Neurons communicate by transmitting signals through highly specialized junctions called synapses. Frequent signaling through a synapse increases the strength of synaptic transmission; changes in the strength of synaptic transmission (also called synaptic plasticity) are believed to underlie learning and the development of complex behaviors. Several nonreceptor tyrosine kinases localize to synapses where they regulate synaptic transmission and plasticity. Since the Arg nonreceptor tyrosine kinase is localized to postsynaptic compartments of neurons, my proposed research will focus on characterizing the molecular interactions that Arg is involved in and whether these interactions lead to changes in synaptic transmission in response to presynaptic stimulus. These studies will lead to a better understanding of Abl family kinases function in neurons and how they affect synaptic transmission. The first step of the proposed research involves identifying substrates of Arg kinase activity by comparing tyrosine phosphorylation in wild-type vs. arg -/- mice and using functional phosphorylation assays in vivo and in vitro to confirm an enzyme-substrate interaction. As a second step, the effect of phosphorylation by Arg on the identified substrates function will be studied. Third, having identified substrates and its role upon phosphorylation, functional studies of the effect of Arg kinase activity will be assessed to establish its role in neurons. The ultimate goal of this work is to obtain valuable knowledge that can be applied in therapeutic procedures of patients that suffer of neurodegenerative disorders involving the loss of memory and/or the establishment of new memories and learning.
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|Hernandez, Samuel E; Settleman, Jeffrey; Koleske, Anthony J (2004) Adhesion-dependent regulation of p190RhoGAP in the developing brain by the Abl-related gene tyrosine kinase. Curr Biol 14:691-6|
|Hernandez, Samuel E; Krishnaswami, Maithreyi; Miller, Ann L et al. (2004) How do Abl family kinases regulate cell shape and movement? Trends Cell Biol 14:36-44|