title: Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence.
abstract: Activating mutations in Ptpn11 (Shp2), a protein tyrosine phosphatase involved in diverse cell signaling pathways, are associated with pediatric leukemias and solid tumors. However, the pathogenic effects of these mutations have not been fully characterized. Here, we report that induction of the Ptpn11(E76K/+) mutation, the most common and active Ptpn11 mutation found in leukemias and solid tumors, in primary mouse embryonic fibroblasts resulted in proliferative arrest and premature senescence. As a result, apoptosis was markedly increased. These cellular responses were accompanied and mediated by up-regulation of p53 and p21. Moreover, intracellular levels of reactive oxygen species (ROS), byproducts of mitochondrial oxidative phosphorylation, were elevated in Ptpn11(E76K/+) cells. Since Shp2 is also distributed to the mitochondria (in addition to the cytosol), the impact of the Ptpn11(E76K/+) mutation on mitochondrial function was analyzed. These analyses revealed that oxygen consumption of Ptpn11(E76K/+) cells and the respiratory function of Ptpn11(E76K/+) mitochondria were significantly increased. Furthermore, we found that phosphorylation of mitochondrial Stat3, one of the substrates of Shp2 phosphatase, was greatly decreased in the mutant cells with the activating mutation Ptpn11(E76K/+). This study provides novel insights into the initial effects of tumor-associated Ptpn11 mutations.
authors.affiliation: From the Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: From the Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Shanhu
authors.initials: S
authors.lastname: Li
authors.affiliation: From the Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Peter
authors.initials: P
authors.lastname: Hsu
authors.affiliation: From the Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106. Electronic address: cxq6@case.edu.
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016159:Tumor Suppressor Protein p53; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: Cell Signaling; Metabolism; Oxidative Stress; Phosphatase; Ptpn11 (Shp2); Senescence