Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma

Shunpei Satoh, Atsushi Takatori, Atsushi Ogura, Kenichi Kohashi, Ryota Souzaki, Yoshiaki Kinoshita, Tomoaki Taguchi, Md Shamim Hossain, Miki Ohira, Yohko Nakamura, Akira Nakagawara

研究成果: ジャーナルへの寄稿記事

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In neuroblastoma (NB), one of the most common paediatric solid tumours, activation of anaplastic lymphoma kinase (ALK) is often associated with poor outcomes. Although genetic studies have identified copy number alteration and nonsynonymous mutations of ALK, the regulatory mechanism of ALK signalling at protein levels is largely elusive. Neuronal leucine-rich repeat 1 (NLRR1) is a type 1 transmembrane protein that is highly expressed in unfavourable NB and potentially influences receptor tyrosine kinase signalling. Here, we showed that NLRR1 and ALK exhibited a mutually exclusive expression pattern in primary NB tissues by immunohistochemistry. Moreover, dorsal root ganglia of Nlrr1+/+ and Nlrr1-/- mice displayed the opposite expression patterns of Nlrr1 and Alk. Of interest, NLRR1 physically interacted with ALK in vitro through its extracellular region. Notably, the NLRR1 ectodomain impaired ALK phosphorylation and proliferation of ALK-mutated NB cells. A newly identified cleavage of the NLRR1 ectodomain also supported NLRR1-mediated ALK signal regulation in trans. Thus, we conclude that NLRR1 appears to be an extracellular negative regulator of ALK signalling in NB and neuronal development. Our findings may be beneficial to comprehend NB heterogeneity and to develop a novel therapy against unfavourable NB.

元の言語英語
記事番号32682
ジャーナルScientific reports
6
DOI
出版物ステータス出版済み - 9 8 2016

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All Science Journal Classification (ASJC) codes

  • General

これを引用

Satoh, S., Takatori, A., Ogura, A., Kohashi, K., Souzaki, R., Kinoshita, Y., ... Nakagawara, A. (2016). Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma. Scientific reports, 6, [32682]. https://doi.org/10.1038/srep32682