Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation.
The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.
Shalin
Sara C
SC
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Hernandez
Caterina M
CM
Dougherty
Michele K
MK
Morrison
Deborah K
DK
Sweatt
J David
JD
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001245:Association Learning / Q000502:physiology; D001362:Avoidance Learning / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D013826:Theta Rhythm
D000318:Adrenergic beta-Agonists; D010703:Phorbol Esters; D005576:Colforsin; C008874:phorbol-12,13-diacetate; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol