Work

Induction of a Tumor-associated Activating Mutation in Protein Tyrosine Phosphatase Ptpn11 (Shp2) Enhances Mitochondrial Metabolism, Leading to Oxidative Stress and Senescence

Year: 2013

Type: article

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. Background: The pathogenic effects of tumor-associated activating mutations of Ptpn11 have not been well characterized. Results: Ptpn11 E76K/+ mouse embryonic fibroblasts display increased ROS levels, cellular senescence, and enhanced mitochondrial respiration upon induction of the mutation. Conclusion: Induction of the Ptpn11 E76K/+ mutation results in oxidative stress by enhancing mitochondrial metabolism. Significance: This study provides novel insights into the initial effects of Ptpn11 -activating mutations.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m113.462291

Authors: Hong Zheng, Shanhu Li, Peter Hsu, Cheng-Kui Qu

Institutions: Case Comprehensive Cancer Center, Case Western Reserve University

Language: English

Topic: Protein Tyrosine Phosphatases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430