Mechanisms of Neurotrophin and Ephrin Signal Integration

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Cell-cell communication represents the combined effects of multiple polypeptide factors. To explain complex effects in the nervous system requires an understanding of how local circuits and signal transduction pathways are integrated. Ephrins and Neurotrophins display both rapid and slower long lasting effects that require receptor signaling to proceed in a linear stop-wise fashion, but also influence each other, either directly or through signaling intermediates. Regulation of Ephrins and Neurotrophins is likely to be determined by the additive effects of their receptors and the duration of second messengers and phosphorylation events. Interactions between Ephrin and Neurotrophin receptors and downstream signaling proteins provide a mechanism for merging the actions of different ligand-receptor systems in order to achieve novel cellular outcomes. This subproject will focus on a set of downstream substrates that are used by both Ephrin and Neurotrophin receptors. The hypothesis is that cooperativity and antagonism between these two different transmembrane protein systems provide additional mechanisms for extracellular signaling. The proposed research is relevant to the understanding and treatment of early developmental disorders, such as autism, and neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis, which depend upon the actions of Ephrins and Neurotrophins for correct developmental patterning and circuit formation.