H2S-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response

Krishnan, N., Fu, C., Pappin, D. J., Tonks, N. K. (2011) H2S-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Science Signaling, 4 (203). ISSN 19450877 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22169477
DOI: 10.1126/scisignal.2002329

Abstract

Although originally considered toxic, hydrogen sulfide (H 2S) has been implicated in mediating various biological processes. Nevertheless, its cellular targets and mode of action are not well understood. Protein tyrosine phosphatases (PTPs), which regulate numerous signal transduction pathways, use an essential cysteine residue at the active site, which is characterized by a low pK a and is susceptible to reversible oxidation. Here, we report that PTP1B was reversibly inactivated by H 2S, in vitro and in cells, through sulfhydration of the active-site cysteine residue. Unlike oxidized PTP1B, the sulfhydrated enzyme was preferentially reduced in vitro by thioredoxin, compared to glutathione or dithiothreitol. Sulfhydration of PTP1B in cells required the presence of cystathionine γ-lyase (CSE), a critical enzyme in H 2S production, and resulted in inhibition of phosphatase activity. Suppression of CSE decreased H 2S production and decreased the phosphorylation of tyrosine-619 in PERK [protein kinase-like endoplasmic reticulum (ER) kinase], thus reducing its activation in response to ER stress. PERK, which phosphorylates the eukaryotic translational initiation factor 2, leading to attenuation of protein translation, was a direct substrate of PTP1B. In addition, CSE knockdown led to activation of the nonreceptor tyrosine kinase SRC, previously shown to be mediated by PTP1B. These effects of suppressing H 2S production on the response to ER stress were abrogated by a small-molecule inhibitor of PTP1B. Together, these data define a signaling function for H 2S in inhibiting PTP1B activity and thereby promoting PERK activity during the response to ER stress.

Item Type: Paper
Uncontrolled Keywords: cystathionine gamma lyase cysteine dithiothreitol glutathione hydrogen sulfide initiation factor 2 protein tyrosine phosphatase 1B thioredoxin article controlled study endoplasmic reticulum stress enzyme active site enzyme activity enzyme inhibition enzyme substrate enzyme synthesis human human cell hydration in vitro study priority journal protein modification protein phosphorylation signal transduction
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Proteomics Service
CSHL Post Doctoral Fellows
CSHL labs > Tonks lab
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
Depositing User: Matt Covey
Date Deposited: 05 Feb 2013 21:40
Last Modified: 30 Oct 2015 14:30
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27187

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