School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100000, China.
School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
Pharmacol Ther. 2022 Feb;230:107966. doi: 10.1016/j.pharmthera.2021.107966. Epub 2021 Aug 14.
Phosphorylation is a reversible post-translational modification regulated by phosphorylase and dephosphorylase to mediate important cellular events. Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by PTPN11 is the first identified oncogenic protein in protein tyrosine phosphatases family. Serving as a convergent node, SHP2 is involved in multiple cascade signaling pathways including Ras-Raf-MEK-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 pathways. Especially, the double-edged roles of SHP2 based on the substrate specificity in various biological contexts dramatically increase the effect complexity in different SHP2-associated diseases. Evidences suggest that by collaborating with other mutations in associated pathways, dysregulation of SHP2 contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer treatment. SHP2 can either act as oncogenic factor or tumor suppressor in different diseases, and both the conserved catalytic dephosphorylation mechanism and the unique allosteric regulation mechanism of SHP2 provide opportunities for the development of SHP2 inhibitors and activators. To date, several small-molecule SHP2 inhibitors have advanced into clinical trials for mono- or combined therapy of cancers. Moreover, SHP2 activators and proteolysis-targeting chimera (PROTAC)-based degraders also display therapeutic promise. In this review, we comprehensively summarize the overall structures, regulation mechanisms, double-edged roles of SHP2 in both physiological and carcinogenic pathways, and SHP2 inhibitors in clinical trials. SHP2 activators and degraders are also briefly discussed. This review aims to provide in-depth understanding of the biological roles of SHP2 and highlight therapeutic potential of targeting SHP2.
磷酸化是一种受磷酸酶和去磷酸酶调节的可逆翻译后修饰，可介导重要的细胞事件。由 PTPN11 编码的含Src 同源结构域-2 的蛋白酪氨酸磷酸酶 2（SHP2）是蛋白酪氨酸磷酸酶家族中第一个被鉴定的致癌蛋白。作为一个汇聚节点，SHP2 参与了多个级联信号通路，包括 Ras-Raf-MEK-ERK、PI3K-AKT、JAK-STAT 和 PD-1/PD-L1 通路。特别是，基于不同生物背景下的底物特异性，SHP2 的双重作用极大地增加了不同 SHP2 相关疾病中的效应复杂性。有证据表明，通过与相关通路中的其他突变协同作用，SHP2 的失调导致不同癌症的发病机制，使 SHP2 成为癌症治疗的有前途的治疗靶点。SHP2 在不同疾病中可以作为致癌因子或肿瘤抑制因子发挥作用，SHP2 的保守催化去磷酸化机制和独特的变构调节机制为 SHP2 抑制剂和激活剂的开发提供了机会。迄今为止，几种小分子 SHP2 抑制剂已进入临床试验，用于癌症的单一或联合治疗。此外，SHP2 激活剂和基于蛋白水解靶向嵌合体（PROTAC）的降解剂也显示出治疗潜力。在这篇综述中，我们全面总结了 SHP2 的总体结构、调节机制、在生理和致癌通路中的双重作用以及临床试验中的 SHP2 抑制剂。简要讨论了 SHP2 激活剂和降解剂。这篇综述旨在深入了解 SHP2 的生物学作用，并强调靶向 SHP2 的治疗潜力。
