The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation

The Pas GTPase plays an essential role in many cellular signal transduction events, Activation of the mitogen activated protein (MAP) kinase is a primary consequence of Pas activation and plays a key role in mediating Pas signal transduction, A novel kinase, KSR, has recently been functionally isolated as a positive regulator of Pas signaling in Caenorhabditis elegans vulval induction and Drosophila photoreceptor differentiation. We have examined the effect of KSR on growth factor and Pas-induced MAP kinase signaling in mammalian cells, Surprisingly, we observed that KSR specifically blocks EGF and Pas-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 Pas-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.