PMID- 26574547
OWN - NLM
STAT- MEDLINE
DCOM- 20160516
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 291
IP  - 2
DP  - 2016 Jan 8
TI  - Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of 
      the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED 
      ERK MAPK ACTIVATION.
PG  - 813-25
LID - 10.1074/jbc.M115.663468 [doi]
AB  - 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 STEP61 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 STEP61 at the PKA sites, Ser-160 and 
      Ser-221 regulates the affinity of STEP61 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 STEP61 hyperphosphorylation and ERK2 
      phosphorylation indicates that loss of function of STEP61 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 STEP61 and also offers a molecular basis for the Zn(2+)-induced sustained 
      activation of ERK2.
CI  - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Poddar, Ranjana
AU  - Poddar R
AD  - From the Departments of Neurology and.
FAU - Rajagopal, Sathyanarayanan
AU  - Rajagopal S
AD  - From the Departments of Neurology and.
FAU - Shuttleworth, C William
AU  - Shuttleworth CW
AD  - Neurosciences University of New Mexico Health Sciences Center, Albuquerque, New 
      Mexico 87131.
FAU - Paul, Surojit
AU  - Paul S
AD  - From the Departments of Neurology and Neurosciences University of New Mexico 
      Health Sciences Center, Albuquerque, New Mexico 87131 spaul@salud.unm.edu.
LA  - eng
GR  - R01 NS083914/NS/NINDS NIH HHS/United States
GR  - UL1 TR001449/TR/NCATS NIH HHS/United States
GR  - P20 GM109089/GM/NIGMS NIH HHS/United States
GR  - R01 NS051288/NS/NINDS NIH HHS/United States
GR  - R01 NS059962/NS/NINDS NIH HHS/United States
GR  - NS051288/NS/NINDS NIH HHS/United States
GR  - NS083914/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20151116
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 17885-08-4 (Phosphoserine)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
RN  - EC 3.1.3.48 (Ptpn5 protein, mouse)
RN  - J41CSQ7QDS (Zinc)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Calcium/pharmacology
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Enzyme Activation/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Female
MH  - HeLa Cells
MH  - Humans
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neurons/drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Phosphoserine/metabolism
MH  - Protein Tyrosine Phosphatases, Non-Receptor/*metabolism
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Zinc/*pharmacology
PMC - PMC4705400
OTO - NOTNLM
OT  - STEP
OT  - brain-derived neurotrophic factor (BDNF)
OT  - extracellular-signal-regulated kinase (ERK)
OT  - protein phosphorylation
OT  - tropomyosin receptor kinase
OT  - tyrosine-protein phosphatase (tyrosine phosphatase)
OT  - zinc
EDAT- 2015/11/18 06:00
MHDA- 2016/05/18 06:00
PMCR- 2017/01/08
CRDT- 2015/11/18 06:00
PHST- 2015/05/06 00:00 [received]
PHST- 2015/11/18 06:00 [entrez]
PHST- 2015/11/18 06:00 [pubmed]
PHST- 2016/05/18 06:00 [medline]
PHST- 2017/01/08 00:00 [pmc-release]
AID - S0021-9258(20)36213-X [pii]
AID - M115.663468 [pii]
AID - 10.1074/jbc.M115.663468 [doi]
PST - ppublish
SO  - J Biol Chem. 2016 Jan 8;291(2):813-25. doi: 10.1074/jbc.M115.663468. Epub 2015 
      Nov 16.