RKTG sequesters B-Raf to the Golgi apparatus and inhibits the proliferation and tumorigenicity of human malignant melanoma cells

Abstract

Raf kinase trapping to Golgi (RKTG) is a newly characterized negative regulator of the Ras-Raf-mitogen-activated and extracellular signal-regulated kinase kinase (MEK) - extracellular signal-regulated kinase (ERK)-signaling pathway via sequestrating Raf-1 to the Golgi apparatus. Among Raf kinase family members, B-Raf is the most frequently mutated gene in human cancers and an activated B-Raf mutation V600E is associated with >60% of human melanomas. Here, we show that RKTG can also bind and translocate B-Raf to the Golgi apparatus. When overexpressed in A375, a human malignant melanoma cell line with B-Raf(V600E), RKTG inhibits ERK activation, cell proliferation and transformation of A375 cells. In addition, the tumorigenicity of the RKTG-expressing A375 cells is suppressed in nude mice. Consistently, cell proliferation rate was reduced in the tumor xenografts in which RKTG was overexpressed. Collectively, our results suggest that RKTG may play a suppressive role in human melanoma that harbors an oncogenic B-Raf mutation via its antagonistic action on B-Raf. © The Author 2008. Published by Oxford University Press. All rights reserved.