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.
| Ritt, Daniel A; Abreu-Blanco, María T; Bindu, Lakshman et al. (2016) Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit. Mol Cell 64:875-887 |
| Shalin, Sara C; Hernandez, Caterina M; Dougherty, Michele K et al. (2006) Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation. Neuron 50:765-79 |
| Ritt, Daniel A; Daar, Ira O; Morrison, Deborah K (2005) KSR Regulation of the Raf-MEK-ERK Cascade. Methods Enzymol 407:224-37 |
| Dougherty, Michele K; Muller, Jurgen; Ritt, Daniel A et al. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215-24 |
| Weber, Hans Oliver; Ludwig, Robert L; Morrison, Deborah et al. (2005) HDM2 phosphorylation by MAPKAP kinase 2. Oncogene 24:1965-72 |
| Murakami, Monica S; Moody, Sally A; Daar, Ira O et al. (2004) Morphogenesis during Xenopus gastrulation requires Wee1-mediated inhibition of cell proliferation. Development 131:571-80 |
| Dougherty, Michele K; Morrison, Deborah K (2004) Unlocking the code of 14-3-3. J Cell Sci 117:1875-84 |
| Ory, Stephane; Morrison, Deborah K (2004) Signal transduction: implications for Ras-dependent ERK signaling. Curr Biol 14:R277-8 |
| Morrison, Deborah K (2004) Cancer: enzymes play molecular tag. Nature 428:813-5 |
| Ory, Stephane; Zhou, Ming; Conrads, Thomas P et al. (2003) Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13:1356-64 |
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