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.

磷酸化是一种可逆的翻译后修饰，由磷酸化酶和去磷酸化酶调节以介导重要的细胞事件。由PTPN11编码的 Src 同源性 2 蛋白酪氨酸磷酸酶 2 (SHP2)是蛋白质酪氨酸磷酸酶家族中第一个鉴定的致癌蛋白。作为汇聚节点，SHP2 参与多个级联信号通路，包括 Ras-Raf-MEK-ERK、PI3K-AKT、JAK-STAT 和 PD-1/PD-L1 通路。特别是，基于底物特异性的 SHP2 在各种生物学环境中的双刃剑作用显着增加了不同 SHP2 相关疾病的效应复杂性。有证据表明，通过与相关途径中的其他突变合作，SHP2 的失调有助于不同癌症的发病机制，使 SHP2 成为癌症治疗的有希望的治疗靶点。SHP2 可以在不同疾病中充当致癌因子或肿瘤抑制因子，而SHP2保守的催化去磷酸化机制和独特的变构调控机制都为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，基于 SHP2 激活剂和蛋白水解靶向嵌合体 (PROTAC) 的降解剂也显示出治疗前景。在这篇综述中，我们全面总结了SHP2在生理和致癌途径中的整体结构、调控机制、双刃剑作用以及临床试验中的SHP2抑制剂。还简要讨论了 SHP2 激活剂和降解剂。本综述旨在深入了解 SHP2 的生物学作用，并突出靶向 SHP2 的治疗潜力。