Dendritic spines in excitatory synapses can undergo dynamic actin-based morphological changes associated with synaptic plasticity. Recent examination into the molecular basis of this plasticity uncovered a role for SPAR, a RapGAP that targets to the PSD of dendritic spines. In turn, SPAR stability is regulated by serine/threonine kinase SNK. SNK phosphorylates SPAR, which promotes SPAR degradation through a proteasomal pathway. Nevertheless, the identity of the E3 Ub-ligases that target SPAR and how they are regulated is still unknown. Our investigation into the E3 Ub-ligases that target SPAR to regulate synaptic plasticity includes the following three major efforts:
Aim 1 investigates roles for SCF Ub-ligases in SPAR degradation and the activation signals they recognize in the substrate;
Aim 2 details a comprehensive approach to identify all E3 Ub-ligases that target SPAR;
and Aim 3 examines how depletion of identified candidate E3 Ub-ligases affects dendritic spine morphology in primary hippocampal neurons. In addition to providing concrete evidence for the involvement of the Ub-pathway in the regulation of dendritic spine morphology, identification of the E3 Ub-ligases that mediate SPAR degradation is intrinsic to understanding the mechanism that may underlie a number of disorders associated with abnormal spine morphology and density, including general mental retardation, fragile-X syndrome, Down's syndrome, and epilepsy.
| Inuzuka, Hiroyuki; Tseng, Alan; Gao, Daming et al. (2010) Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell 18:147-59 |
| Ang, Xiaolu L; Harper, J Wade (2009) A road map of cellular protein homeostasis. Nat Chem Biol 5:9-11 |
| Ang, Xiaolu L; Seeburg, Daniel P; Sheng, Morgan et al. (2008) Regulation of postsynaptic RapGAP SPAR by Polo-like kinase 2 and the SCFbeta-TRCP ubiquitin ligase in hippocampal neurons. J Biol Chem 283:29424-32 |
