Oncotarget

Research Papers:

Shp2 SUMOylation promotes ERK activation and hepatocellular carcinoma development

Rong Deng _, Xian Zhao, YingYing Qu, Cheng Chen, Changhong Zhu, Hailong Zhang, Haihua Yuan, Hui Jin, Xin Liu, Yanli Wang, Qin Chen, Jian Huang and Jianxiu Yu

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Oncotarget. 2015; 6:9355-9369. https://doi.org/10.18632/oncotarget.3323

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Abstract

Rong Deng1, Xian Zhao1, YingYing Qu1, Cheng Chen1, Changhong Zhu1, Hailong Zhang1, Haihua Yuan1, Hui Jin1, Xin Liu1, Yanli Wang1, Qin Chen1, Jian Huang1, Jianxiu Yu1,2,3

1Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

2State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

3Institute of Oncology & Department of Oncology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Correspondence to:

Jianxiu Yu, e-mail: Jianxiu.Yu@gmail.com

Keywords: Shp2, SUMOylation, Gab1, ERK activation, hepatocellular carcinoma (HCC)

Received: October 25, 2014     Accepted: February 09, 2015     Published: March 18, 2015

ABSTRACT

Shp2, an ubiquitously expressed protein tyrosine phosphatase, is essential for regulation of Ras/ERK signaling pathway and tumorigenesis. Here we report that Shp2 is modified by SUMO1 at lysine residue 590 (K590) in its C-terminus, which is reduced by SUMO1-specific protease SENP1. Analysis of wild-type Shp2 and SUMOylation-defective Shp2K590R mutant reveals that SUMOylation of Shp2 promotes EGF-stimulated ERK signaling pathway and increases anchorage-independent cell growth and xenografted tumor growth of hepatocellular carcinoma (HCC) cell lines. Furthermore, we find that mutant Shp2K590R reduces its binding with the scaffolding protein Gab1, and consistent with this, knockdown of SENP1 increased the interaction between Shp2 and Gab1. More surprisingly, we show that human Shp2 (hShp2) and mouse Shp2 (mShp2) have differential effects on ERK activation as a result of different SUMOylation level, which is due to the event of K590 at hShp2 substituted by R594 at mShp2. In summary, our data demonstrate that SUMOylation of Shp2 promotes ERK activation via facilitating the formation of Shp2-Gab1 complex and thereby accelerates HCC cell and tumor growth, which presents a novel regulatory mechanism underlying Shp2 in regulation of HCC development.


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