Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP

Content Provider	Scilit
Author	Poddar, Ranjana Rajagopal, Sathyanarayanan Shuttleworth, C. William Paul, Surojit
Copyright Year	2016
Description	Journal: Journal of Biological Chemistry Excessive release of $Zn^{2+}$ in the brain is implicated in the progression of acute brain injuries. Although several signaling cascades have been reported to be involved in $Zn^{2+}$-induced neurotoxicity, a potential contribution of tyrosine phosphatases in this process has not been well explored. Here we show that exposure to high concentrations of $Zn^{2+}$ led to a progressive increase in phosphorylation of the striatal-enriched phosphatase (STEP), a component of the excitotoxic-signaling pathway that plays a role in neuroprotection. $Zn^{2+}$-mediated phosphorylation of $STEP_{61}$ at multiple sites (hyperphosphorylation) was induced by the up-regulation of brain-derived neurotropic factor (BDNF), tropomyosin receptor kinase (Trk) signaling, and activation of cAMP-dependent PKA (protein kinase A). Mutational studies further show that differential phosphorylation of $STEP_{61}$ at the PKA sites, Ser-160 and Ser-221 regulates the affinity of $STEP_{61}$ toward its substrates. Consistent with these findings we also show that BDNF/Trk/PKA mediated signaling is required for $Zn^{2+}$-induced phosphorylation of extracellular regulated kinase 2 (ERK2), a substrate of STEP that is involved in $Zn^{2+}$-dependent neurotoxicity. The strong correlation between the temporal profile of $STEP_{61}$ hyperphosphorylation and ERK2 phosphorylation indicates that loss of function of $STEP_{61}$ through phosphorylation is necessary for maintaining sustained ERK2 phosphorylation. This interpretation is further supported by the findings that deletion of the STEP gene led to a rapid and sustained increase in ERK2 phosphorylation within minutes of exposure to $Zn^{2+}$. The study provides further insight into the mechanisms of regulation of $STEP_{61}$ and also offers a molecular basis for the $Zn^{2+}$-induced sustained activation of ERK2.
Related Links	http://www.jbc.org/content/291/2/813.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705400/pdf http://www.jbc.org/article/S002192582036213X/pdf
Ending Page	825
Page Count	13
Starting Page	813
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.m115.663468
Journal	Journal of Biological Chemistry
Issue Number	2
Volume Number	291
Language	English
Publisher	Elsevier BV
Publisher Date	2016-01-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Brain-derived Neurotrophic Factor (bdnf) Extracellular-signal-regulated Kinase (erk) Protein Phosphorylation Tropomyosin Receptor Kinase Tyrosine-protein Phosphatase (tyrosine Phosphatase)
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology