Analysis of cellular signal transduction via Neurofibromatosis tumor suppressor gene products and development of their clinical targets

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Neurofibromatosis (NF) tumor suppressor gene products, neurofibromin : NF1 and merlin : NF2, are though to be important regulators of cellular growth, differentiation, and apoptosis, and implicated in the neural abnormality of NF patients. However, the precise cellular function of NF proteins has yet to be clarified. In this study, we utilized proteomic strategies, functional annotation with a proprietary gene ontology (MANGO), and standard biochemical methods to identify proteins related to neuronal differentiation in PC12 cells, which serve as a representative model system for studying NF related neuronal biological processes. Of 1,600 non-redundant proteins quantitatively identified, 72 were novel nerve growth factor-responsive PC12 proteins mostly related to the biological processes of cell morphogenesis, apoptosis/survival, and cell differentiation. Using these proteomic strategies and database, we identified a set of NF-associating cellular proteins, including axon regulator CRMP-2. These associations were crucial for the axon formation in neuron and were regulated by a series of kinase activations by CDK5, GSK-3b, and Rho kinase being controlled by neurofibromin. Our study demonstrates that the functional association of NF proteins and their associating proteins are essential for neuronal cell differentiation and that lack of expression or abnormal regulation of NF proteins can result in impaired function of neural cells, which is likely a factor in NF-related pathogenesis.