and inductor of specific defense processes, including oxidative stress and cellular necrosis initially spurred by microbial compounds.

10820283Pubmed2000Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cellsMuzio, MBosisio, DPolentarutti, ND'amico, GStoppacciaro, AMancinelli, Rvan't Veer, CPenton-Rol, GRuco, LPAllavena, PMantovani, AJ Immunol 164:5998-6004inferred by electronic annotationIEAGOIEA