Journal
JOURNAL OF CELL BIOLOGY
Volume 170, Issue 3, Pages 429-441Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200409157
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Funding
- NIGMS NIH HHS [R01 GM030179-24A1, R01 GM030179-25, R01 GM030179] Funding Source: Medline
- NIMH NIH HHS [R01 MH064801, MH64801] Funding Source: Medline
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The Ras/MAPK pathway regulates synaptic plasticity and cell survival in neurons of the central nervous system. Here, we show that KRas, but not HRas, acutely translocates from the plasma membrane (PM) to the Golgi complex and early/recycling endosomes in response to neuronal activity. Translocation is reversible and mediated by the polybasic-prenyl membrane targeting motif of KRas. We provide evidence that KRas translocation occurs through sequestration of the polybasic-prenyl motif by Ca2+/calmodulin (Ca2+/CaM) and subsequent release of KRas from the PM, in a process reminiscent of GDP dissociation inhibitor-mediated membrane recycling of Rab and Rho GTPases. KRas translocation was accompanied by partial intracellular redistribution of its activity. We conclude that the polybasic-prenyl motif acts as a Ca2+/CaM-regulated molecular switch that controls PM concentration of KRas and redistributes its activity to internal sites. Our data thus define a novel signaling mechanism that differentially regulates KRas and HRas localization and activity in neurons.
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