title: Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity.
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.
authors: College of Life Sciences, Beijing Normal University, Beijing, 100875, China; National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: Zexi
authors: Z
authors: Hu
authors: National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: Xiaobo
authors: X
authors: Wan
authors: BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
authors: Rui
authors: R
authors: Hao
authors: The Central Hospital of Lishui City, Zhejiang, 323000 China.
authors: Heng
authors: H
authors: Zhang
authors: National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: Li
authors: L
authors: Li
authors: National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: Lin
authors: L
authors: Li
authors: Fuzhou Pulmonary Hospital of Fujian, Fujian, 350008, China.
authors: Qiang
authors: Q
authors: Xie
authors: Beijing Ditan Hospital, Beijing, 100015, China.
authors: Peng
authors: P
authors: Wang
authors: Department of Thoracic Surgery, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, 100021, China.
authors: Yibo
authors: Y
authors: Gao
authors: National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: She
authors: S
authors: Chen
authors: BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
authors: Min
authors: M
authors: Wei
authors: Liaoning Medical University, Jinzhou, Liaoning, 121001, China.
authors: Zhidong
authors: Z
authors: Luan
authors: The General Hospital of People's Liberation Army (301 Hospital), Fuxing Road, Beijing, 100853, China.
authors: Aiqun
authors: A
authors: Zhang
authors: National Institute of Biological Sciences, Beijing. Beijing, 102206, China.
authors: Niu
authors: N
authors: Huang
authors: Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing, 102206, China.
authors: Liang
authors: L
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; C508053:ERBB2 protein, human; C487932:neratinib