Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential

• Published in: Bioorganic chemistry Vol. 147; p. 107316
• Main Authors: Hildebrandt, Emily R., Hussain, Shaneela A., Sieburg, Michelle A., Ravishankar, Rajani, Asad, Nadeem, Gore, Sangram, Ito, Takahiro, Hougland, James L., Dore, Timothy M., Schmidt, Walter K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2024
• Subjects: Endopeptidases; Erk; Humans; Molecular Structure; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Protease inhibitor; Protein farnesylation; Proteolysis - drug effects; Ras protein; ras Proteins - antagonists & inhibitors; ras Proteins - genetics; ras Proteins - metabolism; Rce1 CaaX protease; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; ICMT; LSK; PTM; Ras protein; Hs; Protein farnesylation; Sc; TAMRA; Rce1 CaaX protease; ABZ; KD; SEM; Protease inhibitor; Erk

[Display omitted] •N-Ras is mislocalized when its CaaX cleavage is disrupted.•N-Ras that is staged as a farnesylated and uncleaved intermediate has less activity.•Farnesylated substrate mimetics of the Rce1 protease are cell permeable. Ras GTPases and other CaaX proteins undergo multiple post-transl...