The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation.
The Ras GTPase plays an essential role in many cellular signal transduction events. Activation of the mitogen activated protein (MAP) kinase is a primary consequence of Ras activation and plays a key role in mediating Ras signal transduction. A novel kinase, KSR, has recently been functionally isolated as a positive regulator of Ras signaling in Caenorhabditis elegans vulval induction and Drosophila photoreceptor differentiation. We have examined the effect of KSR on growth factor and Ras-induced MAP kinase signaling in mammalian cells. Surprisingly, we observed that KSR specifically blocks EGF and Ras-induced phosphorylation and activation of ternary complex factors (TCF), physiological substrates of MAP kinases, without affecting the activation of MAP kinase itself. A kinase-deficient mutant of KSR, KSR-RM, appears to function as a dominant interfering mutant which elevates phosphorylation of Elk-1, a member of the TCF family, and Elk-1-dependent transcription. The effect of KSR on Elk-1 was significantly decreased by inhibition of calcineurin, a putative Elk-1 phosphatase. These observations demonstrate that KSR is capable of uncoupling the MAP kinase activation from its target phosphorylation, and thus provide a novel mechanism for modulating the Ras-MAP kinase signaling pathway. This study provides the first evidence that signal output of MAP kinase cascades is subject to regulation at a level independent of MAP kinase activity.
Sugimoto
T
T
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0606, USA.
Stewart
S
S
Han
M
M
Guan
K L
KL
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016762:Genes, fos / Q000502:physiology; D016758:Genes, jun / Q000502:physiology; D048369:MAP Kinase Kinase 1; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; C494194:Elk4 protein, mouse; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C489525:p62TCF protein, mouse; D050808:ets-Domain Protein Elk-4; D004815:Epidermal Growth Factor; D016572:Cyclosporine; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D019703:Calcineurin; D018631:ras Proteins