Surface Phosphorylation by Ecto‐Protein Kinase C in Brain Neurons: A Target for Alzheimer's β‐Amyloid Peptides
Surface Phosphorylation by Ecto‐Protein Kinase C in Brain Neurons: A Target for Alzheimer's β‐Amyloid Peptides
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脑神经元中外蛋白激酶 C 的表面磷酸化：阿尔茨海默病 β-淀粉样肽的靶点
作者：
M. V. Hogan;Z. Pawłowska;Hui‐Ai Yang;E. Kornecki;Y. Ehrlich
翻译后摘要：蛋白磷酸化的强大的调节机制在脑的细胞外环境中运作。在脑神经元的表面上检测到具有蛋白激酶C（PKC）的催化特异性的酶活性，在那里它可以作为控制神经元发育和引起神经变性的神经营养和神经毒性物质的直接靶标。该活性符合胞外蛋白激酶（ecto-PK）要求的所有标准。使用特定外源性底物对培养脑神经元表面蛋白磷酸化的详细分析（酪蛋白、组蛋白和髓鞘碱性蛋白），抑制剂（PKC-假底物19 - 36; K252b）和抗体（抗PKC催化区M.Ab.1.9，8种PKC同工酶羧基端的抗体）显示了几种类型的体外PK活性，其中包括具有PKC同工酶β和δ的催化特异性的外PKs。神经元外PKC的活性是组成性的，不受佛波酯的刺激。发现由ecto-PKC-δ引起的12K/13K表面蛋白双链体的磷酸化受到发育调节，在轴突发生期间出现峰值活性。以神经营养浓度应用的阿尔茨海默氏淀粉样肽β 1 - 40和β 25 - 35刺激脑神经元中外PKC活性的内源性底物的磷酸化，但特异性地抑制这种表面磷酸化活性，其具有引起神经变性的相同剂量-反应关系。从相关的病理生理学活性可以预期，β-淀粉样肽1 - 28不抑制这种表面磷酸化。发现外蛋白激酶C介导的蛋白磷酸化作用是β淀粉样肽在其作用位点的靶标，即，在神经元细胞表面，开辟了一个新的研究方向，在分子事件的调查中发挥作用的病因学发育障碍和神经退行性疾病。
Abstract: 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 ectoprotein 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 ζ and δ. 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‐δ was found to be developmentally regulated, with peak activity occurring during the onset of neuritogenesis. Alzheimer's amyloid peptides β1–40 and β25–35 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, β‐amyloid peptide 1–28 did not inhibit this surface phosphorylation. The discovery that ecto‐PKC‐mediated protein phosphorylation serves as a target for β‐amyloid peptides at the very site they operate, i.e., at the neuronal cell surface, opens a new research direction in the investigation of molecular events that play a role in the etiology of developmental disabilities and neurodegenerative disorders.
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蛋白激酶 C 的结构域结构和磷酸化。
DOI：
--
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mochly-Rosen,D;KoshlandJr,DE
通讯作者：
KoshlandJr,DE
影响因子：
3.1
作者：
J. Knops;S. Gandy;P. Greengard;I. Lieberburg;S. Sinha
通讯作者：
J. Knops;S. Gandy;P. Greengard;I. Lieberburg;S. Sinha
通过胞外蛋白激酶/磷酸酶系统对人血小板表面蛋白进行磷酸化和去磷酸化。
DOI：
10.1016/0167-4889(91)90165-t
发表时间：
1991
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Naik,UP;Kornecki,E;Ehrlich,YH
通讯作者：
Ehrlich,YH
影响因子：
56.9
作者：
YANKNER, BA;DUFFY, LK;KIRSCHNER, DA
通讯作者：
KIRSCHNER, DA
影响因子：
56.9
作者：
ASCH, AS;LIU, I;PERNAMBUCO, M
通讯作者：
PERNAMBUCO, M