Differential activation of stress-activated protein kinase kinases SKK4/MKK7 and SKK1/MKK4 by the mixed-lineage kinase-2 and mitogen-activated protein kinase kinase (MKK) kinase-1.
Overexpression of the protein kinases mixed-lineage kinase-2 (MLK2) or mitogen-activated protein kinase (MAPK) kinase kinase-1 (MEKK1) is known to trigger the activation of stress-activated protein kinase (SAPK1)/c-Jun N-terminal kinase (JNK). Here we demonstrate that MLK2 activates SAPK kinase-1 (SKK1)/MAPK kinase 4 (MKK4) and SKK4/MKK7, the two known direct activators of SAPK1/JNK (both in transfection studies and in vitro). In contrast, MEKK1 activates SKK1/MKK4 more efficiently than MLK2, but barely activates SKK4/MKK7. Since SKK4/MKK7 (but not SKK1/MKK4) is activated by interleukin-1 and tumour necrosis factor in several cells and tissues, we suggest that MEKK1 does not mediate the activation of SKK4/MKK7 and SAPK1/JNK induced by these pro-inflammatory cytokines. MLK2 and MEKK1 also activated SKK2/MKK3 and SKK3/MKK6, the direct upstream activators of SAPK2a/p38.
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MRC Protein Phosphorylation Unit, Department of Biochemistry, University of Dundee, Dundee DD1 4HN, Scotland, U.K. and Trescowthick Research Centre, Peter MacCallum Cancer Institute, Melbourne, Victoria 3000, Australia. aicuenda@bad.dundee.ac.uk
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D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007624:KB Cells; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection
D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C093290:MAP3K10 protein, human; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; C482530:MAP2K3 protein, human; C482559:MAP2K4 protein, human; C482566:MAP2K6 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases