Mills J, Laurent Charest D, Lam F, Beyreuther K, Ida N, Pelech S L, Reiner P B
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
J Neurosci. 1997 Dec 15;17(24):9415-22. doi: 10.1523/JNEUROSCI.17-24-09415.1997.
Catabolic processing of the amyloid precursor protein (APP) is subject to regulatory control by protein kinases. We hypothesized that this regulation involves sequential activation of the enzymes mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK). In the present investigation, we provide evidence that MEK is critically involved in regulating APP processing by both nerve growth factor and phorbol esters. Western blot analysis of the soluble N-terminal APP derivative APPs demonstrated that the synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of both APPs production and ERK activation in PC12 cells. Moreover, PD 98059 inhibited phorbol ester stimulation of APPs production and activation of ERK in both human embryonic kidney cells and cortical neurons. Furthermore, overexpression of a kinase-inactive MEK mutant inhibited phorbol ester stimulation of APP secretion and activation of ERK in human embryonic kidney cell lines. Most important, PD 98059 antagonized phorbol ester-mediated inhibition of Abeta secretion from cells overexpressing human APP695 carrying the "Swedish mutation." Taken together, these data indicate that MEK and ERK may be critically involved in protein kinase C and nerve growth factor regulation of APP processing. The mitogen-activated protein kinase cascade may provide a novel target for altering catabolic processing of APP.
淀粉样前体蛋白（APP）的分解代谢过程受蛋白激酶的调控。我们推测这种调控涉及丝裂原活化蛋白激酶激酶（MEK）和细胞外信号调节蛋白激酶（ERK）的顺序激活。在本研究中，我们提供证据表明，MEK在神经生长因子和佛波酯对APP加工的调控中起关键作用。对可溶性N端APP衍生物APPs的蛋白质印迹分析表明，合成的MEK抑制剂PD 98059可拮抗神经生长因子对PC12细胞中APPs产生和ERK激活的刺激作用。此外，PD 98059可抑制佛波酯对人胚肾细胞和皮质神经元中APPs产生及ERK激活的刺激作用。此外，激酶失活的MEK突变体的过表达可抑制佛波酯对人胚肾细胞系中APP分泌及ERK激活的刺激作用。最重要的是，PD 98059可拮抗佛波酯介导的对携带“瑞典突变”的人APP695过表达细胞中β淀粉样蛋白分泌的抑制作用。综上所述，这些数据表明，MEK和ERK可能在蛋白激酶C和神经生长因子对APP加工的调控中起关键作用。丝裂原活化蛋白激酶级联反应可能为改变APP的分解代谢过程提供一个新的靶点。
