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

IRAK2 mediated activation of TAK1 complex

IRAK2 induces TRAF6 oligomerization

Reactome DB_ID: 10662576

plasma membraneGO0005886TRAF6:p-IRAK2 [plasma membrane]

TRAF6:p-IRAK2

Reactome DB_ID: 10662572

UniProt:Q54NN4

Reactomehttp://www.reactome.orgDictyostelium discoideum

NCBI Taxonomy44689UniProtQ54NN4

Chain Coordinates

EQUAL

522

EQUAL

Reactome DB_ID: 10662574

UniProt:Q54LU8

UniProtQ54LU8

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

625

EQUAL

Reactome Database ID Release 7510662576Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662576ReactomeR-DDI-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-DDI-936961.1

Reactome DB_ID: 10652479

cytosolGO0005829

EQUAL

522

EQUAL

Reactome DB_ID: 10662578

p-IRAK2:oligo-TRAF6 [plasma membrane]

p-IRAK2:oligo-TRAF6

Reactome DB_ID: 10662572

EQUAL

522

EQUAL

Reactome DB_ID: 10662576

Reactome Database ID Release 7510662578Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662578ReactomeR-DDI-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-DDI-936990.1Reactome Database ID Release 7510662588Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662588ReactomeR-DDI-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-DDI-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

Converted from EntitySet in Reactome

Reactome DB_ID: 10644946

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityubqG [cytosol]ubqG [cytosol]ubqG [cytosol]ubqJ [cytosol]ubqD [cytosol]ubqF [cytosol]ubqH [cytosol]ubqG [cytosol]ubqD [cytosol]ubqD [cytosol]ubqI [cytosol]ubqD [cytosol]ubqH [cytosol]ubqJ [cytosol]ubqJ [cytosol]ubqJ [cytosol]ubqI [cytosol]ubqG [cytosol]ubqD [cytosol]ubqD [cytosol]ubqG [cytosol]ubqI [cytosol]ubqD [cytosol]ubqF [cytosol]ubqH [cytosol]ubqG [cytosol]ubqH [cytosol]ubqI [cytosol]ubqI [cytosol]ubqH [cytosol]ubqF [cytosol]ubqD [cytosol]ubqF [cytosol]ubqH [cytosol]ubqC [cytosol]ubqF [cytosol]ubqF [cytosol]ubqH [cytosol]ubqB [cytosol]ubqJ [cytosol]ubqJ [cytosol]ubqI [cytosol]ubqH [cytosol]ubqI [cytosol]ubqJ [cytosol]ubqO [cytosol]ubqG [cytosol]ubqI [cytosol]ubqD [cytosol]ubqH [cytosol]ubqI [cytosol]ubqJ [cytosol]ubqF [cytosol]ubqJ [cytosol]ubqG [cytosol]ubqF [cytosol]ubqF [cytosol]

UniProtP0CG79UniProtP0CG88UniProtP0CG77UniProtP0CG78UniProtP0CG81UniProtP0CG80UniProtP14797UniProtP14794UniProtQ54CI0

Reactome DB_ID: 10662578

Reactome DB_ID: 10662583

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

p-IRAK2:K63-linked pUb oligo-TRAF6

Reactome DB_ID: 10662581

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

124

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

522

EQUAL

Reactome DB_ID: 10662574

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 7510662583Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662583ReactomeR-DDI-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-DDI-936988.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10662578

GO0004842

GO molecular function

Reactome Database ID Release 7510662584Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662584Reactome Database ID Release 7510662586Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662586ReactomeR-DDI-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-DDI-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: 10644946

Reactome DB_ID: 10652776

K63polyUb [cytosol]

K63polyUb

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10662583

Reactome Database ID Release 7510662589Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662589Reactome Database ID Release 7510662591Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10662591ReactomeR-DDI-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-DDI-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

Reactome Database ID Release 7510697851Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697851ReactomeR-DDI-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-DDI-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

MAP kinase activation

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

Activated human JNKs migrate to nucleoplasm

Converted from EntitySet in Reactome

Reactome DB_ID: 10652581

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-erkA [cytosol]phospho-p-T221,Y223-MAPK10 [cytosol]phospho-erkA [cytosol]phospho-p-T221,Y223-MAPK10 [cytosol]phospho-p-T183,Y185-MAPK9 [cytosol]phospho-p-T221,Y223-MAPK10 [cytosol]phospho-p-T,Y-MAPK8 [cytosol]phospho-erkA [cytosol]phospho-p-T183,Y185-MAPK9 [cytosol]phospho-p-T,Y-MAPK8 [cytosol]phospho-p-T,Y-MAPK8 [cytosol]phospho-p-T183,Y185-MAPK9 [cytosol]

UniProtP42525UniProtQ54V83UniProtQ54V35UniProtQ54US6Converted from EntitySet in Reactome

Reactome DB_ID: 10660651

nucleoplasmGO0005654

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-T183,Y185-MAPK9 [nucleoplasm]phospho-p-T,Y-MAPK8 [nucleoplasm]phospho-erkA [nucleoplasm]phospho-p-T183,Y185-MAPK9 [nucleoplasm]phospho-p-T183,Y185-MAPK9 [nucleoplasm]phospho-p-T,Y-MAPK8 [nucleoplasm]phospho-erkA [nucleoplasm]phospho-p-T221,Y223-MAPK10 [nucleoplasm]phospho-p-T221,Y223-MAPK10 [nucleoplasm]phospho-p-T,Y-MAPK8 [nucleoplasm]phospho-p-T221,Y223-MAPK10 [nucleoplasm]phospho-erkA [nucleoplasm]

Reactome Database ID Release 7510660653Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660653ReactomeR-DDI-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-DDI-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.

13130464Pubmed2003Expression 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 48:2450-6012193592Pubmed2002Evidence 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 7510697777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697777ReactomeR-DDI-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-DDI-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 28:923-3415837794Pubmed2005Simultaneous 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 280:27728-419851932Pubmed1998Defective T cell differentiation in the absence of Jnk1Dong, CYang, DDWysk, MWhitmarsh, AJDavis, RJFlavell, RAScience 282:2092-511460167Pubmed2001TAK1 is a ubiquitin-dependent kinase of MKK and IKKWang, CDeng, LHong, MAkkaraju, GRInoue, JChen, ZJNature 412:346-518177321Pubmed1994The 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

Active p38 MAPK phosphorylates MAPKAPK2 or 3

Reactome DB_ID: 10660588

p-p38 MAPK: MAPKAPK2,3 [nucleoplasm]

p-p38 MAPK: MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 10660586

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

UniProtQ54BF0UniProtQ54W86Converted from EntitySet in Reactome

Reactome DB_ID: 10655375

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-p-T180,Y182-MAPK11 [nucleoplasm]phospho-p-T180,Y182-MAPK11 [nucleoplasm]phospho-p-T180,Y182-MAPK14 [nucleoplasm]phospho-erkA [nucleoplasm]phospho-erkA [nucleoplasm]phospho-p-T180,Y182-MAPK11 [nucleoplasm]phospho-p-T180,Y182-MAPK14 [nucleoplasm]phospho-p-T180,Y182-MAPK14 [nucleoplasm]

Reactome Database ID Release 7510660588Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660588ReactomeR-DDI-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-DDI-450213.1

Reactome DB_ID: 29358

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 10660600

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

p-p38 MAPK:p-MAPKAPK2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 10655375

Converted from EntitySet in Reactome

Reactome DB_ID: 10660598

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

Reactome Database ID Release 7510660600Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660600ReactomeR-DDI-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-DDI-450254.1

Reactome DB_ID: 113582

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10660588

GO0004674

GO molecular function

Reactome Database ID Release 7510660601Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660601Reactome Database ID Release 7510660603Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660603ReactomeR-DDI-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-DDI-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: 10660600

Reactome DB_ID: 10660605

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: 10653669

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-p-T180,Y182-MAPK14 [cytosol]phospho-p-T180,Y182-MAPK11 [cytosol]phospho-erkA [cytosol]phospho-p-T180,Y182-MAPK11 [cytosol]phospho-p-T180,Y182-MAPK14 [cytosol]phospho-p-T180,Y182-MAPK11 [cytosol]phospho-p-T180,Y182-MAPK14 [cytosol]phospho-erkA [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 10653639

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-p-S,2T-MAPKAPK3 [cytosol]phospho-fhkA [cytosol]phospho-fhkA [cytosol]

Reactome Database ID Release 7510660605Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660605ReactomeR-DDI-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-DDI-450241.1Reactome Database ID Release 7510660607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660607ReactomeR-DDI-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-DDI-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.

9768359Pubmed1998Nuclear 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

Reactome Database ID Release 7510697773Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697773ReactomeR-DDI-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-DDI-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 22:637-458533096Pubmed1995Identification 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 270:2008-118622669Pubmed1996MKK3- 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

MAPK targets/ Nuclear events mediated by MAP kinases

ERK/MAPK targets

2.7.11

ERK1/2 phosphorylates MSK1

Reactome DB_ID: 10655347

UniProt:Q8MYF1

UniProtQ8MYF1

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10655353

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

376

EQUAL

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

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

581

EQUAL

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

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: 10655474

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 7510655475Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655475Reactome Database ID Release 7510655477Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655477ReactomeR-DDI-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-DDI-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: 10655347

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10655353

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: 10655375

Reactome Database ID Release 7510655376Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655376Reactome Database ID Release 7510655378Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655378ReactomeR-DDI-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-DDI-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

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 10655416

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10655441

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-p-4S,T356,T570-RPS6KA2 [nucleoplasm]phospho-p-4S,T359,T573-RPS6KA1 [nucleoplasm]phospho-p-4S,T231,T365-RPS6KA3 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10655469

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 7510655470Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655470Reactome Database ID Release 7510655472Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655472ReactomeR-DDI-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-DDI-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 by protein phosphatase 2A

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted from EntitySet in Reactome

Reactome DB_ID: 10655469

Converted from EntitySet in Reactome

Reactome DB_ID: 10655658

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

Reactome DB_ID: 113550

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

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

ChEBI43474PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10655665

PP2A-ABdeltaC complex [nucleoplasm]

PP2A-ABdeltaC complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10651079

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10651088

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

Reactome DB_ID: 10655663

UniProt:Q54VB6psrA

UniProtQ54VB6

EQUAL

602

EQUAL

Reactome Database ID Release 7510655665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655665ReactomeR-DDI-165970

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

GO molecular function

Reactome Database ID Release 7510655666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655666Reactome Database ID Release 7510655668Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655668ReactomeR-DDI-199959

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DDI-199959.1ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK. Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown.

16456541Pubmed2006B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERKLetourneux, CRocher, GPorteu, FEMBO J 25:727-38inferred by electronic annotationIEAGOIEA

ERKs are inactivated

3.1.3.48

ERKs are inactivated by dual-specific phosphatases (DUSPs)

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 10655469

Converted from EntitySet in Reactome

Reactome DB_ID: 10655658

Reactome DB_ID: 113550

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10656119

ERK-specific DUSP [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitympl1 [nucleoplasm]DUSP7 [nucleoplasm]mpl3 [nucleoplasm]DUSP4 [nucleoplasm]mpl2 [nucleoplasm]mpl2 [nucleoplasm]mpl3 [nucleoplasm]mpl1 [nucleoplasm]DUSP7 [nucleoplasm]mpl3 [nucleoplasm]DUSP4 [nucleoplasm]DUSP7 [nucleoplasm]DUSP6 [nucleoplasm]DUSP6 [nucleoplasm]mpl2 [nucleoplasm]DUSP6 [nucleoplasm]mpl1 [nucleoplasm]DUSP4 [nucleoplasm]

UniProtQ55CS7UniProtQ556Y8UniProtQ54Y32UniProtQ55CS8UniProtQ8T813UniProtQ54N84GO0004725

GO molecular function

Reactome Database ID Release 7510656120Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10656120Reactome Database ID Release 7510656122Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10656122ReactomeR-DDI-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-DDI-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

Reactome Database ID Release 7510697465Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697465ReactomeR-DDI-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-DDI-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 7510697393Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697393ReactomeR-DDI-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-DDI-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

Reactome Database ID Release 7510697395Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697395ReactomeR-DDI-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-DDI-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 7510697397Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697397ReactomeR-DDI-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-DDI-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 7510697425Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697425ReactomeR-DDI-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-DDI-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 7510697431Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697431ReactomeR-DDI-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-DDI-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 7510697427Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697427ReactomeR-DDI-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-DDI-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 7510697429Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10697429ReactomeR-DDI-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-DDI-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