Article

Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1.

Department of Medicine, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Journal of Biological Chemistry (impact factor: 4.77). 06/2001; 276(19):16406-10. DOI:10.1074/jbc.C100079200 pp.16406-10
Source: PubMed

ABSTRACT We recently obtained evidence that treatment of human colon cancer cells with exisulind (sulindac sulfone) and related compounds induces apoptosis by activation of protein kinase G (PKG) and c-Jun kinase (JNK1). The present study further explores this mechanism. We demonstrate that in NIH3T3 cells a constitutively active mutant of PKG causes a dose-dependent activation of JNK1 and thereby transactivates c-Jun and stimulates transcription from the AP-1 enhancer element. The activation of JNK1 and the transactivation of c-Jun by this mutant of PKG were inhibited by a dominant negative MEKK1. In vitro assays showed that a purified PKG directly phosphorylated the N-terminal domain of MEKK1. PKG also directly phosphorylated a full-length MEKK1, and this was associated with enhanced MEKK1 phosphorylation. Thus, it appears that PKG activates JNK1 through a novel PKG-MEKK1-SEK1-JNK1 pathway, by directly phosphorylating and activating MEKK1.

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Keywords

activating MEKK1
 
compounds induces apoptosis
 
constitutively active mutant
 
dominant negative MEKK1
 
dose-dependent activation
 
exisulind
 
full-length MEKK1
 
human colon cancer cells
 
MEKK1
 
MEKK1 phosphorylation
 
N-terminal domain
 
NIH3T3 cells
 
novel PKG-MEKK1-SEK1-JNK1 pathway
 
PKG
 
PKG activates JNK1
 
PKG causes
 
purified PKG
 
stimulates transcription
 
sulindac sulfone
 
transactivation
 

J W Soh