論文

査読有り 国際誌
2019年1月

Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation.

Leukemia
  • Marito Araki
  • ,
  • Yinjie Yang
  • ,
  • Misa Imai
  • ,
  • Yoshihisa Mizukami
  • ,
  • Yoshihiko Kihara
  • ,
  • Yoshitaka Sunami
  • ,
  • Nami Masubuchi
  • ,
  • Yoko Edahiro
  • ,
  • Yumi Hironaka
  • ,
  • Satoshi Osaga
  • ,
  • Akimichi Ohsaka
  • ,
  • Norio Komatsu

33
1
開始ページ
122
終了ページ
131
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41375-018-0181-2

Studies have previously shown that mutant calreticulin (CALR), found in a subset of patients with myeloproliferative neoplasms (MPNs), interacts with and subsequently promotes the activation of the thrombopoietin receptor (MPL). However, the molecular mechanism behind the activity of mutant CALR remains unknown. Here we show that mutant, but not wild-type, CALR interacts to form a homomultimeric complex. This intermolecular interaction among mutant CALR proteins depends on their carboxyl-terminal domain, which is generated by a unique frameshift mutation found in patients with MPN. With a competition assay, we demonstrated that the formation of mutant CALR homomultimers is required for the binding and activation of MPL. Since association with MPL is required for the oncogenicity of mutant CALR, we propose a model in which the constitutive activation of the MPL downstream pathway by mutant CALR multimers induces the development of MPN. This study provides a potential novel therapeutic strategy against mutant CALR-dependent tumorigenesis via targeting the intermolecular interaction among mutant CALR proteins.

リンク情報
DOI
https://doi.org/10.1038/s41375-018-0181-2
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29946189

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