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Title: Phosphorylation of human TRM9L integrates multiple stress-signaling pathways for tumor growth suppression.

Authors: Gu, Chen; Ramos, Jillian; Begley, Ulrike; Dedon, Peter C; Fu, Dragony; Begley, Thomas J

Published In Sci Adv, (2018 Jul)

Abstract: The human transfer RNA methyltransferase 9-like gene (TRM9L, also known as KIAA1456) encodes a negative regulator of tumor growth that is frequently silenced in many forms of cancer. While TRM9L can inhibit tumor cell growth in vivo, the molecular mechanisms underlying the tumor inhibition activity of TRM9L are unknown. We show that oxidative stress induces the rapid and dose-dependent phosphorylation of TRM9L within an intrinsically disordered domain that is necessary for tumor growth suppression. Multiple serine residues are hyperphosphorylated in response to oxidative stress. Using a chemical genetic approach, we identified a key serine residue in TRM9L that undergoes hyperphosphorylation downstream of the oxidative stress-activated MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase)-RSK (ribosomal protein S6 kinase) signaling cascade. Moreover, we found that phosphorylated TRM9L interacts with the 14-3-3 family of proteins, providing a link between oxidative stress and downstream cellular events involved in cell cycle control and proliferation. Mutation of the serine residues required for TRM9L hyperphosphorylation and 14-3-3 binding abolished the tumor inhibition activity of TRM9L. Our results uncover TRM9L as a key downstream effector of the ERK signaling pathway and elucidate a phospho-signaling regulatory mechanism underlying the tumor inhibition activity of TRM9L.

PubMed ID: 30009260 Exiting the NIEHS site

MeSH Terms: 14-3-3 Proteins/metabolism; Amino Acid Sequence; Cell Line, Tumor; Cell Proliferation/drug effects; Extracellular Signal-Regulated MAP Kinases/metabolism; Humans; Hydrogen Peroxide/pharmacology; MAP Kinase Kinase Kinases/metabolism; Neoplasms/metabolism; Neoplasms/pathology; Oxidative Stress*/drug effects; Phosphopeptides/analysis; Phosphorylation/drug effects; Protein Kinase Inhibitors/pharmacology; Ribosomal Protein S6 Kinases/metabolism; Signal Transduction*/drug effects; Tandem Mass Spectrometry; tRNA Methyltransferases/metabolism*

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