Guanine-nucleotide exchange protein C3G activates JNK1 by a ras-independent mechanism. JNK1 activation inhibited by kinase negative forms of MLK3 and DLK mixed lineage kinases.
Recently we have reported that the adaptor protein Crk transmits signals to c-Jun kinase (JNK) through C3G, a guanine-nucleotide exchange protein for the Ras family of small G proteins. Transient expression of C3G in 293T cells induced JNK1 activation without a significant effect on extracellular signal-related kinase 1 (ERK1), whereas mSos1 activated equally both JNK1 and ERK1. Coexpression of the dominant negative form of Ras-N17 did not suppress C3G-induced JNK1 activation but reduced the activity of JNK1 induced by mSos1, suggesting that Ras is not required for JNK activation by C3G. Ras-independent activation of JNK was supported by the finding that C3G-induced JNK activation was not inhibited by the dominant negative forms of Rac or Pak, which are components of the signaling pathway from Ras leading to JNK activation. In contrast, C3G-induced JNK1 activation was strongly inhibited by coexpression of the kinase negative forms of the mixed lineage kinase (MLK) family of proteins, MLK3 and dual leucine zipper kinase (DLK). In addition, MLK3-induced JNK1 activation was found to be suppressed by the kinase negative form of DLK, which bound to MLK3. These results suggest that C3G activates JNK1 through a pathway involving the MLK family of proteins.
Tanaka
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Laboratory of Molecular Oncology, Rockefeller University, New York, New York 10021, USA.
Hanafusa
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D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015852:Eukaryotic Initiation Factor-2; D020662:Guanine Nucleotide Exchange Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11