Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo

Abstract

While scaffold proteins are thought to be key components of signaling pathways, their exact function is unknown. By preassembling multiple components of signaling cascades, scaffolds are predicted to influence the efficiency and/or specificity of signaling events. Here we analyze a potential scaffold of the Ras/mitogen-activated protein kinase (MAPK) pathway, kinase suppressor of Ras (KSR), by generating KSR-deficient mice. KSR-deficient mice were grossly normal even though ERK kinase activation was attenuated to a degree sufficient to block T-cell activation and inhibit tumor development. Consistent with its role as a scaffold, high-molecular-weight complexes containing KSR, MEK, and ERK were lost in the absence of KSR. This demonstrates that KSR is a bona fide scaffold that is not required for but enhances signaling via the Ras/MAPK signaling pathway.

We thank Andrew Chan, Alec Cheng, Osami Kanagawa, and Barry Sleckman for their insight and advice and Jeong Kim for critical reading of the manuscript.

This research was supported by the NIH (A.S.S.), an NIH training grant (A.N.), the Burroughs-Wellcome Fund (W.R.B.), NIH grants CA90400 and DK52809 (R.E.L.), and the American Diabetes Association (R.E.L. and R.K.).