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Autophagy. 2017;13(11):1969-1980. doi: 10.1080/15548627.2017.1371393. Epub 2017 Oct 4.

Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy.

Chen LL1,2,3, Wang YB4, Song JX1,2, Deng WK4, Lu JH5, Ma LL4, Yang CB1,2, Li M1,2, Xue Y4.

Author information

1
a School of Chinese Medicine, Hong Kong Baptist University , Hong Kong SAR , China.
2
b Mr. and Mrs. Ko Chi Ming Centre for Parkinson Disease Research, Hong Kong Baptist University , Hong Kong SAR , China.
3
c Institute of Brain Science and Disease, Qingdao University , Qingdao , Shandong , China.
4
d Key Laboratory of Molecular Biophysics, Ministry of Education , College of Life Science and Technology, and the Collaborative Innovation Center for Biomedical Engineering, Huazhong University of Science and Technology , Wuhan , Hubei , China.
5
e State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau SAR , China.

Abstract

Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signaling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B). To identify key regulators, namely, protein kinases, we developed a novel network-based algorithm of in silico Kinome Activity Profiling (iKAP) to computationally infer potentially important protein kinases from phosphorylation networks. Using this algorithm, we observed that Cory or Cory B potentially regulated several kinases. We predicted and validated that Cory, but not Cory B, downregulated a well-documented autophagy kinase, RPS6KB1/p70S6K (ribosomal protein S6 kinase, polypeptide 1). We also discovered 2 kinases, MAP2K2/MEK2 (mitogen-activated protein kinase kinase 2) and PLK1 (polo-like kinase 1), to be potentially upregulated by Cory, whereas the siRNA-mediated knockdown of Map2k2 and Plk1 significantly inhibited Cory-induced autophagy. Furthermore, Cory promoted the clearance of Alzheimer disease-associated APP (amyloid β [A4] precursor protein) and Parkinson disease-associated SNCA/α-synuclein (synuclein, α) by enhancing autophagy, and these effects were dramatically diminished by the inhibition of the kinase activities of MAP2K2 and PLK1. As a whole, our study not only developed a powerful method for the identification of important regulators from the phosphoproteomic data but also identified the important role of MAP2K2 and PLK1 in neuronal autophagy.

KEYWORDS:

autophagy; corynoxine; kinase activity; phosphoproteome; phosphorylation; protein kinase

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