2020年2月
Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
Leukemia
- 巻
- 34
- 号
- 2
- 開始ページ
- 499
- 終了ページ
- 509
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/s41375-019-0564-z
- 出版者・発行元
- Springer Science and Business Media LLC
Studies have shown that mutant calreticulin (CALR) constitutively activates the thrombopoietin (TPO) receptor MPL and thus plays a causal role in the development of myeloproliferative neoplasms (MPNs). To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we studied the subcellular localization of mutant CALR and its importance for the oncogenic properties of mutant CALR. Here, mutant CALR accumulated in the Golgi apparatus, and its entrance into the secretion pathway and capacity to interact with N-glycan were required for its oncogenic capacity via the constitutive activation of MPL. Mutant CALR-dependent MPL activation was resistant to blockade of intracellular protein trafficking, suggesting that MPL is activated before reaching the cell surface. However, removal of MPL from the cell surface with trypsin shut down downstream activation, implying that the surface localization of MPL is required for mutant CALR-dependent activation. Furthermore, we found that mutant CALR and MPL interact on the cell surface. Based on these findings, we propose a model in which mutant CALR induces MPL activation on the cell surface to promote MPN development.
- リンク情報
- ID情報
-
- DOI : 10.1038/s41375-019-0564-z
- ISSN : 0887-6924
- eISSN : 1476-5551
- PubMed ID : 31462733