Gandy S, Greengard P
Department of Neurology and Neuroscience, Cornell University Medical College, New York, NY 10021.
Biochimie. 1994;76(3-4):300-3. doi: 10.1016/0300-9084(94)90162-7.
The relative utilization of alternative processing pathways for APP can be regulated by the activation state of certain protein phosphorylation signal transduction pathways. For example, activation of protein kinase C (PKC), or inactivation of protein phosphatases 1 and 2A, leads to a relative increase in utilization of the nonamyloidogenic, 'alpha-secretase' cleavage pathway for APP processing at the expense of other pathways. The molecular and cellular basis for this regulatory event is unknown. The possible mechanisms of regulated APP cleavage include (either singly or in combination): 1) substrate (ie APP) activation; 2) substrate redistribution; 3) enzyme (ie alpha-secretase) activation; or 4) enzyme redistribution. APP is a phosphoprotein; however, recent evidence from studies of the metabolism of mutant APP molecules suggests that changes in the APP cytoplasmic tail phosphorylation state may not be necessary for the phosphorylation-dependent activation of 'alpha-secretase' cleavage. Further, indirect immunofluorescent studies of the subcellular distribution of APP in the absence or presence of phorbol esters (PKC activators) fail to disclose obvious phorbol-induced redistribution of APP immunoreactivity. Taken together, current data suggest that major candidate phosphorylation-state sensitive targets relevant to the molecular basis of PKC-activated processing (or 'regulated cleavage') of APP include the APP ectodomain as well as secretase enzymes and/or other components of the APP trafficking/processing apparatus. Progress in distinguishing among these possibilities is discussed.
APP 替代加工途径的相对利用情况可由某些蛋白质磷酸化信号转导途径的激活状态来调节。例如，蛋白激酶 C（PKC）的激活，或蛋白磷酸酶 1 和 2A 的失活，会导致 APP 加工过程中以其他途径为代价，非淀粉样生成的“α-分泌酶”切割途径的利用相对增加。这一调节事件的分子和细胞基础尚不清楚。APP 切割调控的可能机制包括（单独或组合）：1）底物（即 APP）激活；2）底物重新分布；3）酶（即α-分泌酶）激活；或 4）酶重新分布。APP 是一种磷蛋白；然而，最近对突变 APP 分子代谢的研究证据表明，APP 胞质尾磷酸化状态的变化对于“α-分泌酶”切割的磷酸化依赖性激活可能并非必要。此外，在有无佛波酯（PKC 激活剂）的情况下对 APP 亚细胞分布进行的间接免疫荧光研究未能揭示明显的佛波酯诱导的 APP 免疫反应性重新分布。综上所述，目前的数据表明，与 PKC 激活的 APP 加工（或“调控切割”）分子基础相关的主要候选磷酸化状态敏感靶点包括 APP 胞外结构域以及分泌酶和/或 APP 转运/加工装置的其他成分。本文讨论了在区分这些可能性方面取得的进展。
