Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway.

Tomoaki Ohtsuka,Ken Suzawa,Kazunori Tsukuda,Kazuhiko Shien,Mototsugu Watanabe,Tomoko Miyata-Takata,Shinsuke Hashida,Shinichi Toyooka,Shinichiro Miyoshi,Hiroki Sato,Tadashi Yoshino,Kei Namba,Masakiyo Sakaguchi,Hidejiro Torigoe,Hiromasa Yamamoto,Katsuyoshi Takata,Shuta Tomida,Chen Youyi,Junichi Soh

doi:10.1038/srep39557

Abstract

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

Highlights

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers
We found that KRT19 bound to HER2 intracellularly followed by the subsequent activation of HER2 and its downstream Erk protein, indicating the role of KRT19 as an oncogenic molecule
We found that the expression of HER2 was correlated with the expression of KRT19, and the location of KRT19 was affected by the existence of HER2 in lung cancer cells, supporting the intracellular binding of KRT19 and HER2

Summary

Introduction

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Mutations in the tyrosine kinase domain of HER2 have been detected in 2–4% of lung adenocarcinomas[5,6,7] Considering these findings, uncovering molecular interaction involved in HER2 signaling is critical to understand HER2 related oncogenesis and to develop the new treatments for HER2-alterated malignancies. We found the novel functional mutations in the transmembrane domain (TD) (codons 659 and 660) of HER28 These HER2 mutations are considered to be the oncogenic mutations in certain histological types of lung cancers[9,10,11]. In the course of identifying novel partner receptor for TD mutant HER2, we found that cytokeratin 19 (KRT19) is bind to wild type HER2 in A549 lung cancer cell line. We determined the binding sites of KRT19 and HER2 and investigated the impact of KRT19 and HER2 interactions in signal transduction pathways to decode their possible roles in oncogenesis

Methods

Results

Conclusion