Tarr Philip E, Contursi Cristina, Roncarati Roberta, Noviello Cristiana, Ghersi Enrico, Scheinfeld Meir H, Zambrano Nicola, Russo Tommaso, D'Adamio Luciano
Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 1209, Bronx, NY 10461, USA.
Biochem Biophys Res Commun. 2002 Jul 12;295(2):324-9. doi: 10.1016/s0006-291x(02)00678-2.
The cytoplasmic tail of the beta-amyloid precursor protein (APP) contains a Y(682)ENPTY(687) sequence through which APP associates with phosphotyrosine binding (PTB) domain containing proteins in a tyrosine phosphorylation-independent manner. We have recently found that tyrosine phosphorylation of APP-Y(682) promotes docking of Shc proteins that modulate growth factor signaling to the ERK and PI3K/Akt pathways. We have also shown that APP is phosphorylated on Y(682) in cells that overexpress a constitutively active form of the tyrosine kinase abl. Here we present evidence that the nerve growth factor receptor TrkA may also promote phosphorylation of APP. Overexpression of TrkA, but not of mutated, kinase inactive TrkA resulted in tyrosine phosphorylation of APP. Site-directed mutagenesis studies showed that TrkA overexpression was associated with phosphorylation of APP-Y(682). Moreover, overexpression of TrkA also affected APP processing reducing the generation of the APP intracellular domain (AID). Thus, tyrosine phosphorylation of APP may functionally link APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival.
β-淀粉样前体蛋白（APP）的细胞质尾部包含一个Y(682)ENPTY(687)序列，APP通过该序列以酪氨酸磷酸化非依赖的方式与含磷酸酪氨酸结合（PTB）结构域的蛋白质相关联。我们最近发现，APP-Y(682)的酪氨酸磷酸化促进了Shc蛋白的对接，Shc蛋白可调节生长因子信号传导至ERK和PI3K/Akt途径。我们还表明，在过表达组成型活性酪氨酸激酶abl的细胞中，APP在Y(682)位点发生磷酸化。在此，我们提供证据表明神经生长因子受体TrkA也可能促进APP的磷酸化。TrkA的过表达而非突变的、激酶失活的TrkA导致APP的酪氨酸磷酸化。定点诱变研究表明，TrkA的过表达与APP-Y(682)的磷酸化相关。此外，TrkA的过表达还影响APP的加工过程，减少了APP细胞内结构域（AID）的产生。因此，APP的酪氨酸磷酸化可能在功能上连接APP加工和神经营养信号传导与细胞分化和存活相关的细胞内途径。
