Post-translational processing and turnover of delta-catenin and its potential role in modulating neuronal morphology

摘要

The central nervous system is comprised of a complex array of neural connections. Proper establishment and maintenance of these connections requires ongoing cellular morphological changes which provide the structural basis for synaptic plasticity. These morphological changes require highly coordinated intracellular signaling processes that mediate responses to extracellular cues. Proteins that integrate events at the membrane and within the cytoskeleton play a central role in these processes. Consequently, there exists a need for elucidating intracellular signaling pathways that participate in mediating these morphological changes.;delta-Catenin, a beta-catenin superfamily member, is a neuronal specific protein that binds to synaptic membrane proteins and communicates membrane activity to implement neuronal functions. Although maintenance of appropriate delta-catenin levels is critical for cognitive functions, few studies have been undertaken to identify factors that regulate its expression. Studies presented in this dissertation explore the regulatory mechanisms involved in modulating delta-catenin turnover thereby altering its protein expression levels in cells. Two regulator protein candidates are presenilin-1 (PS-1) and glycogen synthase kinase-3beta (GSK-3beta); the enzymatic activities of both are critical for normal neuronal development and function. Information presented in this dissertation demonstrate that post-translational modification of delta-catenin by either PS-1 or GSK-beta (namely cleavage and phosphorylation, respectively) promotes delta-catenin turnover. It was demonstrated that PS-1 expression promoted processing and turnover of delta-catenin. Furthermore, expression of the Alzheimer's disease causing mutant of PS-1 enhanced delta-catenin processing and inhibited delta-catenin induced branching of cellular processes. Additional investigations demonstrated that delta-catenin turnover was also regulated by the GSK-3beta-ubiquitin proteolysis pathway. It was shown that phosphorylation by GSK-3beta targets delta-catenin for proteasome mediated degradation. These studies also identified delta-catenin as a new member of the GSK-3beta molecular destruction complex, and showed that delta-catenin may be involved in the interaction, ubiquitination and subsequent turnover of other signaling effectors important in mediating neuronal growth. Since expression of delta-catenin has a powerful role in inducing dendritic morphogenesis, understanding the regulation of its turnover adds to the knowledge of intracellular signaling events important in normal brain function.