Format

Send to

Choose Destination
Mol Cell. 2014 Sep 4;55(5):782-90. doi: 10.1016/j.molcel.2014.07.018. Epub 2014 Aug 28.

Dephosphorylation of tyrosine 393 in argonaute 2 by protein tyrosine phosphatase 1B regulates gene silencing in oncogenic RAS-induced senescence.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11790, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute.
3
Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Langone School of Medicine, New York, NY 10016, USA.
4
Department of Biochemistry and Department of Medicine, Université de Montréal, Montréal, H3C 3J7 QC, Canada; Montreal Heart Institute, Montréal, H1T 1C8 QC, Canada.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
6
Howard Hughes Medical Institute; Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
7
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Biochemistry and Department of Medicine, Université de Montréal, Montréal, H3C 3J7 QC, Canada; Montreal Heart Institute, Montréal, H1T 1C8 QC, Canada. Electronic address: benoit.boivin@icm-mhi.org.
8
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: tonks@cshl.edu.

Abstract

Oncogenic RAS (H-RAS(V12)) 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-RAS(V12)-induced senescence. We identified protein tyrosine phosphatase 1B (PTP1B) as a major target of H-RAS(V12)-induced ROS. Inactivation of PTP1B was necessary and sufficient to induce premature senescence in H-RAS(V12)-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-RAS(V12)-induced oncogenic miRNAs. Overall, our data illustrate that premature senescence in H-RAS(V12)-transformed primary cells is a consequence of oxidative inactivation of PTP1B and inhibition of miRNA-mediated gene silencing.

PMID:
25175024
PMCID:
PMC4159145
DOI:
10.1016/j.molcel.2014.07.018
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center