期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 52, 页码 18343-18354出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011060
关键词
PTPN2; KRAS; ERK; tyrosine phosphatase; plasma membrane; cell proliferation; cell signaling; GTPase Kras (KRAS); extracellular-signal-regulated kinase (ERK); tyrosine-protein phosphatase (tyrosine phosphatase)
资金
- Natural Science Foundation of China [81530006, 81870112, 81970134, 81770171]
- Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research Grant [2019CXJQ01]
- Samuel Waxman Cancer Research Foundation
- Innovative research team of high-level local universities in Shanghai
RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.
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