Shalin Sara C, Hernandez Caterina M, Dougherty Michele K, Morrison Deborah K, Sweatt J David
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Neuron. 2006 Jun 1;50(5):765-79. doi: 10.1016/j.neuron.2006.04.029.
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.
ERK/MAP激酶级联反应对于长期记忆形成和突触可塑性至关重要，众多上游信号汇聚于ERK激活。尽管存在这种信号汇聚，但神经元通常会对不同刺激激活适当的生物学反应。支架蛋白代表了一种实现信号分隔和ERK依赖性过程适当靶向的机制。我们报告称，Ras激酶抑制因子（KSR1）在海马体中发挥生化作用，以构建ERK级联反应的组件，特别是当ERK的膜部分通过PKC依赖性途径而非cAMP/PKA依赖性途径被激活时，特异性调节该级联反应。KSR1依赖性信号的特异性还延伸至ERK的特定下游靶点。在行为和生理方面，我们发现KSR1的缺失会导致联想学习和theta爆发刺激诱导的长时程增强（LTP）出现缺陷。我们的报告为KSR1在控制神经系统内激酶激活方面的内源性支架作用提供了新的见解。
