ICMT supports BRAF <sup>V600E</sup> -driven tumor growth by membrane targeting of the CAAX protein INPP5E
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Xijie Yang
Department of Medicine, Huddinge, Karolinska Institutet
Xi Qiao
Department of Medicine, Huddinge, Karolinska Institutet
Sarah Schmidt
Department of Medicine, Huddinge, Karolinska Institutet
Ella A. Eklund
Carolina Ebner-Walter
Department of Medicine, Huddinge, Karolinska Institutet
Emil Ivarsson
Sahlgrenska Center for Cancer Research, University of Gothenburg
Michelle Ann Crespo
Department of Medicine, Huddinge, Karolinska Institutet
Nadieh Kersemakers
Department of Medicine, Huddinge, Karolinska Institutet
Jozefina J. Dzanan
Bjarni Thorisson
Sahlgrenska Center for Cancer Research, University of Gothenburg
Christine Lundgren
Sahlgrenska Center for Cancer Research, University of Gothenburg
Hooi Ching Lim
Sahlgrenska Center for Cancer Research, University of Gothenburg
Sam Shkoukani
Sahlgrenska Center for Cancer Research, University of Gothenburg
Elin Tüksammel
Department of Medicine, Huddinge, Karolinska Institutet
Xiufeng Xu
Department of Medicine, Huddinge, Karolinska Institutet
Volkan I. Sayin
Mar Martín-Fontecha
Organic Chemistry Department, Faculty of Optics and Optometry, Universidad Complutense de Madrid
Silvia Ortega-Gutiérrez
Department of Organic Chemistry
Martin Dalin
Sahlgrenska Center for Cancer Research, University of Gothenburg
Martin O. Bergo
Department of Medicine, Karolinska Institutet