Dephosphorylation of Tyrosine 393 in Argonaute 2 by Protein Tyrosine Phosphatase 1B Regulates Gene Silencing in Oncogenic RAS-Induced Senescence

Yang, M., Haase, A. D., Huang, F. K., Coulis, G., Rivera, K. D., Dickinson, B. C., Chang, C. J., Pappin, D. J., Neubert, T. A., Hannon, G. J., Boivin, B., Tonks, N. K. (August 2014) Dephosphorylation of Tyrosine 393 in Argonaute 2 by Protein Tyrosine Phosphatase 1B Regulates Gene Silencing in Oncogenic RAS-Induced Senescence. Mol Cell, 55 (5). pp. 782-790. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/25175024
DOI: 10.1016/j.molcel.2014.07.018

Abstract

Oncogenic RAS (H-RASV12) induces premature senescence in primary cells by triggering production of reactive oxygen species (ROS), but the molecular role of ROS in senescence remains elusive. We investigated whether inhibition of protein tyrosine phosphatases by ROS contributed to H-RASV12-induced senescence. We identified protein tyrosine phosphatase 1B (PTP1B) as a major target of H-RASV12-induced ROS. Inactivation of PTP1B was necessary and sufficient to induce premature senescence in H-RASV12-expressing IMR90 fibroblasts. We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B. Phosphorylation of AGO2 at Tyr 393 inhibited loading with microRNAs (miRNAs) and thus miRNA-mediated gene silencing, which counteracted the function of H-RASV12-induced oncogenic miRNAs. Overall, our data illustrate that premature senescence in H-RASV12-transformed primary cells is a consequence of oxidative inactivation of PTP1B and inhibition of miRNA-mediated gene silencing.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > argonaute proteins
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene silencing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
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 > Cancer Genetics
CSHL Cancer Center Program > Signal Transduction
CSHL labs > Hannon lab
CSHL labs > Pappin lab
CSHL labs > Tonks lab
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
CSHL Cancer Center Shared Resources > Proteomics Service
Depositing User: Matt Covey
Date: 27 August 2014
Date Deposited: 08 Sep 2014 16:41
Last Modified: 30 Oct 2015 14:42
PMCID: PMC4159145
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30732

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