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

MAP kinase activation

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

2.7.11

Phosphorylation of human JNKs by activated MKK4/MKK7

Reactome DB_ID: 113592

cytosolGO0005829

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

Reactomehttp://www.reactome.orgChEBI30616Converted from EntitySet in Reactome

Reactome DB_ID: 10704688

MAPK8,9,10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityspm1 [cytosol]spm1 [cytosol]spm1 [cytosol]sty1 [cytosol]sty1 [cytosol]sty1 [cytosol]

Schizosaccharomyces pombe

NCBI Taxonomy4896UniProtQ92398UniProtQ09892Converted from EntitySet in Reactome

Reactome DB_ID: 10704708

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-spm1 [cytosol]phospho-sty1 [cytosol]phospho-sty1 [cytosol]phospho-sty1 [cytosol]phospho-spm1 [cytosol]phospho-spm1 [cytosol]

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10704738

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-byr1 [cytosol]phospho-wis1 [cytosol]phospho-wis1 [cytosol]phospho-byr1 [cytosol]phospho-skh1 [cytosol]phospho-skh1 [cytosol]

UniProtP10506UniProtP33886UniProtQ9Y884GO0008545

GO molecular function

Reactome Database ID Release 7510704739Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10704739Reactome Database ID Release 7510704741Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10704741ReactomeR-SPO-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-SPO-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).

17875933Pubmed2007Targeted 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 27:7935-4618713996Pubmed2008Synoviocyte 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 48:2450-6016186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-9511062067Pubmed2000Synergistic 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: 10704708

Converted from EntitySet in Reactome

Reactome DB_ID: 10704659

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-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-sty1 [nucleoplasm]

Reactome Database ID Release 7510709481Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10709481ReactomeR-SPO-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-SPO-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 7510725816Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725816ReactomeR-SPO-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-SPO-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

Phosphorylated MKK3/MKK6 migrates to nucleus

Converted from EntitySet in Reactome

Reactome DB_ID: 10709423

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-byr1 [cytosol]phospho-wis1 [cytosol]phospho-skh1 [cytosol]phospho-wis1 [cytosol]phospho-skh1 [cytosol]phospho-byr1 [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 10709441

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-byr1 [nucleoplasm]phospho-wis1 [nucleoplasm]phospho-wis1 [nucleoplasm]phospho-skh1 [nucleoplasm]phospho-byr1 [nucleoplasm]phospho-skh1 [nucleoplasm]

Reactome Database ID Release 7510709443Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10709443ReactomeR-SPO-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-SPO-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

Reactome Database ID Release 7510726202Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10726202ReactomeR-SPO-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-SPO-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

ERKs are inactivated by protein phosphatase 2A

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted from EntitySet in Reactome

Reactome DB_ID: 10706234

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10706248

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: 10706278

PP2A-ABdeltaC complex [nucleoplasm]

PP2A-ABdeltaC complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10706271

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: 10706276

UniProt:Q10428par1

UniProtQ10428

Chain Coordinates

EQUAL

602

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10706262

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

Reactome Database ID Release 7510706278Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10706278ReactomeR-SPO-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-SPO-165970.1GO0004722

GO molecular function

Reactome Database ID Release 7510706279Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10706279Reactome Database ID Release 7510706281Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10706281ReactomeR-SPO-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-SPO-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

Reactome Database ID Release 7510725958Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725958ReactomeR-SPO-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-SPO-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 16:769-7917322878Pubmed2007A 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 7510725954Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725954ReactomeR-SPO-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-SPO-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

Activation of the AP-1 family of transcription factors

2.7.11

Phosphorylated MAPKs phosphorylate ATF-2

Converted from EntitySet in Reactome

Reactome DB_ID: 10704589

Homologues of ATF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityatf1 [nucleoplasm]atf31 [nucleoplasm]atf21 [nucleoplasm]

UniProtP52890UniProtQ09771UniProtP78962

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 10704603

Homologues of p-T69,T71-ATF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-atf21 [nucleoplasm]phospho-atf1 [nucleoplasm]phospho-atf31 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10704665

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-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-sty1 [nucleoplasm]phospho-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-sty1 [nucleoplasm]phospho-spm1 [nucleoplasm]phospho-spm1 [nucleoplasm]

GO0004674

GO molecular function

Reactome Database ID Release 7510704666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10704666Reactome Database ID Release 7510704668Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10704668ReactomeR-SPO-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-SPO-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

Reactome Database ID Release 7510725760Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725760ReactomeR-SPO-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-SPO-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 7510725762Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725762ReactomeR-SPO-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-SPO-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 7510725764Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725764ReactomeR-SPO-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-SPO-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 7510725792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725792ReactomeR-SPO-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-SPO-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 7510725794Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725794ReactomeR-SPO-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-SPO-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 7510725798Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725798ReactomeR-SPO-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-SPO-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 7510725796Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10725796ReactomeR-SPO-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-SPO-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