Surface phosphorylation by ecto-protein kinase C in brain neurons: a target for Alzheimer's beta-amyloid peptides.
The powerful regulatory machinery of protein phosphorylation operates in the extracellular environment of the brain. Enzymatic activity with the catalytic specificity of protein kinase C (PKC) was detected on the surface of brain neurons, where it can serve as a direct target for neurotrophic and neurotoxic substances that control neuronal development and cause neurodegeneration. This activity fulfilled all the criteria required of an ecto-protein kinase (ecto-PK). Detailed analysis of surface protein phosphorylation in cultured brain neurons using specific exogenous substrates (casein, histones, and myelin basic protein), inhibitors (PKC-pseudosubstrate 19-36; K252b) and antibodies (anti-PKC catalytic region M.Ab.1.9, antibodies to the carboxy-terminus of eight PKC isozymes) revealed several types of ecto-PK activity, among them ecto-PKs with catalytic specificity of the PKC isozymes zeta and delta. The activity of the neuronal ecto-PKC is constitutive and not stimulated by phorbol esters. the phosphorylation of a 12K/13K surface protein duplex by ecto-PKC-delta was found to be developmentally regulated, with peak activity occurring during the onset of neuritogenesis. Alzheimer's amyloid peptides beta 1-40 and beta 25-35 applied at neurotrophic concentrations stimulated the phosphorylation of endogenous substrates of ecto-PKC activity in brain neurons but inhibited specifically this surface phosphorylation activity with the same dose-response relationships that cause neurodegeneration. As may be expected from a relevant pathophysiological activity, beta-amyloid peptide 1-28 did not inhibit this surface phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hogan
M V
MV
CSI/IBR Center for Developmental Neuroscience, City University of New York at College of Staten Island 10314, USA.
Pawlowska
Z
Z
Yang
H A
HA
Kornecki
E
E
Ehrlich
Y H
YH
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000502:physiology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002642:Chick Embryo; D007527:Isoenzymes / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D010750:Phosphoproteins; D011494:Protein Kinases; C034454:ectoprotein kinase; D011493:Protein Kinase C