PMID- 17584736
OWN - NLM
STAT- MEDLINE
DCOM- 20071019
LR  - 20231213
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 33
DP  - 2007 Aug 17
TI  - Dissection of a signaling pathway by which pathogen-associated molecular patterns 
      recruit the JNK and p38 MAPKs and trigger cytokine release.
PG  - 24246-54
AB  - Pathogen-associated molecular patterns (PAMPs), molecular moieties produced by 
      invading microbial pathogens, initiate innate immune responses by binding to 
      pattern recognition receptors (PRRs). Engagement of PRRs elicits a wide variety 
      of responses, including the production and release of cytokines and chemokines. 
      These responses require the activation of several parallel signaling pathways, 
      including NF-kappaB, the interferon regulatory factors, and the MAPKs. The JNK 
      and p38 MAPK groups are major PRR effectors and are key to the PRR-dependent 
      induction and release of proinflammatory cytokines such as tumor necrosis factor 
      and interleukin-8. The mammalian Ste20 orthologue germinal center kinase (GCK) is 
      required for the activation of JNK by a subset of PAMPs; however, the mechanisms 
      by which GCK couples to downstream events remain unclear. Here we show that GCK 
      is required for JNK and, unexpectedly, p38 activation by three bacterial PAMPs, 
      lipopolysaccharide, peptidoglycan, and flagellin (FliC). We show that these same 
      PAMPs, in a GCK-dependent manner, activate mixed lineage kinases-2 and -3, MAPK 
      kinase kinases upstream of JNK, and p38. We also show that MLK2 and -3 are 
      required for activation of JNK and p38 by ectopically expressed GCK. Finally, we 
      show that MLK2 and -3 are required for lipopolysaccharide, peptidoglycan, and 
      FliC recruitment of JNK and p38 as well as for PAMP recruitment of the 
      transcription factor c-Jun, and for the induction of interleukin-8. Our results 
      define a signaling pathway whereby PAMPs can trigger MAPK activation and gene 
      expression.
FAU - Zhong, Jian
AU  - Zhong J
AD  - Molecular Cardiology Research Institute, Department of Medicine, Tufts-New 
      England Medical Center and the Boston, Massachusetts 02111, USA.
FAU - Kyriakis, John M
AU  - Kyriakis JM
LA  - eng
GR  - R01-GM46577/GM/NIGMS NIH HHS/United States
GR  - T32-HL069770/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070621
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cytokines)
RN  - 0 (Germinal Center Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP3K10 protein, human)
SB  - IM
MH  - Bacteria/*pathogenicity
MH  - Cytokines/metabolism
MH  - Germinal Center Kinases
MH  - Humans
MH  - Immunity, Innate
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - Jurkat Cells
MH  - MAP Kinase Kinase Kinases/physiology
MH  - MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase 8/*metabolism
MH  - Protein Serine-Threonine Kinases/metabolism/*physiology
MH  - Signal Transduction/*immunology
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
MH  - Mitogen-Activated Protein Kinase Kinase Kinase 11
EDAT- 2007/06/23 09:00
MHDA- 2007/10/20 09:00
CRDT- 2007/06/23 09:00
PHST- 2007/06/23 09:00 [pubmed]
PHST- 2007/10/20 09:00 [medline]
PHST- 2007/06/23 09:00 [entrez]
AID - S0021-9258(20)54408-6 [pii]
AID - 10.1074/jbc.M703422200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Aug 17;282(33):24246-54. doi: 10.1074/jbc.M703422200. Epub 2007 
      Jun 21.