Chronic myeloproliferative neoplasms Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
Chronic myeloproliferative neoplasms Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
复制标题
慢性骨髓增生性肿瘤 突变型钙网蛋白与分泌途径中的 MPL 相互作用，在细胞表面激活
DOI：
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
N. Komatsu
中科院分区：
文献类型：
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作者：
Nami Masubuchi;Marito Araki;Yinjie Yang;Erina Hayashi;M. Imai;Y. Edahiro;Yumi Hironaka;Yoshihisa Mizukami;Yoshihiko Kihara;Hiraku Takei;Mai Nudejima;M. Koike;A. Ohsaka;N. Komatsu
研究表明，突变型钙网蛋白（CALR）组成性激活血小板生成素（TPO）受体MPL，从而在骨髓增生性肿瘤（MPN）的发展中发挥因果作用。为了进一步阐明突变型CALR促进MPN发展的分子机制，我们研究了突变型CALR的亚细胞定位及其对突变型CALR致癌特性的重要性。在这里，突变CALR积累在高尔基体，其进入分泌途径和能力，以相互作用的N-聚糖需要通过组成型激活MPL的致癌能力。突变CALR依赖性MPL激活对细胞内蛋白质运输的阻断具有抗性，表明MPL在到达细胞表面之前被激活。然而，用胰蛋白酶从细胞表面去除MPL关闭下游活化，这意味着MPL的表面定位是突变CALR依赖性活化所必需的。此外，我们发现突变CALR和MPL在细胞表面相互作用。基于这些发现，我们提出了一个模型，其中突变CALR诱导MPL激活细胞表面上，以促进MPN的发展。
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 CALRdependent 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.
影响因子：
28.2
作者：
Elf S;Abdelfattah NS;Chen E;Perales-Patón J;Rosen EA;Ko A;Peisker F;Florescu N;Giannini S;Wolach O;Morgan EA;Tothova Z;Losman JA;Schneider RK;Al-Shahrour F;Mullally A
通讯作者：
Mullally A
影响因子：
8
作者：
Pronier, Elodie;Cifani, Paolo;Levine, Ross L.
通讯作者：
Levine, Ross L.