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PLoS Biol. 2017 Jul 18;15(7):e2002457. doi: 10.1371/journal.pbio.2002457. eCollection 2017 Jul.

Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain.

Author information

1
Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Jefferson Hospital for Neuroscience, Philadelphia, Pennsylvania, United States of America.
2
Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi City, Gunma, Japan.
3
Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
4
Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, United States of America.
5
School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
6
Department of Cell Biology and Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, United States of America.

Abstract

Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function.

PMID:
28719605
PMCID:
PMC5515392
DOI:
10.1371/journal.pbio.2002457
[Indexed for MEDLINE]
Free PMC Article

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