IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways
IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways
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DOI：
10.1074/jbc.m611183200
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发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Iverfeldt, Kerstin
中科院分区：
文献类型：
--
作者：
Adlerz, Linda;Holback, Sofia;Iverfeldt, Kerstin
哺乳动物淀粉样前体蛋白(APP)家族由APP和类淀粉样蛋白1和2(APLP1和APLP2)组成。神经毒性淀粉样多肽(Ass)来源于APP，APP是该蛋白家族中与阿尔茨海默病有关的唯一成员。然而，这三个同源蛋白被认为是以相似的方式加工的，并且具有基本的和重叠的功能。因此，在开发旨在减少Ass产生的治疗药物时，考虑APP样蛋白对加工和功能的影响也是重要的。胰岛素和胰岛素样生长因子-1(IGF-1)已被证明可以调节APP的处理和大脑中Ass的水平。在本研究中，我们发现在SH-SY5Y神经母细胞瘤细胞中，IGF-1促进内源性APP的α-分泌酶处理，并增加APLP1和APLP2的胞外脱落。我们还使用磷脂酰肌醇3-激酶和丝裂原活化蛋白激酶(MAPK)的特异性抑制剂，研究了IGF-1诱导的不同信号通路的作用。我们的结果表明，磷脂酰肌醇3-激酶参与APP和APLP1的胞外脱落，而不参与APLP2的胞外脱落，而MAPK只参与APLP1的胞外脱落。
The mammalian amyloid precursor protein (APP) protein family consists of the APP and the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). The neurotoxic amyloid ss-peptide (A ss) originates from APP, which is the only member of this protein family implicated in Alzheimer disease. However, the three homologous proteins have been proposed to be processed in similar ways and to have essential and overlapping functions. Therefore, it is also important to take into account the effects on the processing and function of the APP- like proteins in the development of therapeutic drugs aimed at decreasing the production of A ss. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of A ss in the brain. In the present study, we show that IGF-1 increases alpha-secretase processing of endogenous APP and also increases ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells. We also investigated the role of different IGF-1-induced signaling pathways, using specific inhibitors for phosphatidylinositol 3- kinase and mitogenactivated protein kinase (MAPK). Our results indicate that phosphatidylinositol 3-kinase is involved in ectodomain shedding of APP and APLP1, but not APLP2, and that MAPK is involved only in the ectodomain shedding of APLP1.