Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases.
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 TAO2beta, 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. TAO2beta is a MAPKKK that activates the MEK3 MAPKK, which phosphorylates the p38 MAPK. Activation of p38 feeds-back on TAO2beta, 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/TAO2beta/MEK3/p38 provides a molecular mechanism for transducing neuronal activity into changes in synaptic morphologies.
Yasuda
Shin
S
Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
Tanaka
Hidekazu
H
Sugiura
Hiroko
H
Okamura
Ko
K
Sakaguchi
Taiki
T
Tran
Uyen
U
Takemiya
Takako
T
Mizoguchi
Akira
A
Yagita
Yoshiki
Y
Sakurai
Takeshi
T
De Robertis
E M
EM
Yamagata
Kanato
K
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004558:Electric Stimulation; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary / Q000235:genetics; D000091363:Protocadherins; D051381:Rats; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D015820:Cadherins; C120170:Pcdh8 protein, rat; D000091363:Protocadherins; D017346:Protein Serine-Threonine Kinases; C122016:Taok2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases