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.