SECRETED BETA-AMYLOID PRECURSOR PROTEIN STIMULATES MITOGEN-ACTIVATED PROTEIN-KINASE AND ENHANCES TAU-PHOSPHORYLATION
SECRETED BETA-AMYLOID PRECURSOR PROTEIN STIMULATES MITOGEN-ACTIVATED PROTEIN-KINASE AND ENHANCES TAU-PHOSPHORYLATION
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DOI：
10.1073/pnas.91.15.7104
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发表时间：
1994-07-19
影响因子：
11.1
通讯作者：
KOSIK, KS
中科院分区：
文献类型：
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作者：
GREENBERG, SM;KOO, EH;KOSIK, KS
与细胞生长相关的生物学效应以及在阿尔茨海默病发病机制中的作用已被归因于β-淀粉样前体蛋白（β-APP）。然而，关于介导这些效应的细胞内级联反应知之甚少。我们报告说，分泌形式的β-APP有力地刺激丝裂原活化蛋白激酶（MAPK）。将PC-12嗜铬细胞瘤细胞短暂暴露于转染的中国仓鼠卵巢细胞分泌的β-APP，刺激43-kDa形式的MAPK超过10倍。在PC 12衍生的细胞系中诱导ras的显性抑制形式阻止了分泌的β-APP对MAPK的刺激，证明了对p21（ras）的作用的依赖性。由于微管相关蛋白tau在阿尔茨海默病中过度磷酸化，我们寻求并发现与β-APP诱导的MAPK刺激相关的tau磷酸化的2倍增强。在ras显性抑制细胞系中，β-APP未能增强tau的磷酸化。这里提供的数据提供了分泌的β-APP和tau的磷酸化状态之间的联系。
Biological effects related to cell growth, as well as a role in the pathogenesis of Alzheimer disease, have been ascribed to the beta-amyloid precursor protein (beta-APP). Little is known, however, about the intracellular cascades that mediate these effects. We report that the secreted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to beta-APP secreted by transfected Chinese hamster ovary cells stimulated the 43-kDa form of MAPK by >10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21(ras). Because the microtubule-associated protein tau is hyperphosphorylated in Alzheimer disease, we sought and found a 2-fold enhancement in tau phosphorylation associated with the beta-APP-induced MAPK stimulation. In the ras dominant inhibitory cell line, beta-APP failed to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau.