Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells
Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells
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DOI：
10.1111/j.1471-4159.2005.03440.x
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发表时间：
2005-11-01
影响因子：
4.7
通讯作者：
Iverfeldt, K
中科院分区：
文献类型：
--
作者：
Holback, S;Adlerz, L;Iverfeldt, K
淀粉样前体蛋白(APP)属于保守基因家族，也包括APLP1和APLP2。我们先前已经证明，APP蛋白家族的所有成员在维甲酸(RA)诱导的SH-SY5Y神经母细胞瘤细胞的神经元分化中都上调。在这里，我们证明RA也影响APLP2和APP的处理，表现为sAPLP2和SAPPα的脱落增加，以及APP胞内域(AICD)水平的升高。脑源性神经营养因子(BDNF)可诱导APP启动子活性，RA可诱导神经母细胞瘤细胞酪氨酸激酶受体B(TrkB)表达。我们表明，APLP2和APP对RA的反应中脱落的增加不是通过TrkB受体介导的。而BDNF与RA联合应用则进一步增加APP的表达。此外，BDNF还增加了sAPLP2和sAPPα的分泌以及AICD的水平。相反，膜结合APP C末端片段C99的水平显著降低。我们的结果表明，RA和BDNF将APP的处理转移到α-分泌酶途径。此外，我们还发现维甲酸和脑源性神经营养因子调节APLP1的N-连接糖基化。
The amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. We have previously shown that all members of the APP protein family are up-regulated upon retinoic acid (RA)-induced neuronal differentiation of SH-SY5Y neuroblastoma cells. Here, we demonstrate that RA also affects the processing of APLP2 and APP, as shown by increased shedding of both sAPLP2 and sAPP alpha, as well as elevated levels of the APP intracellular domains (AICDs). Brain-derived neurotrophic factor (BDNF) has been reported to induce APP promoter activity and RA induces expression of the tyrosine kinase receptor B (TrkB) in neuroblastoma cells. We show that the increase in shedding of both APLP2 and APP in response to RA is not mediated through the TrkB receptor. However, BDNF concomitant with RA increased the expression of APP even further. In addition, the secretion of sAPLP2 and sAPP alpha as well as the levels of AICDs were increased in response to BDNF. In contrast, the levels of membrane-bound APP C-terminal fragment C99 significantly decreased. Our results suggest that RA and BDNF shifts APP processing towards the alpha-secretase pathway. In addition, we show that RA and BDNF regulate N-linked glycosylation of APLP1.