title: Dephosphorylation of tyrosine 393 in argonaute 2 by protein tyrosine phosphatase 1B regulates gene silencing in oncogenic RAS-induced senescence.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11790, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute.
authors.forename: Astrid D
authors.initials: AD
authors.lastname: Haase
authors.affiliation: 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.
authors.forename: Fang-Ke
authors.initials: FK
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Department of Medicine, Université de Montréal, Montréal, H3C 3J7 QC, Canada; Montreal Heart Institute, Montréal, H1T 1C8 QC, Canada.
authors.forename: Gérald
authors.initials: G
authors.lastname: Coulis
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Rivera
authors.affiliation: Howard Hughes Medical Institute; Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Dickinson
authors.affiliation: Howard Hughes Medical Institute; Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Pappin
authors.affiliation: 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.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hannon
authors.affiliation: 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Boivin
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: tonks@cshl.edu.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Tonks
mesh_terms: D060565:Argonaute Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D014443:Tyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D018631:ras Proteins