KRAS and Rho prenylation-dependent signaling

KRAS and Rho prenylation-dependent signaling is a critical regulatory axis involving the post-translational lipid modification of small GTPases, which is essential for their membrane localization and biological activity. This process is mediated by protein prenyltransferases, primarily farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase-I), which recognize the C-terminal CAAX motif of target proteins (Wang & Casey, 2016). While KRAS is normally farnesylated, it can undergo alternative geranylgeranylation when FTase is inhibited, a mechanism that has historically limited the efficacy of farnesyltransferase inhibitors (FTIs) in KRAS-driven cancers (Cox & Der, 2002). In contrast, Rho family proteins like RhoB are key mediators of the cellular response to these inhibitors, as their prenylation status influences cell survival and cytoskeletal organization (Prendergast, 2001). Therapeutic targeting of this pathway aims to disrupt the oncogenic signaling of Ras and Rho proteins in various malignancies, though challenges remain regarding specificity and compensatory resistance mechanisms (Berndt et al., 2011).

Other names

Protein prenylation pathwayRas/Rho prenylation axisFarnesyltransferase and geranylgeranyltransferase signalingCAAX prenylation signaling

The mechanism involves the inhibition of farnesyltransferase (FTase) and/or geranylgeranyltransferase I (GGTase-I) enzymes. These enzymes catalyze the covalent attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid lipids to the cysteine residue of the C-terminal CAAX motif of proteins such as KRAS, HRAS, NRAS, and Rho family members (e.g., RhoA, RhoB, RhoC). This lipid modification is essential for the proteins to anchor to the plasma membrane and engage in downstream signaling cascades like the MAPK and PI3K pathways (Berndt et al., 2011; Wang & Casey, 2016).