Regulation of Ras-Dependent Signal Transduction Pathways

Basic Sciences

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Abstract

The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Due to its integral role in cell signaling, Raf-1 activity must be precisely controlled. During this past fiscal year, our reseach identified critical feedback phosphorylation sites that contribute to the downregulation of Raf-1 following mitogen stimulation. This work elucidated a key mechanism contributing to the temporal regulation of Ras/Raf signaling signaling and identified critical molecules involved in this process - ERK, PP2A and Pin1. KSR is a conserved component of the Ras pathway that acts as a molecular scaffold to facilitate signal transmission through the ERK cascade. During the past fiscal year, our studies provided novel insight into the endogenous scaffolding role of KSR1 within the nervous system. This work demonstrated that KSR1 functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Consistent with these findings, mice lacking KSR1 were found to have deficits in associative learning and certain typses of synaptic plasticity.