Positive feedback loop between NRASQ61R mutation and RAB27B expression in endothelial cells.

Recent findings implicate somatic NRASQ61R mutation in human endothelial cells in the pathogenesis of vascular anomalies. Our previous study demonstrated that RAB27B, a small GTPase of the RAB family, regulates NRAS palmitoylation in leukemia cells and is essential for NRAS-mutant leukemia development. However, the role of RAB27B in NRASQ61R mutant endothelial cells are still unknown. Our present study revealed that knockdown of RAB27B, but not knockdown of RAB27A, inhibited the enhanced proliferation and migration of human umbilical vein endothelial cells (HUVEC) overexpressing NRASQ61R by suppressing ERK activation. Notably, RAB27B protein and gene expression levels were significantly elevated in HUVEC overexpressing NRASQ61R compared to those overexpressing NRASWT or empty vector. Treatment with a MEK1/2 inhibitor, but not a PI3K/mTOR inhibitor, markedly decreased RAB27B gene expression in HUVEC overexpressing NRASQ61R. Furthermore, we identified CCAAT enhancer binding protein beta as a downstream transcription factor of NRASQ61R/ERK pathway that induced RAB27B gene expression. Taken together, our study unmasked a positive feedback loop between NRASQ61R mutation and RAB27B expression in endothelial cells. Moreover, RAB27B is associated with the dysfunction of NRASQ61R mutant endothelial cells, highlighting RAB27B as a potential therapeutic target for NRAS-mutant vascular anomalies.