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.
Highlights
Modification of protein function by phosphorylation controls many aspects of cellular function and signaling [1]
We show that the interaction between EphB2—which occurs upon receptor activation by its ligand ephrin-B—and the N-methyl-D-aspartate receptor (NMDAR) depends on extracellular phosphorylation of EphB2
The extracellular domain of the ephrin-B binding sites (EphBs) receptor consists of a globular domain required for ephrin-B binding, a cysteine-rich domain, and 2 fibronectin type III (FN3) repeat domains of unknown function (Fig 1C)
Summary
Modification of protein function by phosphorylation controls many aspects of cellular function and signaling [1]. Protein kinases that mediate the selective phosphorylation of extracellular serine, threonine, and tyrosine amino acids have been identified. Extracellular phosphorylation of serine and threonine residues can be mediated by Fam20C [4, 5] and phosphorylation of extracellular tyrosine residues can be accomplished by vertebrate lonesome kinase (VLK or PKDCC), an essential gene expressed throughout the body, including the nervous system [6, 7]. Of particular importance are interactions that maintain the proper localization of Nmethyl-D-aspartate receptors (NMDARs), glutamate receptors that are essential for synaptic plasticity and development [8]. The synaptic localization, function, and signaling of NMDARs are regulated by intracellular scaffolding proteins such as PSD-95 [9], extracellular interacting proteins such as neuroligin-1 [10], and the EphB receptor tyrosine kinases (RTKs) [11]. While the mechanisms mediating intracellular interactions are well understood, the mechanisms mediating extracellular protein—protein interactions are not
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