Randall Centre for Cell and Molecular Biophysics, and.
School of Cancer Sciences, King's College London, London, United Kingdom.
Blood Adv. 2018 Jul 10;2(13):1551-1561. doi: 10.1182/bloodadvances.2017014506.
CD38 is a transmembrane exoenzyme that is associated with poor prognosis in chronic lymphocytic leukemia (CLL). High CD38 levels in CLL cells are linked to increased cell migration, but the molecular basis is unknown. CD38 produces nicotinic acid adenine dinucleotide phosphate and adenosine 5'-diphosphate-ribose, both of which can act to increase intracellular Ca levels. Here we show that CD38 expression increases basal intracellular Ca levels and stimulates CLL cell migration both with and without chemokine stimulation. We find that CD38 acts via intracellular Ca to increase the activity of the Ras family GTPase Rap1, which is in turn regulated by the Ca-sensitive Rap1 guanine-nucleotide exchange factor RasGRP2. Both Rap1 and RasGRP2 are required for CLL cell migration, and RasGRP2 is polarized in primary CLL cells with high CD38 levels. These results indicate that CD38 promotes RasGRP2/Rap1-mediated CLL cell adhesion and migration by increasing intracellular Ca levels.
CD38 是一种跨膜外切酶，与慢性淋巴细胞白血病（CLL）的不良预后相关。CLL 细胞中高水平的 CD38 与细胞迁移增加有关，但分子基础尚不清楚。CD38 产生烟酰胺腺嘌呤二核苷酸磷酸和腺苷 5'-二磷酸核糖，两者都可以增加细胞内 Ca 水平。在这里，我们表明 CD38 表达增加基础细胞内 Ca 水平，并刺激 CLL 细胞迁移，无论是在没有趋化因子刺激的情况下。我们发现 CD38 通过细胞内 Ca 来增加 Ras 家族 GTPase Rap1 的活性，Rap1 反过来又受到 Ca 敏感的 Rap1 鸟嘌呤核苷酸交换因子 RasGRP2 的调节。Rap1 和 RasGRP2 都需要 CLL 细胞迁移，并且 RasGRP2 在具有高 CD38 水平的原发性 CLL 细胞中极化。这些结果表明，CD38 通过增加细胞内 Ca 水平促进 RasGRP2/Rap1 介导的 CLL 细胞黏附和迁移。
