Open AccessProtein lysine methyltransferase SMYD 3 is involved in tumorigenesis through regulation of HER 2 homodimerization
Author(s) -
Yoshioka Yuichiro,
Suzuki Takehiro,
Matsuo Yo,
Tsurita Giichiro,
Watanabe Toshiaki,
Dohmae Naoshi,
Nakamura Yusuke,
Hamamoto Ryuji
Publication year - 2017
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1099
Subject(s) - autophosphorylation , lysine , methylation , carcinogenesis , chemistry , tyrosine , receptor tyrosine kinase , methyltransferase , biochemistry , biology , phosphorylation , microbiology and biotechnology , protein kinase a , amino acid , gene
HER 2 is a receptor tyrosine kinase, which is amplified and overexpressed in a subset of human cancers including breast and gastric cancers, and is indicated in its involvement in progression of cancer. Although its specific ligand(s) has not been detected, HER 2 homodimerization, which is critical for its activation, is considered to be dependent on its expression levels. Here, we demonstrate a significant role of HER 2 methylation by protein lysine methyltransferase SMYD 3 in HER 2 homodimerization. We found that SMYD 3 trimethylates HER 2 protein at lysine 175. HER 2 homodimerization was enhanced in the presence of SMYD 3, and substitution of lysine 175 of HER 2 with alanine ( HER 2‐K175A) reduced the formation of HER 2 homodimers. Furthermore, HER 2‐K175A revealed lower level of autophosphorylation than wild‐type HER 2. We also identified that knockdown of SMYD 3 attenuated this autophosphorylation in breast cancer cells. Our results imply that SMYD 3‐mediated methylation of HER 2 at Lysine 175 may regulate the formation of HER 2 homodimer and subsequent autophosphorylation and suggest that the SMYD 3‐mediated methylation pathway seems to be a good target for development of novel anti‐cancer therapy.