Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
Prion. 2012 Nov-Dec;6(5):477-88. doi: 10.4161/pri.21914. Epub 2012 Aug 23.
Cellular prion protein (PrP (C) ) has attracted considerable attention for its role in transmissible spongiform encephalopathies (TSEs). In spite of being a point of intense research effort critical questions still remain regarding the physiological function of PrP (C) and how these functions may change with the conversion of the protein into the infectious and pathological conformation (PrP (Sc) ). While emerging evidence suggests PrP (C/Sc) are involved in signal transduction there is little consensus on the signaling pathways associated with the normal and diseased states. The purported involvement of PrP (C) in signal transduction, and the association of TSEs with neural pathology, makes kinome analysis of human neurons an interesting and appropriate model to characterize patterns of signal transduction following activation of PrP (C) by two commonly employed experimental ligands; antibody-induced dimerization by 6H4 and the amino acids 106-126 PrP peptide fragment (PrP 106-126). Analysis of the induced kinome responses reveals distinct patterns of signaling activity following each treatment. Specifically, stimulation of human neurons with the 6H4 antibody results in alterations in mitogen activated protein kinase (MAPK) signaling pathways while the 106-126 peptide activates growth factor related signaling pathways including vascular endothelial growth factor (VEGF) signaling and the phosphoinositide-3 kinase (PI3K) pathway. These pathways were validated through independent functional assays. Collectively these results indicate that stimulation of PrP (C) with distinct ligands, even within the same cell type, results in unique patterns of signaling. While this investigation highlights the apparent functional versatility of PrP (C) as a signaling molecule and may offer insight into cellular mechanisms of TSE pathology it also emphasizes the potential dangers associated with attributing activation of specific intracellular events to particular receptors through artificial models of receptor activation.
细胞朊蛋白（PrP（C））因其在传染性海绵状脑病（TSE）中的作用而引起了相当大的关注。尽管它是一个研究的重点，但关于 PrP（C）的生理功能以及这些功能如何随着蛋白质转化为传染性和病理构象（PrP（Sc））而改变，仍然存在一些关键问题。虽然有新的证据表明 PrP（C/Sc）参与信号转导，但与正常和患病状态相关的信号通路仍没有共识。PrP（C）参与信号转导的假定，以及 TSE 与神经病理学的关联，使得人类神经元的激酶组分析成为一个有趣且合适的模型，可以描述通过两种常用的实验配体激活 PrP（C）后的信号转导模式；6H4 诱导的抗体二聚化和 PrP 肽片段 106-126（PrP 106-126）的氨基酸。对诱导的激酶组反应的分析揭示了每种处理后的信号活性的不同模式。具体而言，用 6H4 抗体刺激人类神经元会导致丝裂原激活蛋白激酶（MAPK）信号通路的改变，而 106-126 肽则激活与生长因子相关的信号通路，包括血管内皮生长因子（VEGF）信号通路和磷酸肌醇-3 激酶（PI3K）通路。这些通路通过独立的功能测定得到验证。这些结果表明，即使在相同的细胞类型中，用不同的配体刺激 PrP（C）也会导致独特的信号模式。虽然这项研究强调了 PrP（C）作为信号分子的明显功能多样性，并可能为 TSE 病理学的细胞机制提供一些见解，但它也强调了通过人工受体激活模型将特定细胞内事件的激活归因于特定受体的潜在危险。
