ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E

• 成果类型: Article
• 署名作者: Yang, Xijie; Qiao, Xi; Schmidt, Sarah; Eklund, Ella A.; Ebner-Walter, Carolina; Ivarsson, Emil; Crespo, Michelle Ann; Kersemakers, Nadieh; Dzanan, Jozefina J.; Thorisson, Bjarni; Lundgren, Christine; Lim, Hooi Ching; Shkoukani, Sam; Tuksammel, Elin; Xu, Xiufeng; Sayin, Volkan I.; Martin-Fontecha, Mar; Ortega-Gutierrez, Silvia; Dalin, Martin; Bergo, Martin O.
• 署名单位: Karolinska Institutet; University of Gothenburg; University of Gothenburg; University of Gothenburg; Complutense University of Madrid; Complutense University of Madrid; University of Gothenburg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2601795123
• 发表日期: 2026-05-19
• 页码: e2601795123
• 关键词: CAAX protein processing; ICMT; BRAFV600E-driven cancer; inpp5e; ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE; K-RAS; CARBOXYLMETHYLTRANSFERASE

摘要

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 BRAFV600E-driven cancers and critical substrates remains unclear. Here, genetic and pharmacologic (UCM-1336) ICMT inhibition suppressed proliferation and invasion in BRAFV600E-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)P2. Forced INPP5E membrane targeting partially rescued growth defects caused by ICMT inhibition. These findings implicate an ICMT-INPP5E-axis that supports BRAFV600E-driven tumor growth.