Molecular analysis of autonomous activating mutation of c-mpl responsible for familial essential thrombocythemia

我们以前报道过编码血小板生成素受体的c-MPL跨膜区(TMD)的显性正向激活突变(Asn505)导致家族性原发性血小板增多症。在这里，我们证明了Asn505突变诱导了c-MPL的自主二聚化和在没有其配体的情况下的信号激活。缺失c-MPL胞外区的Asn505突变体保留了信号激活。我们还发现，用其他强极性的氨基酸(Glu、Asp或Gln)取代505位氨基酸(AA)也能在没有配体刺激的情况下导致活性二聚。总体而言，这些数据表明，由于强烈的AA极性，Asn505突变通过c-MPL蛋白的自主二聚来传递信号。这一发现为细胞因子/造血受体TMD突变导致疾病的机制提供了新的见解。

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-Mpl. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-Mpl protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors.