Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2

被引：50

作者：

Chen, Chuan ^{[1
]}

Cao, Mengmeng ^{[1
]}

Zhu, Siyu ^{[1
]}

Wang, Cuicui ^{[1
]}

Liang, Fan ^{[1
]}

Yan, Leilei ^{[1
]}

Luo, Duqiang ^{[1
]}

机构：

[1] Hebei Univ, Minist Educ, Key Lab Med Chem & Mol Diag, Coll Life Sci, Baoding 071002, Hebei, Peoples R China

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

中国国家自然科学基金;

关键词：

BREAST-CANCER; KINASE-ACTIVITY; ACTIVATION; GAB1; RAS; SRC; PTPN11; FAMILY; EXPRESSION; PAXILLIN;

D O I：

10.1038/srep17626

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF-induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2-dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases.

引用

页数：13

共 58 条

[1]

Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop [J].