MAG induces regulated intramembrane proteolysis of the p75 neurotrophin receptor to inhibit neurite outgrowth.
The three known inhibitors of axonal regeneration present in myelin--MAG, Nogo, and OMgp--all interact with the same receptor complex to effect inhibition via protein kinase C (PKC)-dependent activation of the small GTPase Rho. The transducing component of this receptor complex is the p75 neurotrophin receptor. Here we show that MAG binding to cerebellar neurons induces alpha- and then gamma-secretase proteolytic cleavage of p75, in a protein kinase C-dependent manner, and that this cleavage is necessary for both activation of Rho and inhibition of neurite outgrowth.
Domeniconi
Marco
M
Biology Department, Hunter College, City University of New York, 695 Park Avenue, New York, New York 10021, USA.
Zampieri
Niccolò
N
Spencer
Tim
T
Hilaire
Melissa
M
Mellado
Wilfredo
W
Chao
Moses V
MV
Filbin
Marie T
MT
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D010450:Endopeptidases; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018992:Myelin-Associated Glycoprotein; D009842:Oligopeptides; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; D020741:rho GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; C078846:epoxomicin