PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

Zhangsen Huang; Mingzhu Liu; Donghe Li; Yun Tan; Ruihong Zhang; Zhizhou Xia; Peihong Wang; Bo Jiao; Ping Liu; Ruibao Ren

doi:10.1074/jbc.RA119.011060

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PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

Journal article

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Peer reviewed

PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

Zhangsen Huang, Mingzhu Liu, Donghe Li, Yun Tan, Ruihong Zhang, Zhizhou Xia, Peihong Wang, Bo Jiao, Ping Liu and Ruibao Ren

The Journal of biological chemistry, Vol.295(52), pp.18343-18354

12/25/2020

DOI: https://doi.org/10.1074/jbc.RA119.011060

PMID: 33122197

Abstract

Biomarkers, Tumor - genetics

Biomarkers, Tumor - metabolism

Cell Proliferation

Gene Expression Regulation, Neoplastic

Humans

Neoplasms - genetics

Neoplasms - metabolism

Neoplasms - pathology

Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics

Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism

Proto-Oncogene Proteins p21(ras) - genetics

Proto-Oncogene Proteins p21(ras) - metabolism

Tumor Cells, Cultured

Apoptosis

Mutation

Phosphorylation

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.

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

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Title: PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells
Creators: Zhangsen Huang - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Mingzhu Liu - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Donghe Li - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yun Tan - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ruihong Zhang - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zhizhou Xia - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Peihong Wang - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Bo Jiao - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ping Liu - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: liupingjize@126.com
Ruibao Ren - Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ren@brandeis.edu
Publication Details: The Journal of biological chemistry, Vol.295(52), pp.18343-18354
Identifiers: 9924014243801921
Academic Unit: Rosenstiel Basic Medical Sciences Research Center; Department of Biology
Language: English
Resource Type: Journal article

PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

Abstract

UN Sustainable Development Goals (SDGs)

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