Synaptic clustering of PSD-95 is regulated by c-Abl through tyrosine phosphorylation.
The c-Abl tyrosine kinase is present in mouse brain synapses, but its precise synaptic function is unknown. We found that c-Abl levels in the rat hippocampus increase postnatally, with expression peaking at the first postnatal week. In 14 d in vitro hippocampal neuron cultures, c-Abl localizes primarily to the postsynaptic compartment, in which it colocalizes with the postsynaptic scaffold protein postsynaptic density protein-95 (PSD-95) in apposition to presynaptic markers. c-Abl associates with PSD-95, and chemical or genetic inhibition of c-Abl kinase activity reduces PSD-95 tyrosine phosphorylation, leading to reduced PSD-95 clustering and reduced synapses in treated neurons. c-Abl can phosphorylate PSD-95 on tyrosine 533, and mutation of this residue reduces the ability of PSD-95 to cluster at postsynaptic sites. Our results indicate that c-Abl regulates synapse formation by mediating tyrosine phosphorylation and clustering of PSD-95.
Perez de Arce
Karen
K
Laboratorio de Señalización Celular, Departmento de Biología Celular y Molecular, Pontificia Universidad Católica de Chile, 8331010 Santiago, Chile.
de Arce
Karen Perez
KP
Varela-Nallar
Lorena
L
Farias
Olivia
O
Cifuentes
Alejandra
A
Bull
Paulina
P
Couch
Brian A
BA
Koleske
Anthony J
AJ
Inestrosa
Nibaldo C
NC
Alvarez
Alejandra R
AR
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D014443:Tyrosine / Q000378:metabolism*
D015415:Biomarkers; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl