Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
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DOI：
10.1038/s41375-019-0564-z
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发表时间：
2020-02-01
期刊：
影响因子：
11.4
通讯作者：
Komatsu, Norio
中科院分区：
文献类型：
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作者：
Masubuchi, Nami;Araki, Marito;Komatsu, Norio
研究表明，突变型钙网蛋白(CALR)结构性激活血小板生成素(TPO)受体MPL，从而在骨髓增生性肿瘤(MPN)的发生发展中起因果作用。为了进一步阐明突变型CALR促进MPN发育的分子机制，我们研究了突变型CALR的亚细胞定位及其对突变型CALR致癌特性的影响。在这里，突变的CALR在高尔基体中积累，它进入分泌途径并与N-糖链相互作用的能力是其通过MPL的结构性激活而具有的致癌能力所必需的。突变的依赖CALR的MPL激活抵抗细胞内蛋白运输的阻断，这表明MPL在到达细胞表面之前就被激活了。然而，用胰酶从细胞表面去除MPL会关闭下游的激活，这意味着突变的CALR依赖的激活需要MPL的表面定位。此外，我们还发现突变体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，在该模型中，突变的CALR诱导细胞表面的MPL激活，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 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.