Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

被引：193

作者：

Bunda, Severa ^{[1
]}

Burrell, Kelly ^{[2
]}

Heir, Pardeep ^{[1
]}

Zeng, Lifan ^{[3
]}

Alamsahebpour, Amir ^{[2
]}

Kano, Yoshihito ^{[1
,4
]}

Raught, Brian ^{[5
]}

Zhang, Zhong-Yin ^{[3
]}

Zadeh, Gelareh ^{[2
]}

Ohh, Michael ^{[1
,4
]}

机构：

[1] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[2] Univ Hlth Network, Brain Tumour Res Ctr, Hosp Sick Children, Toronto, ON M5G 1L7, Canada

[3] Indiana Univ, Dept Biochem & Mol Biol, Sch Med, Indianapolis, IN 46202 USA

[4] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[5] Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

加拿大健康研究院;

关键词：

PROTEIN-TYROSINE-PHOSPHATASE; PTPN11; MUTATIONS; SIGNAL-TRANSDUCTION; NOONAN-SYNDROME; INITIATING CELLS; MOUSE MODEL; SHP2; ACTIVATION; LEUKEMIA; GROWTH;

D O I：

10.1038/ncomms9859

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：

07 ; 0710 ; 09 ;

摘要：

Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously 'undruggable' oncogenic or hyperactive Ras.

引用

页数：12

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