PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells.
PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells.
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PTPN2 调节 KRAS 的激活，并在 KRAS 驱动的癌细胞的增殖和存活中发挥关键作用
DOI：
10.1074/jbc.ra119.011060
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发表时间：
2020-12-25
期刊：
影响因子：
--
通讯作者：
Ren R
中科院分区：
文献类型：
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作者：
Huang Z;Liu M;Li D;Tan Y;Zhang R;Xia Z;Wang P;Jiao B;Liu P;Ren R
RAS基因是人类癌症中最常见的突变基因，在肿瘤的发生、发展和耐药性中起着关键作用。确定阻断RAS信号传导的靶点对于开发RAS相关癌症的治疗方法至关重要。由于RAS转运到质膜（PM）是其有效的信号转导所必需的，我们设计了一个高含量的筛选试验，以寻找调控KRAS膜缔合的基因。我们发现酪氨酸磷酸酶PTPN 2调节KRAS的质膜定位。PTPN2的敲除降低了KRAS依赖性癌细胞的增殖并促进了凋亡，但在KRAS非依赖性细胞中没有。PTPN2负性调节KRAS的酪氨酸磷酸化，进而影响KRAS的活化及其下游信号传导。因此，TCGA数据库的分析表明PTPN 2的高表达与KRAS突变胰腺癌患者的不良预后显著相关。这些结果表明，PTPN2是KRAS的关键调节因子，并可能成为KRAS驱动的癌症治疗的新靶点。
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.