Mechanisms for regulation of RAS palmitoylation and plasma membrane trafficking in hematopoietic malignancies

Abstract

Palmitoylation is a critical posttranslational modification that enables the cellular membrane localization and subsequent activation of RAS proteins, including HRAS, KRAS, and NRAS. However, the molecular mechanism that regulates RAS palmitoylation in malignant diseases remains unclear. In this issue of the JCI, Ren, Xing, and authors shed light on this topic and revealed how upregulation of RAB27B, as a consequence of CBL loss and Janus kinase 2 (JAK2) activation, contributes to leukemogenesis. The authors found that RAB27B mediated NRAS palmitoylation and plasma membrane localization by recruiting ZDHHC9. The findings suggest that targeting RAB27B could provide a promising therapeutic strategy for NRAS-driven cancers.

Figure 1. The proposed mechanism for the regulation of NRAS mutation-driven hematopoietic malignancies involves the CBL/JAK2/RAB27B signaling axis.

Deletion or loss-of-function mutations of CBL stabilize JAK2, leading to upregulation of the transcription of RAB27B. RAB27B facilitates NRAS trafficking to the plasma membrane and regulates its palmitoylation, thereby activating the RAS/RAF/MEK/ERK signaling pathway and promoting leukemogenesis.