Structure, Function, and Pathogenesis of SHP2 in Developmental Disorders and Tumorigenesis
Structure, Function, and Pathogenesis of SHP2 in Developmental Disorders and Tumorigenesis
复制标题
SHP2在发育障碍和肿瘤发生中的结构、功能和发病机制
DOI：
10.2174/1568009614666140717105001
复制
发表时间：
2014-01-01
影响因子：
3
通讯作者：
Tzeng, Chi-Meng
中科院分区：
文献类型：
--
作者：
Huang, Wen-Qing;Lin, Qing;Tzeng, Chi-Meng
含SRC同源2(SH2)的蛋白酪氨酸磷酸酶2(SHP2)由人PTPN11基因编码，是一种普遍表达的蛋白酪氨酸磷酸酶(PTP)，由两个串联的Src同源(SH2)结构域(N-SH2和C-SH2)、一个PTP催化结构域和一个带有酪氨酸磷酸化位点的C-末端组成。它通过PTP催化活性依赖和非依赖的方式调节各种信号通路，在多种细胞过程中发挥重要作用。SHP2的致病突变和异常表达导致SHP2功能障碍，导致多条信号通路失调，从而导致不同的人类疾病。PTPN11的种系和体细胞突变与Noonan综合征(NS)、豹综合征(LS)、血液系统恶性肿瘤以及几种实体瘤有关。在这篇报告中，我们概述了SHP2的结构和功能的现有知识，并进一步讨论了SHP2在人类疾病中的分子和致病机制，特别是肿瘤的发生。此外，我们总结说，SHP2本身可能是预防和治疗癌症的潜在药物靶点。正在进行的SHP2特异性抑制剂的研究和开发将增强这一潜力。
Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the human PTPN11 gene, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that consists of two tandem Src homology (SH2) domains (N-SH2 and C-SH2), a PTP catalytic domain, and a C-terminal tail with tyrosyl phosphorylation sites. It plays critical roles in numerous cellular processes through the regulation of various signaling pathways in PTP catalytic activity-dependent and -independent manners. Dysfunction of SHP2 resulting from pathogenic mutations and aberrant expression leads to the dysregulation of multiple signaling pathways, thus contributing to different human disorders. Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors. In this report, we provide an overview of the current knowledge of the structure and function of SHP2, and further discuss the molecular and pathogenic mechanism of SHP2 in human diseases, with a special focus on tumorigenesis. Furthermore, we summarize that SHP2 might itself represent a potential drug target for cancer prevention and treatment. Ongoing research and development of SHP2-specific inhibitors would enhance this potential.