Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity

Zexi Hu; Xiaobo Wan; Rui Hao; Heng Zhang; Li Li; Lin Li; Qiang Xie; Peng Wang; Yibo Gao; She Chen; Min Wei; Zhidong Luan; Aiqun Zhang; Niu Huang; Liang Chen

doi:10.1371/journal.pone.0123623

Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity

PLoS One. 2015 Apr 8;10(4):e0123623. doi: 10.1371/journal.pone.0123623. eCollection 2015.

Authors

Zexi Hu¹, Xiaobo Wan², Rui Hao³, Heng Zhang⁴, Li Li², Lin Li², Qiang Xie⁵, Peng Wang⁶, Yibo Gao⁷, She Chen², Min Wei³, Zhidong Luan⁸, Aiqun Zhang⁹, Niu Huang², Liang Chen¹⁰

Affiliations

¹ College of Life Sciences, Beijing Normal University, Beijing, 100875, China; National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
² National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
³ BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
⁴ The Central Hospital of Lishui City, Zhejiang, 323000 China.
⁵ Fuzhou Pulmonary Hospital of Fujian, Fujian, 350008, China.
⁶ Beijing Ditan Hospital, Beijing, 100015, China.
⁷ Department of Thoracic Surgery, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, 100021, China.
⁸ Liaoning Medical University, Jinzhou, Liaoning, 121001, China.
⁹ The General Hospital of People's Liberation Army (301 Hospital), Fuxing Road, Beijing, 100853, China.
¹⁰ Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing, 102206, China.

Abstract

Amplification, overexpression, and somatic mutation of the HER2 gene have been reported to play a critical role in tumorigenesis of various cancers. The HER2 H878Y mutation was recently reported in 11% of hepatocellular carcinoma (HCC) patients. However, its functional impact on the HER2 protein and its role in tumorigenesis has not been determined. Here, we show that HER2 H878Y is a gain-of-function mutation. Y878 represents a phosphorylation site, and phospho-Y878 interacts with R898 residue to stabilize the active conformation of HER2, thereby enhancing its kinase activity. H878Y mutant is transforming and the transformed cells are sensitive to HER2 kinase inhibitors. Thus, our study reveals the following novel mechanism underlying the tumorigenic function of the HER2 H878Y mutation: the introduction of a tyrosine residue into the kinase activation loop via mutagenesis modulates the conformation of the kinase, thereby enhancing its activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amino Acid Substitution
Animals
Carcinogenesis / genetics
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Humans
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Mice
Molecular Sequence Data
NIH 3T3 Cells
Phosphorylation
Protein Processing, Post-Translational*
Quinolines / pharmacology
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*
Signal Transduction
Tyrosine / genetics
Tyrosine / metabolism*

Substances

Quinolines
Tyrosine
ERBB2 protein, human
Receptor, ErbB-2
neratinib

Grants and funding

Funding was provided by the Chinese Ministry of Science and Technology grant 2011CB812401 to LC, National Natural Science Foundation of China grant 81472606 to LC, National Science and Technology Major Project for Infectious Diseases of China 2012ZX10002-017 to AZ (http://www.most.gov.cn/eng/). BeiGene (Beijing) Co., Ltd. provided support in the form of salaries for authors RH and MW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.