Revealing Regulation and Organization of Signaling Networks by Scaffolding Proteins

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2007-05-23

Authors

Swanik, Jackie Thomas

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Abstract

Understanding the molecular mechanism that controls how cells respond to their environment is of major biological significance. The RAS/RAF signal transduction pathway is a good model with which to investigate this question as the major catalytic components of the pathway have been identified and it has been shown to elicit a wide variety of cellular responses such as proliferation, migration, differentiation, and apoptosis. The pathway is a three-tiered MAPK kinase cascade consisting of RAF, MEK, and ERK. Although the pathway has been extensively studied, pathway regulation is not completely understood. Genetic studies aimed at understanding pathway regulation have identified candidate scaffolding proteins. We used transient loss of function analysis to assess the contribution of the scaffolding proteins, Suppressor of RAS-8 (Sur-8) and Kinase Suppressor of RAS (KSR), to ligand mediated RAS/RAF signal transduction pathway activation. We show that Sur-8 and KSR are integral components of the RAS/RAF signal transduction pathway in mammalian cells. In addition, they display ligand specific coupling in that Sur-8 is required for EGF induced MEK activation while KSR is involved in LPA mediated MEK activation. to ligand mediated RAS/RAF signal transduction pathway activation. We show that Sur-8 and KSR are integral components of the RAS/RAF signal transduction pathway in mammalian cells. In addition, they display ligand specific coupling in that Sur-8 is required for EGF induced MEK activation while KSR is involved in LPA mediated MEK activation. Investigation of the molecular mechanism of action of Sur-8 and KSR found that Sur-8 is required for both EGF induced RAF-1 and B-RAF activation while KSR is involved in EGF induced RAF-1 activation. Additionally, Sur-8 contributes to RAF-1 localization as well as being associated with a RAF-1 activating kinase. Futhermore, we found that KSR does not impact LPA induced MEK activation through either RAF-1 or B-RAF activation and even though it impacts EGF induced RAF-1 activation it is not a limiting component to EGF induced MEK activation. In this study, we show that a function of scaffolding proteins in the RAS/RAF signal transduction pathway is to contribute to ligand specific coupling of MEK/ERK to distinct stimuli.

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