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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Article number39557
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Dec 23 2016

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Keratin-19
Lung Neoplasms
Cytoplasm
Cell Membrane
Receptor Protein-Tyrosine Kinases
Neoplasms
Up-Regulation
Head
Phosphorylation
T-Lymphocytes
Kidney
Mutation

ASJC Scopus subject areas

  • General

Cite this

Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. / Ohtsuka, Tomoaki; Sakaguchi, Masakiyo; Yamamoto, Hiromasa; Tomida, Shuta; Takata, Katsuyoshi; Shien, Kazuhiko; Hashida, Shinsuke; Miyata-Takata, Tomoko; Watanabe, Mototsugu; Suzawa, Ken; Sou, Junichi; Youyi, Chen; Sato, Hiroki; Namba, Kei; Torigoe, Hidejiro; Tsukuda, Kazunori; Yoshino, Tadashi; Miyoshi, Shinichiro; Toyooka, Shinichi.

In: Scientific Reports, Vol. 6, 39557, 23.12.2016.

Research output: Contribution to journalArticle

Ohtsuka, T, Sakaguchi, M, Yamamoto, H, Tomida, S, Takata, K, Shien, K, Hashida, S, Miyata-Takata, T, Watanabe, M, Suzawa, K, Sou, J, Youyi, C, Sato, H, Namba, K, Torigoe, H, Tsukuda, K, Yoshino, T, Miyoshi, S & Toyooka, S 2016, 'Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway', Scientific Reports, vol. 6, 39557. https://doi.org/10.1038/srep39557
Ohtsuka, Tomoaki ; Sakaguchi, Masakiyo ; Yamamoto, Hiromasa ; Tomida, Shuta ; Takata, Katsuyoshi ; Shien, Kazuhiko ; Hashida, Shinsuke ; Miyata-Takata, Tomoko ; Watanabe, Mototsugu ; Suzawa, Ken ; Sou, Junichi ; Youyi, Chen ; Sato, Hiroki ; Namba, Kei ; Torigoe, Hidejiro ; Tsukuda, Kazunori ; Yoshino, Tadashi ; Miyoshi, Shinichiro ; Toyooka, Shinichi. / Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. In: Scientific Reports. 2016 ; Vol. 6.
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AU - Takata, Katsuyoshi

AU - Shien, Kazuhiko

AU - Hashida, Shinsuke

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AU - Sou, Junichi

AU - Youyi, Chen

AU - Sato, Hiroki

AU - Namba, Kei

AU - Torigoe, Hidejiro

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AU - Yoshino, Tadashi

AU - Miyoshi, Shinichiro

AU - Toyooka, Shinichi

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AB - 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.

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