Araki Marito
Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine.
Rinsho Ketsueki. 2018;59(8):1072-1077. doi: 10.11406/rinketsu.59.1072.
Unique frameshift mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone present in the endoplasmic reticulum, were identified in a subset of patients with myeloproliferative neoplasms (MPNs). Recently, it has been reported that mutant CALR constitutively activates the thrombopoietin (TPO) receptor MPL, even in the absence of TPO, thereby inducing cellular transformation. Hence, the tumorigenic role of mutant CALR in the development of MPNs is now clear; nevertheless, the precise molecular mechanism the interaction between mutant CALR and MPL remains elusive. We recently illustrated that the accumulation of mutant CALR in the Golgi apparatus and its N-glycan binding capacity are needed for its tumorigenic capacity, including the interaction and activation of MPL. These findings implied that mutant CALR recognizes MPL during the receptor maturation using its original property as a molecular chaperone. Although the molecular mechanism underlying the activation of MPL by CALR remains elusive, it became clear that the mechanism of interaction between mutant CALR and MPL is quite different from that of TPO, the natural ligand, and MPL.
在一部分骨髓增殖性肿瘤（MPN）患者中，发现了钙网蛋白（CALR）基因中的独特移码突变，该基因编码一种存在于内质网中的分子伴侣。最近有报道称，即使在没有血小板生成素（TPO）的情况下，突变型CALR也能持续激活血小板生成素受体MPL，从而诱导细胞转化。因此，突变型CALR在MPN发生发展中的致瘤作用现已明确；然而，突变型CALR与MPL之间相互作用的确切分子机制仍不清楚。我们最近阐明，突变型CALR在高尔基体中的积累及其N-聚糖结合能力是其致瘤能力所必需的，包括与MPL的相互作用和激活。这些发现表明，突变型CALR在受体成熟过程中利用其作为分子伴侣的原始特性识别MPL。尽管CALR激活MPL的分子机制仍不清楚，但很明显，突变型CALR与MPL之间的相互作用机制与天然配体TPO和MPL的相互作用机制截然不同。
