Plk2 Raps up Ras to subdue synapses

Abstract

We recently identified the activityinducible protein kinase Plk2 as a novel overseer of the balance between Ras and Rap small GTPases. Plk2 achieves a profound level of regulatory control by interacting with and phosphorylating at least four Ras and Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Combined, these actions result in synergistic suppression of Ras and hyperstimulation of Rap signaling. Perturbation of Plk2 function abolished homeostatic adaptation of synapses to enhanced activity and impaired behavioral adaptation in various learning tasks, indicating that this regulation was critical for maintaining appropriate Ras/Rap levels. These studies provide insights into the highly cooperative nature of Ras and Rap regulation in neurons. However, different GEF and GAP substrates of Plk2 also controlled specific aspects of dendritic spine morphology, illustrating the ability of individual GAPs/GEFs to assemble microdomains of Ras and Rap signaling that respond to different stimuli and couple to distinct output pathways.

Mammalian target of rapamycin complex 1 activation negatively regulates Polo-like kinase 2-mediated homeostatic compensation following neonatal seizures

“…2B). PLK2 mediates its compensatory functions in part through eliminating dendritic spines and attenuating AMPAR function through phosphorylation and degradation of the SPAR and PSD95 (22)(23)(24). We thus examined the expression of SPAR and PSD95 at 48-72 h following HS at P10 using immunocytochemistry and found that SPAR expression was significantly reduced in hippocampal pyramidal cell bodies and apical dendrites of CA1 neurons (88.62 ± 3.06% of control in stratum pyramidale, n = 6, P < 0.05; 84.93 ± 3.08% of control in stratum radiatum, n = 6, P < 0.05) ( Fig.…”

“…Among the known mediators, PLK2 is believed to play a pivotal role in homeostatic synaptic downscaling (22)(23)(24). In vitro neuronal cell and slice culture studies have shown an important role of PLK2 in homeostatic down-regulation of AMPAR function and intrinsic excitability in responses to chronic activity increases in hippocampal neurons (22).…”

“…The small GTPases Ras and Rap are molecular signaling switches critically involved in modulating synaptic AMPAR trafficking during long-term potentiation and longterm depression, and many forms of memory formation (24,42). Importantly, PLK2 has been shown to directly phosphorylate both Ras and Rap at synapses (24,43).…”

“…The small GTPases Ras and Rap are molecular signaling switches critically involved in modulating synaptic AMPAR trafficking during long-term potentiation and longterm depression, and many forms of memory formation (24,42). Importantly, PLK2 has been shown to directly phosphorylate both Ras and Rap at synapses (24,43). Indeed, HS-induced increases in PLK2 expression led to degradation of SPAR and associated PSD95 in hippocampal CA1 neurons, which may be because of degradation downstream of Ras/Rap signaling (23,44).…”

“…PLK2 is also critically involved in down-regulation of synaptic strength in response to prolonged increases in neuronal activity (22). Active PLK2 promotes the phosphorylation and degradation of SPAR, a postsynaptic Rap GAP (GTPase-activating protein) and PSD95, and thus mediates compensatory effects through down-regulating AMPAR function in response to elevated activity in vitro (22)(23)(24). Here we hypothesized that, in addition to previously documented Hebbian increases in synaptic function (7), PLK2-mediated homeostatic plasticity may provide endogenous protection against HS-induced neural overactivation in immature brain in vivo.…”