Regulation of NOTCH signaling by RAB7 and RAB8 requires carboxyl methylation by ICMT

Marc Amoyel

Research output: Contribution to journalArticle (Academic Journal)peer-review

8 Citations (Scopus)
146 Downloads (Pure)

Abstract

Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal
prenylcysteine residues of CaaX proteins and some RAB GTPases. Deficiency of either ICMT or NOTCH1 accelerates pancreatic neoplasia in Pdx1-Cre;LSL- Kras G12D mice, suggesting that ICMT is required for NOTCH signaling. We employed D. melanogaster wing vein and scutellar bristle development to screen Rab proteins predicted to be substrates for ICMT (ste14 in flies). We identified Rab7 and Rab8 as ICMT substrates that, when silenced, phenocopy ste14 deficiency. ICMT, RAB7 and RAB8 were all required for efficient NOTCH1 signaling in mammalian cells. Overexpression of RAB8 rescued NOTCH activation following ICMT knockdown both in U2OS cells expressing NOTCH1 and in fly wing vein development. ICMT deficiency induced mislocalization of GFP-RAB7 and GFP-RAB8 from endomembrane to cytosol, enhanced binding to RABGDI, and decreased GTP-loading of RAB7 and RAB8. Deficiency of ICMT, RAB7 or RAB8 led to mislocalization and diminished processing of NOTCH1-GFP. Thus NOTCH signaling requires ICMT in part because it requires methylated RAB7 and RAB8.
Original languageEnglish
JournalJournal of Cell Biology
DOIs
Publication statusPublished - 19 Oct 2017

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