Tonic ATP-mediated growth suppression in peripheral nerve glia requires arrestin-PP2 and is evaded in NF1

被引:8
作者
Coover, Robert A. [1 ]
Healy, Tabitha E. [1 ]
Guo, Li [1 ]
Chaney, Katherine E. [1 ]
Hennigan, Robert F. [1 ]
Thomson, Craig S. [1 ]
Aschbacher-Smith, Lindsey E. [1 ]
Jankowski, Michael P. [2 ,3 ]
Ratner, Nancy [1 ]
机构
[1] Cincinnati Childrens Hosp, Div Expt Hematol & Canc Biol, 3333 Burnet Ave,ML 7017, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp, Div Pain Management, Dept Anesthesia, Cincinnati, OH 45229 USA
[3] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45229 USA
来源
ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2018年 / 6卷
关键词
Glia; Schwann; PP2A; AKT; Purinergic; Neurofibromatosis; P2Y2; Arrestin; ATP; SCHWANN-CELL PROLIFERATION; WALLERIAN DEGENERATION; BETA-ARRESTINS; NEURAL CREST; RECEPTOR; ACTIVATION; NEUROFIBROMATOSIS; ADENOSINE; PLEXIFORM; PATHWAY;
D O I
10.1186/s40478-018-0635-9
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Normal Schwann cells (SCs) are quiescent in adult nerves, when ATP is released from the nerve in an activity dependent manner. We find that suppressing nerve activity in adult nerves causes SC to enter the cell cycle. In vitro, ATP activates the SC G-protein coupled receptor (GPCR) P2Y2. Downstream of P2Y2, -arrestin-mediated signaling results in PP2-mediated de-phosphorylation of AKT, and PP2 activity is required for SC growth suppression. NF1 deficient SC show reduced growth suppression by ATP, and are resistant to the effects of -arrestin-mediated signaling, including PP2-mediated de-phosphorylation of AKT. In patients with the disorder Neurofibromatosis type 1, NF1 mutant SCs proliferate and form SC tumors called neurofibromas. Elevating ATP levels in vivo reduced neurofibroma cell proliferation. Thus, the low proliferation characteristic of differentiated adult peripheral nerve may require ongoing, nerve activity-dependent, ATP. Additionally, we identify a mechanism through which NF1 SCs may evade growth suppression in nerve tumors.
引用
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页数:15
相关论文
共 94 条
[1]   Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation [J].
Anastasaki, Corina ;
Gutmann, David H. .
HUMAN MOLECULAR GENETICS, 2014, 23 (25) :6712-6721
[2]   Immunity, inflammation and cancer: a leading role for adenosine [J].
Antonioli, Luca ;
Blandizzi, Corrado ;
Pacher, Pal ;
Hasko, Gyoergy .
NATURE REVIEWS CANCER, 2013, 13 (12) :842-857
[3]   The protooncogene Ski Schwann cell proliferation controls and myelination [J].
Atanasoski, S ;
Notterpek, L ;
Lee, HY ;
Castagner, F ;
Young, P ;
Ehrengruber, MU ;
Meijer, D ;
Sommer, L ;
Stavnezer, E ;
Colmenares, C ;
Suter, U .
NEURON, 2004, 43 (04) :499-511
[4]   The P2Y2 nucleotide receptor interacts with αv integrins to activate Go and induce cell migration [J].
Bagchi, S ;
Liao, ZJ ;
Gonzalez, FA ;
Chorna, NE ;
Seye, CI ;
Weisman, GA ;
Erb, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (47) :39050-39057
[5]  
Beaulieu JM, 2008, CELL, V135, P39, DOI 10.1016/j.cell.2007.11.041
[6]   An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior [J].
Beaulieu, JM ;
Sotnikova, TD ;
Marion, S ;
Lefkowitz, RJ ;
Gainetdinov, RR ;
Caron, MG .
CELL, 2005, 122 (02) :261-273
[7]   A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling [J].
Beautrait, Alexandre ;
Paradis, Justine S. ;
Zimmerman, Brandon ;
Giubilaro, Jenna ;
Nikolajev, Ljiljana ;
Armando, Sylvain ;
Kobayashi, Hiroyuki ;
Yamani, Lama ;
Namkung, Yoon ;
Heydenreich, Franziska M. ;
Khoury, Etienne ;
Audet, Martin ;
Roux, Philippe P. ;
Veprintsev, Dmitry B. ;
Laporte, Stephane A. ;
Bouvier, Michel .
NATURE COMMUNICATIONS, 2017, 8
[8]   Purinergic regulation of the immune system [J].
Cekic, Caglar ;
Linden, Joel .
NATURE REVIEWS IMMUNOLOGY, 2016, 16 (03) :177-192
[9]  
Chen SC, 2015, INT J CLIN EXP MED, V8, P13203
[10]   Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons [J].
Chen, Yong ;
Zhang, Xiaofei ;
Wang, Congying ;
Li, GuangWen ;
Gu, Yanping ;
Huang, Li-Yen Mae .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (43) :16773-16778