Rheb belongs to the Ras family, which encodes a carboxyl-terminal CAAX box, suggesting that the protein undergoes posttranslational farnesylation--the membrane localization of Rheb through farnesylation is important for upstream regulation of mTOR signaling (Basso et al.
The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling.
Molecularly, bisphosphonates block farnesyl diphosphate (FPP) synthase, an enzyme required in the production of cholesterol, farnesylation
, and geranyl-geranylation.
It targets the farnesylation
pathway upstream at the level of farnesyl diphosphate synthase.
Major post-translational modifications like phosphorylation, acetylation, ribosylation, methylation, farnesylation
Yeast cells activate Ras through farnesylation
, proteolysis, methylation, and palmitoylation in the same manner as multicellular organisms.
Inhibition of protein farnesylation
alters the activity of a number of proteins important in tumor cell proliferation, including the Ras oncogene family.
Figure 29: Proteins undergoing farnesylation by farnesyltransferase 94
Figure 32: Proteins undergoing farnesylation by farnesyltransferase 104
or geranylgeranylation of these proteins directs their cellular localization and function.
A third compound, CP-609,754, is an inhibitor of ras farnesylation
and is being developed to block this modification.
the EGF or IGF receptor), angiogenesis, farnesylation
, the MEK pathway, the mTOR pathway, apoptosis, DNA synthesis and repair, and the proteasome.