BioPAX pathway converted from "Fc epsilon receptor (FCERI) signaling" in the Reactome database.

Fc epsilon receptor (FCERI) signaling

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

2.7.10

Autophosphorylation of LYN kinase

Reactome DB_ID: 10063167

plasma membraneGO0005886

UniProt:F1N261LYN

Reactomehttp://www.reactome.orgBos taurus

NCBI Taxonomy9913UniProtF1N261

Chain Coordinates

EQUAL

512

EQUAL

Reactome DB_ID: 113592

cytosolGO0005829

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216

Reactome DB_ID: 10063170

O4'-phospho-L-tyrosine at 396 (in Homo sapiens)

396

EQUAL

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

EQUAL

512

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063167

EQUAL

512

EQUAL

GO0004713

GO molecular function

Reactome Database ID Release 7510063171Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063171Reactome Database ID Release 7510063173Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063173ReactomeR-BTA-2730862

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730862.1LYN localized in lipid rafts undergoes an intermolecular autophosphorylation at tyrosine 396. This residue is present in the activation loop, and its phosphorylation promotes LYN kinase activity.

9477973Pubmed1998Spontaneous autophosphorylation of Lyn tyrosine kinase at both its activation segment and C-terminal tail confers altered substrate specificityDonella-Deana, ACesaro, LRuzzene, MBrunati, A MMarin, OPinna, L ABiochemistry 37:1438-46inferred by electronic annotationIEAGOIEA

FCERI mediated MAPK activation

Interaction of GRB2:SOS complex with p-SHC1

Reactome DB_ID: 10062589

UniProt:Q0IIE2SHC1

UniProtQ0IIE2

O4'-phospho-L-tyrosine at 239 (in Homo sapiens)

239

EQUAL

O4'-phospho-L-tyrosine at 240 (in Homo sapiens)

240

EQUAL

O4'-phospho-L-tyrosine at 317 (in Homo sapiens)

317

EQUAL

111

EQUAL

583

EQUAL

Reactome DB_ID: 10032498

GRB2-1:SOS1 [cytosol]

GRB2-1:SOS1

Reactome DB_ID: 10032492

UniProt:Q3T0F9GRB2

UniProtQ3T0F9

EQUAL

217

EQUAL

Reactome DB_ID: 10032496

UniProt:F1N7C3SOS1

UniProtF1N7C3

EQUAL

1333

EQUAL

Reactome Database ID Release 7510032498Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10032498ReactomeR-BTA-109797

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-109797.1

Reactome DB_ID: 10062591

p-SHC1:GRB2:SOS [cytosol]

p-SHC1:GRB2:SOS

Reactome DB_ID: 10062589

O4'-phospho-L-tyrosine at 239 (in Homo sapiens)

239

EQUAL

O4'-phospho-L-tyrosine at 240 (in Homo sapiens)

240

EQUAL

O4'-phospho-L-tyrosine at 317 (in Homo sapiens)

317

EQUAL

111

EQUAL

583

EQUAL

Reactome DB_ID: 10032498

Reactome Database ID Release 7510062591Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10062591ReactomeR-BTA-2685672

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685672.1Reactome Database ID Release 7510063132Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063132ReactomeR-BTA-2730844

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730844.1GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). GRB2-SOS complex binds to phosphotyrosine Y239 and Y317 of SHC1. SHC1 associates with the tyrosine-phosphorylated ITAMs of the FCERI beta-chain and can recruit SOS to membrane. SHC1 and SOS have also been described to associate with LAT via GRB2. Shc binding to Phospho-ITAMs (in vitro binding to phospho peptides) has never been linked to any biological function (activation) and is probably not relevant in a physiological setting.

8493579Pubmed1993Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2Chardin, PCamonis, JHGale, NWVan Aelst, LSchlessinger, JWigler, Michael HBar-Sagi, DafnaScience 260:1338-4319909365Pubmed2009Adapters in the organization of mast cell signalingAlvarez-Errico, DamianaLessmann, EvaRivera, JuanImmunol. Rev. 232:195-21717365510Pubmed2007Analysis of proteins binding to the ITAM motif of the beta-subunit of the high-affinity receptor for IgE (FcepsilonRI)Soto-Cruz, IsabelOliver, Janet MOrtega, EnriqueJ. Recept. Signal Transduct. Res. 27:67-819199344Pubmed1997Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytesHarmer, SLDeFranco, ALMol Cell Biol 17:4087-95inferred by electronic annotationIEAGOIEA

SOS mediated nucleotide exchange of RAS (SHC)

Reactome DB_ID: 29438

GTP [ChEBI:15996]

GTP

Guanosine 5'-triphosphate

ChEBI15996

Reactome DB_ID: 10037175

p21 RAS:GDP [plasma membrane]

p21 RAS:GDP

Reactome DB_ID: 29420

GDP [ChEBI:17552]

GDP

Guanosine 5'-diphosphateGuanosine diphosphate

ChEBI17552Converted from EntitySet in Reactome

Reactome DB_ID: 10036659

mature p21 RAS [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNRAS [plasma membrane]HRAS [plasma membrane]

UniProtA5D7R9UniProtA0A3Q1LKB7Reactome Database ID Release 7510037175Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10037175ReactomeR-BTA-109796

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-109796.1

Reactome DB_ID: 10036661

p21 RAS:GTP [plasma membrane]

p21 RAS:GTP

Reactome DB_ID: 29438

Converted from EntitySet in Reactome

Reactome DB_ID: 10036659

Reactome Database ID Release 7510036661Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10036661ReactomeR-BTA-109783

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-109783.1

Reactome DB_ID: 29420

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10062593

p-5Y-LAT:p-SHC1:GRB2:SOS1 [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1

Reactome DB_ID: 10062591

Reactome DB_ID: 10062584

Ghost homologue of p-5Y-LAT-2 [plasma membrane]

Ghost homologue of p-5Y-LAT-2

Reactome Database ID Release 7510062593Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10062593ReactomeR-BTA-2424468

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2424468.1GO0005088

GO molecular function

Reactome Database ID Release 7510062594Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10062594Reactome Database ID Release 7510062596Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10062596ReactomeR-BTA-2424477

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2424477.1GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation.

9690470Pubmed1998The structural basis of the activation of Ras by SosBoriack-Sjodin, PAMargarit, SMBar-Sagi, DafnaKuriyan, JNature 394:337-43inferred by electronic annotationIEAGOIEA

Phosphorylation and activation of VAV

Reactome DB_ID: 113592

Reactome DB_ID: 10063111

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV

Reactome DB_ID: 10038355

UniProt:A0A3Q1MQP9

UniProtA0A3Q1MQP9

EQUAL

878

EQUAL

Reactome DB_ID: 10063095

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG

Converted from EntitySet in Reactome

Reactome DB_ID: 10060531

PLC gamma1,2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPLCG2 [cytosol]PLCG1 [cytosol]

UniProtA0A3Q1MMD9UniProtF1MYF9

Reactome DB_ID: 10063093

GADS:p-Y113,Y128,Y145-SLP-76 [cytosol]

GADS:p-Y113,Y128,Y145-SLP-76

Reactome DB_ID: 10044014

UniProt:E1BKA6GRAP2

UniProtE1BKA6

EQUAL

330

EQUAL

Reactome DB_ID: 10063091

Ghost homologue of p-Y113,128,145-LCP2 [cytosol]

Ghost homologue of p-Y113,128,145-LCP2

Reactome Database ID Release 7510063093Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063093ReactomeR-BTA-2424466

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2424466.1

Reactome DB_ID: 10062593

Reactome Database ID Release 7510063095Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063095ReactomeR-BTA-2424460

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2424460.1Reactome Database ID Release 7510063111Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063111ReactomeR-BTA-2685668

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685668.1

Reactome DB_ID: 10063113

p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV [plasma membrane]

p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV

Reactome DB_ID: 10046368

O4'-phospho-L-tyrosine at 172 (in Homo sapiens)

172

EQUAL

878

EQUAL

Reactome DB_ID: 10063095

Reactome Database ID Release 7510063113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063113ReactomeR-BTA-2685666

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685666.1

Reactome DB_ID: 29370

Reactome Database ID Release 7510063115Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063115ReactomeR-BTA-2730841

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730841.1Phosphorylation of VAV stimulates its GEF activity for RAC1, and thus it plays an important role in linking FCERI to the RAC1-JNK pathway. VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV is phosphorylated on tyrosine residue (Y174 in VAV1/172 in VAV2/173 in VAV3) in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV is involved in the activation of RAC1, PAK1, MEK and ERK and cytokine production.

9099726Pubmed1997Tyrosine phosphorylation of the vav proto-oncogene product links FcepsilonRI to the Rac1-JNK pathwayTeramoto, HSalem, PRobbins, K CBustelo, X RGutkind, J SJ. Biol. Chem. 272:10751-511007481Pubmed2000Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylationAghazadeh, BLowry, WEHuang, XYRosen, MKCell 102:625-3310395673Pubmed1999Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathwaySong, J SHaleem-Smith, HArudchandran, RGomez, JScott, P MMill, J FTan, T HRivera, JJ. Immunol. 163:802-108986718Pubmed1996Functional and physical interactions of Syk family kinases with the Vav proto-oncogene productDeckert, MTartare-Deckert, SCouture, CMustelin, TAltman, AImmunity 5:591-604inferred by electronic annotationIEAGOIEA

ACTIVATION

Reactome Database ID Release 758951567Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8951567ReactomeR-HSA-8951567

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8951567.1

Reactome DB_ID: 179838

1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618]

1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate

PIP3

ChEBI16618

Activated human JNKs migrate to nucleoplasm

Converted from EntitySet in Reactome

Reactome DB_ID: 10036470

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-MAPK9 [cytosol]phospho-MAPK8 [cytosol]

UniProtA0A3Q1LJU7UniProtA0A3Q1LWJ8Converted from EntitySet in Reactome

Reactome DB_ID: 10036457

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-MAPK8 [nucleoplasm]phospho-MAPK9 [nucleoplasm]

Reactome Database ID Release 7510047176Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10047176ReactomeR-BTA-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-BTA-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

2.7.11

Activated JNKs phosphorylate c-JUN

Reactome DB_ID: 10036441

UniProt:Q08DH1JUN

UniProtQ08DH1

EQUAL

331

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10036445

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

EQUAL

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

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10036457

GO0004705

GO molecular function

Reactome Database ID Release 7510036458Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10036458Reactome Database ID Release 7510036460Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10036460ReactomeR-BTA-168136

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-168136.1JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.

18793328Pubmed2008c-Jun expression, activation and function in neural cell death, inflammation and repairRaivich, GJ Neurochem 107:898-9069561845Pubmed1998Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to developmentIp, YTDavis, RJCurr Opin Cell Biol 10:205-1910871633Pubmed2000c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activityDennler, SPrunier, CFerrand, NGauthier, JMAtfi, AJ Biol Chem 275:28858-65inferred by electronic annotationIEAGOIEA

Formation of Activated Protein 1 (AP-1) complex. cFOS/c-JUN heterodimer.

Reactome DB_ID: 10036445

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

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10047124

UniProt:O77628

UniProtO77628

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

362

EQUAL

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

374

EQUAL

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

325

EQUAL

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

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

331

EQUAL

380

EQUAL

Reactome DB_ID: 10047126

p-2S-cJUN:p-2S,2T-cFOS [nucleoplasm]

p-2S-cJUN:p-2S,2T-cFOS

Reactome DB_ID: 10036445

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

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10047124

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

362

EQUAL

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

374

EQUAL

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

325

EQUAL

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

331

EQUAL

380

EQUAL

Reactome Database ID Release 7510047126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10047126ReactomeR-BTA-450327

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-450327.1Reactome Database ID Release 7510047128Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10047128ReactomeR-BTA-450292

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-450292.1The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).

9030721Pubmed1997Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agentsAinbinder, EBergelson, SPinkus, RDaniel, VEur J Biochem 243:49-577816143Pubmed1995Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNAGlover, JNHarrison, SCNature 373:257-61inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510088629Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10088629ReactomeR-BTA-2871796

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2871796.1Formation of the LAT signaling complex leads to activation of MAPK and production of cytokines. The sequence of events that leads from LAT to cytokine production has not been as clearly defined as the sequence that leads to degranulation. However, the pathways that lead to cytokine production require the guanine-nucleotide-exchange factors SOS and VAV that regulate GDP-GTP exchange of RAS. After its activation, RAS positively regulates the RAF-dependent pathway that leads to phosphorylation and, in part, activation of the mitogen-activated protein kinases (MAPKs) extracellular-signal-regulated kinase 1 (ERK1) and ERK2 (Gilfillan & Tkaczyk 2006).

17420272Pubmed2007LAT and NTAL mediate immunoglobulin E-induced sustained extracellular signal-regulated kinase activation critical for mast cell survivalYamasaki, ShoIshikawa, EriSakuma, MachieKanagawa, OsamiCheng, Alec MMalissen, BernardSaito, TakashiMol. Cell. Biol. 27:4406-1517122878Pubmed2006Intracellular signaling pathways in IgE-dependent mast cell activationKope?, AgnieszkaPanaszek, BernardFal, Andrzej MArch. Immunol. Ther. Exp. (Warsz.) 54:393-40119290926Pubmed2009The tyrosine kinase network regulating mast cell activationGilfillan, Alasdair MRivera, JuanImmunol. Rev. 228:149-6916470226Pubmed2006Integrated signalling pathways for mast-cell activationGilfillan, Alasdair MTkaczyk, ChristineNat. Rev. Immunol. 6:218-30inferred by electronic annotationIEAGOIEA

FCERI mediated Ca+2 mobilization

2.7.10

Autophosphorylation of BTK/ITK

Reactome DB_ID: 10063102

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3 [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3

Reactome DB_ID: 10038355

EQUAL

878

EQUAL

Reactome DB_ID: 10063095

Reactome DB_ID: 179838

Reactome DB_ID: 10063100

UniProt:F1MSH3TEC

UniProtF1MSH3

O4'-phospho-L-tyrosine at 519 (in Homo sapiens)

519

EQUAL

631

EQUAL

Reactome Database ID Release 7510063102Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063102ReactomeR-BTA-2685675

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685675.1

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10063149

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinases [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinases

Reactome DB_ID: 10063147

O4'-phospho-L-tyrosine at 519 (in Homo sapiens)

519

EQUAL

O4'-phospho-L-tyrosine at 206 (in Homo sapiens)

206

EQUAL

631

EQUAL

Reactome DB_ID: 10038355

EQUAL

878

EQUAL

Reactome DB_ID: 10063095

Reactome DB_ID: 179838

Reactome Database ID Release 7510063149Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063149ReactomeR-BTA-2685650

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685650.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063102

Reactome Database ID Release 7510063150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063150Reactome Database ID Release 7510063152Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063152ReactomeR-BTA-2730858

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730858.1After initial phosphorylation by SFK's, subsequently Y223 (Y180 in ITK and Y206 in TEC) in the SH3 domain of BTK is autophosphorylated, which may prevent inhibitory intramolecular interactions (Nore et al. 2003, Joseph et al. 2007, Park et al. 1996)

7518558Pubmed1994Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linkingKawakami, YYao, LMiura, TTsukada, SWitte, O NKawakami, TMol. Cell. Biol. 14:5108-1317897671Pubmed2007Mechanism and functional significance of Itk autophosphorylationJoseph, Raji EFulton, D BruceAndreotti, Amy HJ. Mol. Biol. 373:1281-928629002Pubmed1996Activation of BTK by a phosphorylation mechanism initiated by SRC family kinasesRawlings, D JScharenberg, A MPark, HWahl, M ILin, SKato, R MFluckiger, A CWitte, O NKinet, J PScience 271:822-58630736Pubmed1996Regulation of Btk function by a major autophosphorylation site within the SH3 domainPark, HWahl, M IAfar, D ETurck, C WRawlings, D JTam, CScharenberg, A MKinet, J PWitte, O NImmunity 4:515-2512573241Pubmed2003Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinasesNore, Beston FMattsson, Pekka TAntonsson, PerBäckesjö, Carl-MagnusWestlund, AnnaLennartsson, JohanHansson, HenrikLöw, PeterRönnstrand, LarsSmith, C I EdvardBiochim. Biophys. Acta 1645:123-32inferred by electronic annotationIEAGOIEA

3.1.4.11

Hydrolysis of PIP2 by PLCG

Reactome DB_ID: 29356

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 179856

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

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

PIP2

ChEBI18348

Reactome DB_ID: 114520

1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595]

1D-myo-inositol 1,4,5-trisphosphate

ChEBI16595

Reactome DB_ID: 112275

diglyceride [ChEBI:18035]

diglyceride

ChEBI18035PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063141

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3 [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3

Reactome DB_ID: 10038355

EQUAL

878

EQUAL

Reactome DB_ID: 10063139

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:p-PLCG [plasma membrane]

p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:p-PLCG

Converted from EntitySet in Reactome

Reactome DB_ID: 10063137

p-4Y-PLCG [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-PLCG1 [plasma membrane]phospho-p-4Y-PLCG2 [plasma membrane]

Reactome DB_ID: 10063093

Reactome DB_ID: 10062593

Reactome Database ID Release 7510063139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063139ReactomeR-BTA-2685659

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685659.1

Reactome DB_ID: 179838

Reactome DB_ID: 10063100

O4'-phospho-L-tyrosine at 519 (in Homo sapiens)

519

EQUAL

631

EQUAL

Reactome Database ID Release 7510063141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063141ReactomeR-BTA-2685707

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685707.1GO0004435

GO molecular function

Reactome Database ID Release 7510063142Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063142Reactome Database ID Release 7510063144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063144ReactomeR-BTA-2730847

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730847.1Phosphoinositol 4,5-bisphosphate (PIP2) is cleaved in to two most important second messengers diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC). DAG remains within the membrane and activates protein kinase C (PKC) while IP3 leaves the cell membrane and binds to IP3 receptor that releases Ca2+ from endoplasmic reticulum (ER).

11395409Pubmed2001Regulation of phosphoinositide-specific phospholipase CRhee, S GAnnu. Rev. Biochem. 70:281-312inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510089883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10089883ReactomeR-BTA-2871809

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2871809.1Increase of intracellular calcium in mast cells is most crucial for mast cell degranulation. Elevation of intracellular calcium is achieved by activation of PLC-gamma. Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms and activation of these enzymes leads to conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The production of IP3 leads to mobilization of intracellular Ca+2, which later results in a sustained Ca+2 flux response that is maintained by an influx of extracellular Ca+2. In addition to degranulation, an increase in intracellular calcium concentration also activates the Ca2+/calmodulin-dependent serine phosphatase calcineurin. Calcineurin dephosphorylates the nuclear factor for T cell activation (NFAT) which exposes nuclear-localization signal sequence triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Once in the nucleus, NFAT regulates the transcription of several cytokine genes (Kambayashi et al. 2007, Hoth & Penner 1992, Ebinu et al. 2000, Siraganian et al).

1309940Pubmed1992Depletion of intracellular calcium stores activates a calcium current in mast cellsHoth, MPenner, RNature 355:353-610807788Pubmed2000RasGRP links T-cell receptor signaling to RasEbinu, J OStang, S LTeixeira, CBottorff, D AHooton, JBlumberg, P MBarry, MBleakley, R COstergaard, H LStone, J CBlood 95:3199-20320696166Pubmed2010Mast cell signaling: the role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participantsSiraganian, Reuben Pde Castro, Rodrigo OBarbu, Emilia AZhang, JuanFEBS Lett. 584:4933-4017336609Pubmed2007Proximal signaling events in Fc epsilon RI-mediated mast cell activationKambayashi, TakuKoretzky, Gary AJ. Allergy Clin. Immunol. 119:544-52; quiz 553-4inferred by electronic annotationIEAGOIEA

FCERI mediated NF-kB activation

Translocation of PKC theta to plasma membrane

Reactome DB_ID: 10040158

UniProt:E1BMG4PRKCQ

UniProtE1BMG4

EQUAL

706

EQUAL

Reactome DB_ID: 112275

Reactome DB_ID: 10040317

PKC-theta (open): DAG [plasma membrane]

PKC-theta (open): DAG

Reactome DB_ID: 112275

Reactome DB_ID: 10040315

EQUAL

706

EQUAL

Reactome Database ID Release 7510040317Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10040317ReactomeR-BTA-202187

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-202187.1Reactome Database ID Release 7510040319Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10040319ReactomeR-BTA-202328

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-202328.1DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.<br>MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007).

17548359Pubmed2007Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase CthetaMelowic, Heather RStahelin, Robert VBlatner, Nichole RTian, WenHayashi, KeitaroAltman, AmnonCho, WonhwaJ. Biol. Chem. 282:21467-7616978534Pubmed2006Selective function of PKC-theta in T cellsManicassamy, SGupta, SSun, ZCell Mol Immunol 3:263-7011358993Pubmed2001Protein kinase C theta is expressed in mast cells and is functionally involved in Fcepsilon receptor I signalingLiu, YGraham, CParravicini, VBrown, M JRivera, JShaw, SJ. Leukoc. Biol. 69:831-4012473184Pubmed2002Protein kinase C-theta (PKC theta): a key enzyme in T cell life and deathAltman, AVillalba, MJ Biochem (Tokyo) 132:841-6inferred by electronic annotationIEAGOIEA

Autophosphorylation of PKC-theta

Reactome DB_ID: 10040296

p-Y90-PKC-theta:DAG [plasma membrane]

p-Y90-PKC-theta:DAG

Reactome DB_ID: 10040294

O4'-phospho-L-tyrosine at 90 (in Homo sapiens)

EQUAL

706

EQUAL

Reactome DB_ID: 112275

Reactome Database ID Release 7510040296Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10040296ReactomeR-BTA-202300

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-202300.1

Reactome DB_ID: 113592

Reactome DB_ID: 10063107

p-5Y-PKC-theta:DAG [plasma membrane]

p-5Y-PKC-theta:DAG

Reactome DB_ID: 10063105

O4'-phospho-L-tyrosine at 90 (in Homo sapiens)

EQUAL

O-phospho-L-threonine at 219 (in Homo sapiens)

219

EQUAL

O-phospho-L-threonine at 538 (in Homo sapiens)

538

EQUAL

O-phospho-L-serine at 676 (in Homo sapiens)

676

EQUAL

O-phospho-L-serine at 695 (in Homo sapiens)

695

EQUAL

706

EQUAL

Reactome DB_ID: 112275

Reactome Database ID Release 7510063107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063107ReactomeR-BTA-2685674

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685674.1

Reactome DB_ID: 29370

Reactome Database ID Release 7510063109Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063109ReactomeR-BTA-2730835

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730835.1T219, T538 at the activation loop, S676 at the turn motif and S695 at the hydrophobic motif are autophosphorylated in cis-maanner. Posphorylation of T538 is critical for kinase activation and it stabilises the open active conformation. Some studies suggest the involvement of PDK1 (3-phosphoinositide-dependent protein kinase 1) and GLK kinases in the phosphorylation T538.

16252004Pubmed2005Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytesThuille, NikolausHeit, IsabelleFresser, FriedrichKrumböck, NinaBauer, BirgitLeuthaeusser, SabineDammeier, SaschaGraham, CarolineCopeland, Terry DShaw, SteveBaier, GottfriedEMBO J. 24:3869-8011772397Pubmed2002Phosphorylation of the protein kinase C-theta activation loop and hydrophobic motif regulates its kinase activity, but only activation loop phosphorylation is critical to in vivo nuclear-factor-kappaB inductionLiu, YinGraham, CarolineLi, AiqunFisher, Robert JShaw, StephenBiochem. J. 361:255-6522798961Pubmed2012Regulation of PKC-? function by phosphorylation in T cell receptor signalingWang, XiaohongChuang, Huai-ChiaLi, Ju-PiTan, Tse-HuaFront Immunol 3:197inferred by electronic annotationIEAGOIEA

2.7.11.13

Phosphorylation of CARMA1 by PKC-theta

Reactome DB_ID: 10063175

UniProt:A0A3S5ZPB2CARD11

UniProtA0A3S5ZPB2

EQUAL

1154

EQUAL

Reactome DB_ID: 10063107

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10063177

DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 [plasma membrane]

DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1

Reactome DB_ID: 10063159

O-phospho-L-serine at 552 (in Homo sapiens)

552

EQUAL

O-phospho-L-serine at 645 (in Homo sapiens)

645

EQUAL

1154

EQUAL

Reactome DB_ID: 10063107

Reactome Database ID Release 7510063177Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063177ReactomeR-BTA-2685711

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685711.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063107

GO0004697

GO molecular function

Reactome Database ID Release 7510063178Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063178Reactome Database ID Release 7510063180Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063180ReactomeR-BTA-2730863

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730863.1CARMA1 (CARD11/Caspase recruitment domain-containing protein 11), BCL10 (B-cell lymphoma/leukemia 10) and MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1)/paracaspase have been identified as signaling components that act downstream of PKC-theta. CARMA1 is a scaffold protein and recruits BCL10, MALT1, PKC and TRAF6 to form a multi protein complex. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. Upon stimulation S552 and S645 linker residues are phosphorylated by PKC-theta and this may weaken this interaction, inducing an open conformation of CARMA1. Further phosphorylation studies have revealed other phosphorylation sites (S109, S551 and S555) that may also promote activation of CARMA1. Serene/threonine kinases PKC-beta, IKKbeta, HPK1 and CaMKII are involved in triggering CARMA1 activation (Thome et al. 2010, Rueda & Thome 2005). (only phosphorylated S552 and S645 are represented in this reaction)

16356853Pubmed2005Phosphorylation of CARMA1: the link(er) to NF-kappaB activationRueda, DThome, MImmunity 23:551-320685844Pubmed2010Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1Thome, MargotCharton, Jean EnnoPelzer, ChristianeHailfinger, StephanCold Spring Harb Perspect Biol 2:a00300416356856Pubmed2005Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activationMatsumoto, ReikoWang, DonghaiBlonska, MarzennaLi, HongxiuKobayashi, MasayukiPappu, BhanuChen, YuhongWang, DeminLin, XinImmunity 23:575-85inferred by electronic annotationIEAGOIEA

Oligomerization of p-CARMA1

Reactome DB_ID: 10063159

O-phospho-L-serine at 552 (in Homo sapiens)

552

EQUAL

O-phospho-L-serine at 645 (in Homo sapiens)

645

EQUAL

1154

EQUAL

Reactome DB_ID: 10063177

Reactome DB_ID: 10063218

DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomer [plasma membrane]

DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomer

Reactome DB_ID: 10063107

Reactome DB_ID: 10063161

p-CARMA1 oligomer [plasma membrane]

p-CARMA1 oligomer

Reactome Database ID Release 7510063218Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063218ReactomeR-BTA-2685699

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685699.1Reactome Database ID Release 7510063220Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063220ReactomeR-BTA-2730902

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730902.1CARMA1 phosphorylation initiates its oligomerization and the coiled-coil (CC) domain of CARMA1 is hypothesized to mediate this clustering (Tanner et al. 2007).

17428801Pubmed2007CARMA1 coiled-coil domain is involved in the oligomerization and subcellular localization of CARMA1 and is required for T cell receptor-induced NF-kappaB activationTanner, MJHanel, WGaffen, SLLin, XJ Biol Chem 282:17141-7inferred by electronic annotationIEAGOIEA

Recruitment of TRAF6 to CBM complex by binding to MALT1

Reactome DB_ID: 10063184

DAG:p-5Y-PKC-theta:CBM oligomer [plasma membrane]

DAG:p-5Y-PKC-theta:CBM oligomer

Reactome DB_ID: 10063182

CBM oligomer [plasma membrane]

CBM oligomer

Reactome DB_ID: 10063156

MALT1 oligomer [cytosol]

MALT1 oligomer

Reactome DB_ID: 10063161

Reactome DB_ID: 10063154

BCL10 oligomer [cytosol]

BCL10 oligomer

Reactome Database ID Release 7510063182Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063182ReactomeR-BTA-2685684

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685684.1

Reactome DB_ID: 10063107

Reactome Database ID Release 7510063184Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063184ReactomeR-BTA-2685671

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685671.1

Reactome DB_ID: 10036425

UniProt:Q3ZCC3TRAF6

UniProtQ3ZCC3

EQUAL

522

EQUAL

Reactome DB_ID: 10063192

DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 [plasma membrane]

DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6

Reactome DB_ID: 10063190

CBM oligomer:TRAF6 [plasma membrane]

CBM oligomer:TRAF6

Reactome DB_ID: 10063188

BCL10 oligomer:MALT1 oligomer:TRAF6 [cytosol]

BCL10 oligomer:MALT1 oligomer:TRAF6

Reactome DB_ID: 10063186

MALT1oligomer:TRAF6 [cytosol]

MALT1oligomer:TRAF6

Reactome DB_ID: 10063156

Reactome DB_ID: 10036425

EQUAL

522

EQUAL

Reactome Database ID Release 7510063186Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063186ReactomeR-BTA-2685676

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685676.1

Reactome DB_ID: 10063154

Reactome Database ID Release 7510063188Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063188ReactomeR-BTA-2685667

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685667.1

Reactome DB_ID: 10063161

Reactome Database ID Release 7510063190Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063190ReactomeR-BTA-2685697

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685697.1

Reactome DB_ID: 10063107

Reactome Database ID Release 7510063192Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063192ReactomeR-BTA-2685682

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685682.1Reactome Database ID Release 7510063194Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063194ReactomeR-BTA-2730864

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730864.1TRAF6 is a ubiquitin ligase that plays a central role in the IKK-dependent canonical NF-kB pathway. It is recruited to the CBM complex by binding to MALT1. The MALT1 C-terminal Ig domain and extension contain two binding motifs for TRAF6 (Noels et al 2007). After oligomerzation TRAF6, together with Ubc13/Uev1A, activates TAK1 and IKK. It also acts as an E3 ligase for MALT1 and mediates lysine 63-linked ubiquitination (Oeckinghaus et al. 2007).

17287209Pubmed2007A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2middle dotMALT1 fusionsNoels, Heidivan Loo, GHagens, SofieBroeckx, VickyBeyaert, RudiMarynen, PBaens, MathijsJ. Biol. Chem. 282:10180-917948050Pubmed2007Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activationOeckinghaus, AndreaWegener, ElmarWelteke, VerenaFerch, UtaArslan, Seda CölRuland, JürgenScheidereit, ClausKrappmann, DanielEMBO J. 26:4634-4518772140Pubmed2008TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulationYang, Yong JunChen, WeiCarrigan, Svetlana OChen, Wei-MinRoth, KristyAkiyama, TaishinInoue, Jun-ichiroMarshall, Jean SBerman, Jason NLin, Tong-JunJ. Biol. Chem. 283:32110-8inferred by electronic annotationIEAGOIEA

Oligomerization of TRAF6

Reactome DB_ID: 10063192

Reactome DB_ID: 10036425

EQUAL

522

EQUAL

Reactome DB_ID: 10063226

DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomer [plasma membrane]

DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomer

Reactome DB_ID: 10063224

CBM oligomer:TRAF6 oligomer [plasma membrane]

CBM oligomer:TRAF6 oligomer

Reactome DB_ID: 10063156

Reactome DB_ID: 10063222

TRAF6 oligomer [cytosol]

TRAF6 oligomer

Reactome DB_ID: 10063154

Reactome DB_ID: 10063161

Reactome Database ID Release 7510063224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063224ReactomeR-BTA-2685695

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685695.1

Reactome DB_ID: 10063107

Reactome Database ID Release 7510063226Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063226ReactomeR-BTA-2685713

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685713.1Reactome Database ID Release 7510063228Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063228ReactomeR-BTA-2730903

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730903.1BCL10-MALT1 oligomers bind to TRAF6 and this in turn promotes the oligomerization of TRAF6 and activates its E3 ligase activity (Sun et al. 2004).

15125833Pubmed2004The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytesSun, LDeng, LEa, CKXia, ZPChen, ZJMol Cell 14:289-301inferred by electronic annotationIEAGOIEA

2.7.11

Activation of TAK1 complex bound to pUb-TRAF6

Reactome DB_ID: 10063213

DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3 [plasma membrane]

DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3

Reactome DB_ID: 10063211

TAB1:TAB2,TAB3:TAK1 [cytosol]

TAB1:TAB2,TAB3:TAK1

Reactome DB_ID: 10063209

Ghost homologue of MAP3K7 [cytosol]

Ghost homologue of MAP3K7

Reactome DB_ID: 10047157

UniProt:A0A3Q1LT51

UniProtA0A3Q1LT51

EQUAL

504

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10047169

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

UniProtE1B7Z0UniProtA0A3Q1M7T8Reactome Database ID Release 7510063211Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063211ReactomeR-BTA-450277

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-450277.1

Reactome DB_ID: 10063165

DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6 [plasma membrane]

DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6

Reactome DB_ID: 10063107

Reactome DB_ID: 10063163

CBM oligomer:oligo-K63-poly Ub-TRAF6 oligomer [plasma membrane]

CBM oligomer:oligo-K63-poly Ub-TRAF6 oligomer

Reactome DB_ID: 10063156

Reactome DB_ID: 10040401

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 (in Homo sapiens)

124

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

522

EQUAL

Reactome DB_ID: 10063154

Reactome DB_ID: 10063161

Reactome Database ID Release 7510063163Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063163ReactomeR-BTA-2685678

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685678.1Reactome Database ID Release 7510063165Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063165ReactomeR-BTA-2685691

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685691.1Reactome Database ID Release 7510063213Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063213ReactomeR-BTA-2685689

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685689.1

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10063213

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063213

GO0004674

GO molecular function

Reactome Database ID Release 7510063214Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063214Reactome Database ID Release 7510063216Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063216ReactomeR-BTA-2730900

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730900.1Binding of TAB2 and TAB3 to K63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Phosphorylation of TAK1 within the activation loop of the kinase is absolutely required for TAK1 activity. TAB1 is known to augment TAK1 catalytic activity by mediating spontaneous oligomerization and induces autophosphorylation of TAK1 (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Some biochemical studies revealed that free K63 polyubiquitin chains, which are not conjugated to any cellular protein, can directly activate the TAK1 kinase complex (Xia et al. 2009).

10838074Pubmed2000Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1Sakurai, HMiyoshi, HMizukami, JSugita, TFEBS Lett. 474:141-510702308Pubmed2000TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loopKishimoto, KMatsumoto, KNinomiya-Tsuji, JJ Biol Chem 275:7359-6417496917Pubmed2007Ubiquitin-mediated activation of TAK1 and IKKAdhikari, AXu, MChen, ZJOncogene 26:3214-2616186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-9515327770Pubmed2004TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chainsKanayama, ASeth, RBSun, LEa, CKHong, MShaito, AChiu, YHDeng, LChen, ZJMol Cell 15:535-4819675569Pubmed2009Direct activation of protein kinases by unanchored polyubiquitin chainsXia, ZPSun, LChen, XPineda, GJiang, XAdhikari, AZeng, WChen, ZJNature14633987Pubmed2003Role of the TAB2-related protein TAB3 in IL-1 and TNF signalingIshitani, TTakaesu, GNinomiya-Tsuji, JShibuya, HGaynor, RBMatsumoto, KEMBO J 22:6277-88inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510088929Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10088929ReactomeR-BTA-2871837

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2871837.1The increase in intracellular Ca+2 in conjunction with DAG also activates PKC and RasGRP, which inturn contributes to cytokine production by mast cells (Kambayashi et al. 2007). Activation of the FCERI engages CARMA1, BCL10 and MALT1 complex to activate NF-kB through PKC-theta (Klemm et al. 2006, Chen et al. 2007). FCERI stimulation leads to phosphorylation, and degradation of IkB which allows the release and nuclear translocation of the NF-kB proteins. Activation of the NF-kB transcription factors then results in the synthesis of several cytokines. NF-kB activation by FCERI is critical for proinflammatory cytokine production during mast cell activation and is crucial for allergic inflammatory diseases (Klemm et al. 2006).

16432253Pubmed2006The Bcl10-Malt1 complex segregates Fc epsilon RI-mediated nuclear factor kappa B activation and cytokine production from mast cell degranulationKlemm, StefanieGutermuth, JanHültner, LotharSparwasser, TBehrendt, HeidrunPeschel, ChristianMak, Tak WJakob, ThiloRuland, JürgenJ. Exp. Med. 203:337-4717182539Pubmed2007B cell lymphoma 10 is essential for FcepsilonR-mediated degranulation and IL-6 production in mast cellsChen, YuhongPappu, Bhanu PZeng, HuXue, LiquanMorris, Stephan WLin, XinWen, RenrenWang, DeminJ. Immunol. 178:49-57inferred by electronic annotationIEAGOIEA

Role of LAT2/NTAL/LAB on calcium mobilization

PI3K associates with phosphorylated GAB2

Reactome DB_ID: 10032530

PI3K [cytosol]

PI3K

Converted from EntitySet in Reactome

Reactome DB_ID: 10032528

PI3K-catalytic subunit [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPIK3CA [cytosol]PIK3CB [cytosol]

UniProtP32871UniProtF1MYM3

Reactome DB_ID: 10032518

UniProt:P23726PIK3R2

UniProtP23726

EQUAL

728

EQUAL

Reactome Database ID Release 7510032530Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10032530ReactomeR-BTA-74693

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-74693.1

Reactome DB_ID: 10063126

p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2 [plasma membrane]

p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2

Reactome DB_ID: 10063119

p-10Y-NTAL:p-SHC1:GRB2:SOS [plasma membrane]

p-10Y-NTAL:p-SHC1:GRB2:SOS

Reactome DB_ID: 10062591

Reactome DB_ID: 10063117

Ghost homologue of p-10Y-LAT2 [plasma membrane]

Ghost homologue of p-10Y-LAT2

Reactome Database ID Release 7510063119Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063119ReactomeR-BTA-2685692

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685692.1

Reactome DB_ID: 10063124

UniProt:A0A3Q1M864

UniProtA0A3Q1M864

O4'-phospho-L-tyrosine at 452 (in Homo sapiens)

452

EQUAL

O4'-phospho-L-tyrosine at 476 (in Homo sapiens)

476

EQUAL

O4'-phospho-L-tyrosine at 584 (in Homo sapiens)

584

EQUAL

676

EQUAL

Reactome DB_ID: 179838

Reactome Database ID Release 7510063126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063126ReactomeR-BTA-2685687

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685687.1

Reactome DB_ID: 10063128

p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3K [plasma membrane]

p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3K

Reactome DB_ID: 10032530

Reactome DB_ID: 10063126

Reactome Database ID Release 7510063128Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063128ReactomeR-BTA-2685700

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2685700.1Reactome Database ID Release 7510063130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063130ReactomeR-BTA-2730842

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730842.1Phosphorylated Y452, Y476, and Y584 of GAB2 binds p85 regulatory subunit of PI3K kinase, resulting in activation of PI3K pathway. PI3K is required for mast cell degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity (Nishida et al. 2011). Activated PI3K generates second messenger PtdInsP3 (PIP3) at the inner membrane, which provides docking sites for pleckstrin homology (PH) domains of PDK1, AKT and BTK. Activated AKT controls major downstream targets like mTORC1, FOXO3 and GSK3beta pathways that regulate mast cell growth, homeostasis, and cytokine production. BTK triggers PLCgamma2 activation, thereby inducing activation of the transcription factor NFAT and NF-kB.

16456001Pubmed2006Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcepsilonRIYu, MinLowell, Cliff ANeel, Benjamin GGu, HaihuaJ. Immunol. 176:2421-921653832Pubmed2011Gab2, via PI-3K, regulates ARF1 in Fc?RI-mediated granule translocation and mast cell degranulationNishida, KeigoYamasaki, SatoruHasegawa, AikoIwamatsu, AkihiroKoseki, HaruhikoHirano, ToshioJ. Immunol. 187:932-4110068651Pubmed1999Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptorsNishida, KYoshida, YItoh, MFukada, TOhtani, TShirogane, TAtsumi, TTakahashi-Tezuka, MIshihara, KHibi, MHirano, TBlood 93:1809-16inferred by electronic annotationIEAGOIEA

2.7.1.153

Phosphorylation of PIP2 to PIP3 by PI3K

Reactome DB_ID: 179856

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 179838

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10063128

GO0046934

GO molecular function

Reactome Database ID Release 7510063195Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063195Reactome Database ID Release 7510063197Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10063197ReactomeR-BTA-2730870

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730870.1PI3K catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and AKT.

12660731Pubmed2003The role of PI3K in immune cellsKoyasu, SNat Immunol 4:313-92833705Pubmed1988Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphateWhitman, MDownes, C PKeeler, MKeller, TCantley, Lewis CNature 332:644-6inferred by electronic annotationIEAGOIEA

Translocation of PDK1 to Plasma membrane

Reactome DB_ID: 10040272

UniProt:F1MQJ7PDPK1

UniProtF1MQJ7

EQUAL

556

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 202277

PIP3, PI(3,4)P2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPI(3,4)P2 [plasma membrane]PI(3,4,5)P3 [plasma membrane]

ChEBI16152

Reactome DB_ID: 10040274

PDK1:PIP2,PIP3 [plasma membrane]

PDK1:PIP2,PIP3

Converted from EntitySet in Reactome

Reactome DB_ID: 202277

Reactome DB_ID: 10033676

EQUAL

556

EQUAL

Reactome Database ID Release 7510040274Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10040274ReactomeR-BTA-202311

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-202311.1Reactome Database ID Release 7510040276Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10040276ReactomeR-BTA-202164

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-202164.1PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck & Alessi 2000).

10698680Pubmed2000The PI3K-PDK1 connection: more than just a road to PKBVanhaesebroeck, BAlessi, DRBiochem J 346:561-76inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510088927Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10088927ReactomeR-BTA-2730905

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2730905.1The lipid raft resident adaptor molecules LAT1 and Non-T cell activation linker (NTAL), also known as linker for activation of B cells (LAB)/LAT2 are known participants in the regulation of mast cell calcium responses. Both LAT and NTAL are expressed and phosphorylated following engagement of FCERI on mast cells. NTAL is functionally and topographically different from LAT. There is a considerable debate on the role of NTAL in mast cell. Depending on the circumstances, NTAL appears to have a dual role as positive and negative regulator of MC responses elicited via FCERI. Studies conducted in bone marrow-derived mast cells (BMMCs) of mice lacking NTAL displayed enhanced FCERI-mediated tyrosine phosphorylation of several substrates, calcium response, degranulation, and cytokine production. This indicated that NTAL negatively regulates FCERI-mediated degranulation. However, in mice lacking both LAT and NTAL showed severe block in FCERI-mediated signaling than BMMCs deficient in LAT alone, suggesting that NTAL also shares a redundant function with LAT to play a positive role (Draberova et al. 2007, Orr & McVicar. 2011, Zhu et al. 2004, Volna et al. 2004). The major steps in NTAL mediated Ca+2 influx involves NTAL--> GAB2--> PI3K

17993265Pubmed2008Kit- and Fc epsilonRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cellsIwaki, ShokoSpicka, JiriTkaczyk, ChristineJensen, Bettina MFurumoto, YasukoCharles, NicolasKovarova, MRivera, JuanHorejsí, VáclavMetcalfe, Dean DGilfillan, Alasdair MCell. Signal. 20:195-20515477348Pubmed2004Negative regulation of mast cell signaling and function by the adaptor LAB/NTALVolná, PetraLebduska, PavelDráberová, LubicaSímová, SárkaHeneberg, PetrBoubelík, MichaelBugajev, ViktorMalissen, BernardWilson, Bridget SHorejsí, VáclavMalissen, MarieDráber, PetrJ. Exp. Med. 200:1001-1320643813Pubmed2011LAB/NTAL/Lat2: a force to be reckoned with in all leukocytes?Orr, Selinda JMcVicar, Daniel WJ. Leukoc. Biol. 89:11-915477350Pubmed2004Positive and negative regulation of FcepsilonRI-mediated signaling by the adaptor protein LAB/NTALZhu, MinghuaLiu, YanKoonpaew, SurapongGranillo, OliviaZhang, WeiguoJ. Exp. Med. 200:991-100017911602Pubmed2007Regulation of Ca2+ signaling in mast cells by tyrosine-phosphorylated and unphosphorylated non-T cell activation linkerDráberová, LubicaShaik, Gouse MohiddinVolná, PetraHeneberg, PetrT?mová, MagdaLebduska, PavelKorb, JanDráber, PetrJ. Immunol. 179:5169-80inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510088631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10088631ReactomeR-BTA-2454202

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-BTA-2454202.1GO0038095

GO biological process

Mast cells (MC) are distributed in tissues throughout the human body and have long been recognized as key cells of type I hypersensitivity reactions. They also play important roles in inflammatory and immediate allergic reactions. Activation through FCERI-bound antigen-specific IgE causes release of potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells (Borish & Joseph 1992, Amin 2012, Metcalfe et al. 1993). FCERI is a multimeric cell-surface receptor that binds the Fc fragment of IgE with high affinity. On mast cells and basophils FCERI exists as a tetrameric complex consisting of one alpha-chain, one beta-chain, and two disulfide-bonded gamma-chains, and on dendritic cells, Langerhans cells, macrophages, and eosinophils it exists as a trimeric complex with one alpha-chain and two disulfide-bonded gamma-chains (Wu 2011, Kraft & Kinet 2007). FCERI signaling in mast cells includes a network of signaling molecules and adaptor proteins. These molecules coordinate ultimately leading to effects on degranulation, eicosanoid production, and cytokine and chemokine production and cell migration and adhesion, growth and survival.<br>The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001).

22112783Pubmed2012The role of mast cells in allergic inflammationAmin, KawaRespir Med 106:9-1414630197Pubmed2003Mast cell signal transduction from the high-affinity IgE receptorSiraganian, Reuben PCurr. Opin. Immunol. 15:639-4621799019Pubmed2011Immunoglobulin E receptor signaling and asthmaWu, Lawren CJ. Biol. Chem. 286:32891-715099567Pubmed2004The ins and outs of IgE-dependent mast-cell exocytosisBlank, UlrichRivera, JuanTrends Immunol. 25:266-7311449275Pubmed2001Essential role for Gab2 in the allergic responseGu, HSaito, KKlaman, L DShen, JinlongFleming, TWang, YPratt, J CLin, GLim, BKinet, J PNeel, B GNature 412:186-909354811Pubmed1997Mast cellsMetcalfe, D DBaram, DMekori, Y APhysiol. Rev. 77:1033-79inferred by electronic annotationIEAGOIEA