Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization

Abstract 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.