Role of the protein phosphatase 1 inhibitor CPI-17 in ERM- and adhesion-dependent Ras regulation in neurons

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Neurotrophic actions are controlled and transmitted to cellular responses by the Ras family of small G-proteins. Ras is required for the normal functioning and plasticity of the developing, as well as the adult, nervous system. Induction and counter regulatory mechanisms that affect Ras in neurons must be tightly controlled, since loss of proper Ras regulation has been associated with memory and learning deficits, as well as age-related brain degeneration. We have recently identified a novel pathway controlling Ras activity in non-neuronal cells, which includes the phosphatase MYPT-1-PP1δ and its inhibitor CPI-17. This level of Ras activation involves the phosphorylation status of the MYPT-1-PP1δ targets ezrin and merlin. Preliminary results showing that CPI-17 is normally expressed in the hippocampus have prompted us to study the role of neuronal CPI-17 on merlin/ERM-dependent Ras regulation in specific areas of the brain important for learning and memory. Specifically, the signalling activities of CPI-17 as a protein phosphatase 1 (PP1) inhibitor will be correlated to functional readouts such as cell proliferation, differentiation, synaptic plasticity and learning capabilities. Our studies will range from cell culture studies on various neuronal cell model systems, including work on primary hippocampal neurons, to the use of a transgenic mouse model with inducible neuronal-restricted CPI-17 overexpression as well as knockout of CPI-17 in specific areas of the brain. We intend to create such mice and analyse the effects of CPI-17 on learning, memory, synaptic transmission and synaptic plasticity. The outcome of the experiments will provide a detailed picture of Ras regulation, involving the phosphorylation status of ezrin and merlin. This mechanism will likely represent a totally novel aspect of Ras control in neuronal stability and plasticity within the adult nervous system.