ICMT supports BRAF V600E -driven tumor growth by membrane targeting of the CAAX protein INPP5E
- Xijie Yang
- Xi Qiao
- Sarah Schmidt
- Ella A. Eklund
- Carolina Ebner-Walter
- Emil Ivarsson
- Michelle Ann Crespo
- Nadieh Kersemakers
- Jozefina J. Dzanan
- Bjarni Thorisson
- Christine Lundgren
- Hooi Ching Lim
- Sam Shkoukani
- Elin Tüksammel
- Xiufeng Xu
- Volkan I. Sayin
- Mar Martín-Fontecha
- Silvia Ortega-Gutiérrez
- Martin Dalin
- Martin O. Bergo
2026-05-13
Isoprenylcysteine carboxyl methyltransferase (ICMT) catalyzes C-terminal methylation of prenylated CAAX proteins, a final processing step promoting membrane association and signaling. Although ICMT has been pursued to disrupt RAS membrane targeting, its role in BRAF V600E -driven cancers and critical substrates remains unclear. Here, genetic and pharmacologic (UCM-1336) ICMT inhibition suppressed proliferation and invasion in BRAF V600E -mutant melanoma cells and reduced tumor growth in xenografts and mice. ICMT knockdown inhibited proliferation of BRAF-inhibitor-resistant melanoma cells. We identify INPP5E as an ICMT-dependent substrate: ICMT inhibition reduced INPP5E methylation, displaced it from membranes, and increased PI(4,5)P 2 . Forced INPP5E membrane targeting partially rescued growth defects caused by ICMT inhibition. These findings implicate an ICMT-INPP5E-axis that supports BRAF V600E -driven tumor growth.