Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth

doi:10.1038/onc.2016.246

	Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth
	Piao, H-I 3,6; Wang, Y.1,3; Hong, X.2,4; Wang, J.1; Yin, Y.3; Zhang, Y.5; Zhou, Y.6; Liang, Z.6; Zhang, L.6; Li, G.5
刊名	ONCOGENE
	2017-02-09
卷号	36 期号:6 页码:756-765
ISSN号	0950-9232
DOI	10.1038/onc.2016.246
文献子类	Article
英文摘要	Rheb is a Ras family GTPase, which binds to and activates mammalian target of rapamycin complex 1 (mTORC1) when GTP loaded. Recently, cancer genome sequencing efforts have identified recurrent Rheb Tyr35Asn mutations in kidney and endometrial carcinoma. Here we show that Rheb-Y35N causes not only constitutive mTORC1 activation, but sustained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent manner, contributing to intrinsic resistance to rapamycin. Rheb-Y35N transforms NIH3T3 cells, resulting in aggressive tumor formation in xenograft nude mice, which could be suppressed by combined treatment with rapamycin and an extracellular signal-regulated kinase (ERK) inhibitor. Furthermore, Rheb-Y35N inhibits AMPKa activation in response to nutrient depletion or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), leading to attenuated phosphorylation of BRAF-S729 and retained mitogen-activated protein kinase (MAPK) activation. Finally, we demonstrate that Rheb-WT can bind AMPK to facilitate AMPK activation, whereas Rheb-Y35N competitively binds AMPK, impairing AMPK phosphorylation. In summary, our findings indicate that Rheb-Y35N is a dominantly active tumor driver that activates both mTORC1 and MAPK to promote tumor growth, suggesting a combination of mTORC1 and MAPK inhibitors may be of therapeutic value in patients whose cancers sustain this mutation.
WOS关键词	TSC2 GAP ACTIVITY ; RHEB GTPASE ; CELL-PROLIFERATION ; MAMMALIAN TARGET ; MTOR ; ACTIVATION ; KINASE ; MUTATIONS ; AMPK ; IDENTIFICATION
WOS研究方向	Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000394168200003
内容类型	期刊论文
源URL	[http://cas-ir.dicp.ac.cn/handle/321008/169590]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
通讯作者	Kwiatkowski, D. J.; Liu, Y.
作者单位	1.Dalian Univ, Sch Life Sci, Dalian, Peoples R China 2.Peking Union Med Coll, Beijing, Peoples R China 3.Chinese Acad Sci, Sci Res Ctr Translat Med, Dalian Inst Chem Phys, Dept Biotechnol, 457 Zhongshan Rd,Rm 114, Dalian 116023, Liaoning, Peoples R China 4.Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Gen Surg, Beijing, Peoples R China 5.Chinese Acad Sci, Dalian Inst Chem Phys, Dept Biotechnol, State Key Lab Mol React Dynam,Lab Mol Modelling &, Dalian, Peoples R China 6.Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China 7.Harvard Med Sch, Brigham & Women Hosp, Div Pulm & Crit Care Med, Boston, MA USA
推荐引用方式 GB/T 7714	Piao, H-I,Wang, Y.,Hong, X.,et al. Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth[J]. ONCOGENE,2017,36(6):756-765.
APA	Piao, H-I.,Wang, Y..,Hong, X..,Wang, J..,Yin, Y..,...&Liu, Y..(2017).Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth.ONCOGENE,36(6),756-765.
MLA	Piao, H-I,et al."Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth".ONCOGENE 36.6(2017):756-765.