PTPIP51 通过促进 PTEN 介导的 EGFR 降解来抑制非小细胞肺癌。

PTPIP51 inhibits non-small-cell lung cancer by promoting PTEN-mediated EGFR degradation.

机构信息

Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology of the Ministry of Public Health, Beijing, China; Institute of Health Service and Transfusion Medicine, Beijing, 100850, P. R. China.

Department of Thoracic Surgery II, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, China; Department of Thoracic Surgery, Shanghai General Hospital, Shanghai, China.

出版信息

Life Sci. 2022 May 15;297:120293. doi: 10.1016/j.lfs.2021.120293. Epub 2022 Feb 28.

DOI:10.1016/j.lfs.2021.120293

PMID:35240162

Abstract

Protein tyrosine phosphatase interacting protein 51 (PTPIP51) interacts with two non-receptor tyrosine phosphatases and induces apoptosis. In the present study, we showed that PTPIP51 is downregulated in non-small cell lung cancer (NSCLC), and its elevated expression correlates with improved outcomes. PTPIP51 overexpression in NSCLC cells significantly inhibits downstream epidermal growth factor receptor (EGFR) signaling in PI3K/Akt, RAS/RAF/ERK, and JAK/STAT3 pathways. The efficacy of the EGFR inhibitor gefitinib improves in combination with PTPIP51 to accelerate apoptosis and inhibit NSCLC growth in vivo and in vitro. Here, we demonstrated that PTPIP51 interacts with phosphatase and tensin homolog (PTEN) to form a PTPIP51-PTEN-CK2 complex, which induces phosphorylation of the C-tail region of PTEN (p-PTEN Thr382 and Thr383). This subsequently induces ubiquitylation of EGFR and its degradation via lysosomes. Therefore, PTPIP51 acts as a tumor suppressor in NSCLC by inducing PTEN phosphorylation and by promoting EGFR degradation.

摘要

蛋白酪氨酸磷酸酶相互作用蛋白 51（PTPIP51）与两种非受体酪氨酸磷酸酶相互作用，并诱导细胞凋亡。在本研究中，我们表明 PTPIP51 在非小细胞肺癌（NSCLC）中下调，其表达水平升高与改善预后相关。在 NSCLC 细胞中过表达 PTPIP51 可显著抑制下游表皮生长因子受体（EGFR）信号通路中的 PI3K/Akt、RAS/RAF/ERK 和 JAK/STAT3 通路。与 PTPIP51 联合使用，EGFR 抑制剂吉非替尼的疗效得到改善，可加速细胞凋亡，并抑制体内外 NSCLC 的生长。在这里，我们证明 PTPIP51 与磷酸酶和张力蛋白同源物（PTEN）相互作用形成 PTPIP51-PTEN-CK2 复合物，诱导 PTEN C 尾区域（p-PTEN Thr382 和 Thr383）的磷酸化。这随后通过溶酶体诱导 EGFR 的泛素化及其降解。因此，PTPIP51 通过诱导 PTEN 磷酸化和促进 EGFR 降解，在 NSCLC 中发挥肿瘤抑制作用。