The following is the text of the short description of the reaction involved in Dectin-1 signalling.
DECTIN-1 SIGNALLING
SENSING MODULE – SYK
• The 1,3-β-glucan particles binds to the C-type lectin Dectin-1 in glucan containing phagosome.
• The adaptor Dectin-1 dimerizes and becomes tyrosine phosphorilated.
• Syk binds to dectin-1 dimer and autophosphorilates.
TRANSDUCTION MODULE – NFkB - RELA
• Syk autophosphorilates and phosphorilates the transmembrane adaptor CARD9
• The effector molecule BLC10 binds to MALT1 by PLCG2 activity.
• After a conformational change CARD9 binds to the complex BLC10:MALT1.
• The complex binds to TRAF6.
• The protein TRAF6 binds to the serine/threonine kinases TAK1, TAB1, TAB2 (TRAF6:TAK1:TAB1:TAB2).
• The complex of the serine/threonine kinases TAB1-TAB2 phosphorylated-TAK1 phosphorylated and the protein TRAF6 (TAB1:TAB2-p:TAK1-p:TRAF6) translocates from the cytoplasmic membrane to the cytosol.
• The complex of the serine/threonine kinases TAB1-TAB2 phosphorylated-TAK1 phosphorylated and the protein TRAF6 (TAB1:TAB2-p:TAK1-p:TRAF6) binds the E2 ubiquitin ligases Uev1A and Ubc13 and the protein TRAF6 is ubiquitinated.
• The protein TRAF6 ubiquitinated controls the unknown process that leads to the activation of the serine/threonine kinaseTAK1 phosphorylated.
• The serine/threonine kinase TAK1-phosporilated phosphorilates the serine/threonine kinases IKK-alpha and IKK-beta of the complex IKK (IKK-alpha-IKK-beta-IKK-gamma)
• The phosphorylation of the transcriptional regulator IkB-alpha by the IKK complex phosphorylated leads the translocation of the general transcription factor NFkB p65 complexed with c-Rel into the nucleus.
• The transcriptional regulator IkB-alpha is ubiquitinated and degraded in the proteosome.
OUTCOME NFkB - RELA
• The transcription factor NFkB translocates in the nucleus.
• The transcription factor NFkB binds DNA and activates the transcription of the genes:
IL-23A, IL-6, IL-2, IL-10, TNF-alpha, MIP2.
TRANSDUCTION MODULE – NFkB - RELB
• Syk autophosphorilates and phosphorilates the transmembrane adaptor CARD9
• The effector molecule BLC10 binds to MALT1 by PLCG2 activity..
• After a conformational change CARD9 binds to the complex BLC10:MALT1.
• The complex binds to TRAF6.
• The protein TRAF6 binds to the serine/threonine kinases TAK1, TAB1, TAB2 (TRAF6:TAK1:TAB1:TAB2).
• The complex of the serine/threonine kinases TAB1-TAB2 phosphorylated-TAK1 phosphorylated and the protein TRAF6 (TAB1:TAB2-p:TAK1-p:TRAF6) translocates from the cytoplasmic membrane to the cytosol.
• The complex of the serine/threonine kinases TAB1-TAB2 phosphorylated-TAK1 phosphorylated and the protein TRAF6 (TAB1:TAB2-p:TAK1-p:TRAF6) binds the E2 ubiquitin ligases Uev1A and Ubc13 and the protein TRAF6 is ubiquitinated.
• The protein TRAF6 ubiquitinated controls the unknown process that leads to the activation of the serine/threonine kinaseTAK1 phosphorylated.
• The serine/threonine kinase TAK1-phosporilated phosphorilates the serine/threonine kinases IKKa and IKKb of the complex IKK (IKK-alpha:IKK-beta:IKK-gamma)
• The phosphorylation of the transcriptional regulator IkB-alpha by the IKK complex phosphorylated leads the translocation of the general transcription factor NFkB complexed with RelB into the nucleus.
• The transcriptional regulator IkB-alpha is ubiquitinated and degraded in the proteosome.
OUTCOME NFkB-RELB
• The transcription factor NFkB translocates in the nucleus.
• The transcription factor NFkB complexed with RelB binds DNA and activates the transcription of the genes: CCL17, CCL22.
• The transcription factor NFkB complexed with RelB binds DNA and repress the transcription of the genes IL10, IL12A, IL12B, IL6, IL1B
TRANSDUCTION MODULE -ERK
• Syk autophosphorylates and phosphorylates the complex Grb2/Sos and PLCG
• The phosphorylated Grb2/Sos:PLCG2 complex phosphorylates the transcription factor ERK.
• The transcription factor ERK translocates into the nucleus.
OUTCOME ERK
• The transcription factor ERK translocates in the nucleus.
• The transcription factor ERK binds to AP1.
• AP1 binds to DNA and activates the transcription of the genes of the cytokines: IL-10.
TRANSDUCTION MODULE NFAT
• Syk autophosphorylates and phosphorylates PLC-g2.
• PLCG2 hydrolyzes the membrane phospholipid PIP2 to IP3 and DAG.
• IP3 opens IP3R which permits Ca2+ efflux from ER Ca2+ stores.
• The ER Ca2+ sensor STIM1 and STIM2 sense the resulting reduction of ER Ca2+ stores via their paired N-terminal EF hands located in the ER lumen.
• After Ca2+ dissociation from the EF, STIM proteins aggregate into small cluster in the ER membrane and trigger store-operated Ca2+ entry via the CRAC channel, ORAI1.
• Ca2+ influx elevates intracellular Ca2+ concentration and activates the calcineurin-NFAT pathway by dephosphorylation of NFAT.
• The dephosphorylated transcription factors NFATC1 and NFATC2 translocate into the nucleus.
OUTCOME NFAT
• The dephosphorylated transcription factor NFAT translocates into the nucleus.
• The transcription factor NFAT binds DNA and activates the transcription of the genes of the cytokines: EGR2, EGR3, COX2, IL2, IL10, PGE2, IL12.
TRANSDUCTION MODULE JNK
• Syk phosphorylates CARD9
• CARD9 binds BLC10 and MALT1
• With an unknown process, JNK phosporilates.
TRANSDUCTION MODULE p38
• Syk phosphorylates CARD9
• CARD9 binds BLC10 and MALT1
• With an unknown process, p38 phosporilates
SENSING MODULE – RAF1
• The 1,3-b-glucan particles binds to the C-type lectin Dectin-1 in glucan containing phagosome.
• The C-type lectin Dectin-1 dimerizes and becomes tyrosine phosphorilated.
• The C-Type lectin Dectin-1 dimer autophosphorilates.
• The C-type lectin Dectin-1 phosphorilates the MAP kinase Raf1 through Pac and Src kinases.
TRANSDUCTION MODULE - RAF1
The subunit RelB of the transcription factor NFkB complexes with the subunit RelA of the transcription factor NFkB.
The MAP kinase Raf1 acetylates NFkB RelA by CPB and p300 The inactive transcription factor NFkB translocates into the nucleus.
OUTCOME MODULE – RAF1
The transcription factor NFkB translocates into the nucleus.
The transcription factor NFkB induces the transcription of the genes IL12A, IL12B, IL1B, IL10, IL6 and represses the transcription of the gene IL23A.