The C-terminal Kinase and ERK-binding Domains of Drosophila S6KII (RSK) Are Required for Phosphorylation of the Protein and Modulation of Circadian Behavior

Abstract

Background: S6KII (RSK) kinase is important for neuronal plasticity and behavior. Results: Using genetic approaches, we identified functional S6KII domains relevant for circadian behavior. Conclusion: ERK binding to S6KII and activation of its C-terminal kinase modulate circadian period whereas the N-terminal kinase is dispensable for circadian function. Significance: This is the first in vivo structure/function analysis of S6KII (RSK) in the context of behavior.

Drosophila RSK Influences the Pace of the Circadian Clock by Negative Regulation of Protein Kinase Shaggy Activity

“…In this way, RSK proteins mediate ERK signals, but they can also down-regulate ERK by feed-back inhibition. The model of sequential activation was challenged by the finding that Drosophila RSK is functional without catalytic activity of the NTKD in the circadian clock ( Tangredi et al, 2012 ).…”

“…In Drosophila , RSK acts as a negative regulator of ERK during eye development ( Kim et al, 2006 ) and at the larval neuromuscular junction, where it is involved in anterograde axonal transport, synapse formation, and synaptic transmission ( Fischer et al, 2009 ; Beck et al, 2015 ). Adult rsk - mutant flies show defects in olfactory, operant and spatial learning as well as shortened circadian periodicity ( Putz et al, 2004 ; Neuser et al, 2008 ; Akten et al, 2009 ; Tangredi et al, 2012 ). The observed behavioral deficits do not correlate with obvious structural brain abnormalities.…”

Loss of the Coffin-Lowry syndrome associated geneRSK2alters ERK activity, synaptic function and axonal transport inDrosophilamotoneurons

“…Binding of ERK is essential for RSK function in eye and wing development and for circadian behavior, and it stimulates activation of the C-terminal kinase domain by phosphorylation. In contrast to biochemical studies with vertebrate RSK proteins, subsequent activation of the N-terminal kinase domain as the effector kinase for phosphorylation of substrate proteins is dispensable, at least for these processes ( Kim et al, 2006 ; Tangredi et al, 2012 ). Based on genetic studies using different combinations of loss- and gain-of-function mutations, it was concluded that in the case of the developing Drosophila eye, RSK acts as a cytoplasmic anchor for ERK to regulate nuclear entry and thereby ERK-dependent transcription ( Kim et al, 2006 ).…”

“…The conservation of all phosphorylation sites in all RSK proteins from different species suggests a common activation mechanism. However, recent studies in flies also suggested N-terminal kinase domain-independent functions of RSK ( Kim et al, 2006 ; Tangredi et al, 2012 ). In addition to its function as a downstream effector of MAPK signaling, RSK acts as a localization determinant of ERK and can negatively feed back to prevent hyperactivation of the MAPK pathway ( Romeo et al, 2012 ).…”

“…Distinct deficits in different behavioral paradigms, such as spatial learning, long-term spatial memory and consolidation of fear memory in mice ( Poirier et al, 2007 ; Morice et al, 2013 ) and in olfactory, operant and spatial learning in flies, were observed ( Putz et al, 2004 ; Neuser et al, 2008 ). Drosophila RSK is also required in clock neurons to maintain normal circadian periodicity ( Akten et al, 2009 ; Tangredi et al, 2012 ). No gross alterations in brain structure of RSK2 mutants are evident, although a decrease in differentiation of cortical radial progenitors into neurons was observed in mice, which indicated a function of RSK2 in neurogenesis ( Dugani et al, 2010 ).…”