Journal
NEURON
Volume 56, Issue 3, Pages 456-471Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2007.08.020
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Funding
- NICHD NIH HHS [R01 HD021502-21A1, R01 HD021502] Funding Source: Medline
- NINDS NIH HHS [R01 NS020147, NS20147] Funding Source: Medline
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Synaptic activity induces changes in the number of dendritic spines. Here, we report a pathway of regulated endocytosis triggered by arcadlin, a protocadherin induced by electroconvulsive and other excitatory stimuli in hippocampal neurons. The homophilic binding of extracellular arcadlin domains activates TAO2 beta, a splice variant of the thousand and one amino acid protein kinase 2, cloned here by virtue of its binding to the arcadlin intracellular domain. TAO2 beta is a MAPKKK that activates the MEK3 MAPKK, which phosphorylates the p38 MAPK Activation of p38 feeds-back on TAO2 beta, phosphorylating a key serine required for triggering endocytosis of N-cadherin at the synapse. Arcadlin knockout increases the number of dendritic spines, and the phenotype is rescued by siRNA knockdown of N-cadherin. This pathway of regulated endocytosis of N-cadherin via protocadherin/TAO2 beta/ MEK3/p38 provides a molecular mechanism for transducing neuronal activity into changes in synaptic morphologies.
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