Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors.
Mixed lineage kinases (MLKs) are a family of serine/threonine kinases that function in the SAPK signaling cascade. MLKs activate JNK/SAPK in vivo by directly phosphorylating and activating the JNK kinase SEK-1 (MKK4 and -7). Importantly, the MLK member MLK3/SPRK has been shown recently to be a direct target of ceramide and tumor necrosis factor-alpha (TNF-alpha) and to mediate the TNF-alpha and ceramide-induced JNK activation in Jurkat cells. Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. Surprisingly, this induction of MEK phosphorylation does not result in ERK activation in vivo. Rather, in cells expressing active MLK3, ERK becomes resistant to activation by growth factors and mitogens. This restriction in ERK activation requires MLK3 kinase activity, is independent of Raf activation, and is reversed by JNK pathway inhibition either at the level of SEK-1, JNK, or Jun. These results demonstrate that sustained JNK activation uncouples ERK activation from MEK in a manner requiring Jun-mediated gene transcription. This in turn points to the existence of a negative cross-talk relationship between the stress-activated JNK pathway and the mitogen-activated ERK pathway. Thus, our findings imply that some of the biological functions of JNK activators, such as TNF-alpha and ceramide, may be attributed to their ability to block cell responses to growth and survival factors acting through the ERK/MAPK pathway.
Shen
Ying H
YH
Cardiovascular Research Institute, Division of Molecular Cardiology, the Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.
Godlewski
Jakub
J
Zhu
Jun
J
Sathyanarayana
Pradeep
P
Leaner
Virna
V
Birrer
Michael J
MJ
Rana
Ajay
A
Tzivion
Guri
G
D000818:Animals; D019556:COS Cells; D002227:Carbazoles / Q000494:pharmacology; D002518:Ceramides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D002227:Carbazoles; D002518:Ceramides; D004791:Enzyme Inhibitors; D007211:Indoles; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D019908:Proto-Oncogene Proteins c-raf; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C469298:CEP-11004; C482125:MAP2K1 protein, human