Post-translational modification of KRAS: potential targets for cancer therapy

Abstract

Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.

Keywords: KRAS; SUMOylation; acetylation; cancer therapy; nitrosylation; oncogene; palmitoylation; phosphorylation; post-translational modification; postprenylation; prenylation; ubiquitination.

Fig. 1. PTMsof KRAS proteins.

A diagram of the full length of KRAS4A and KRAS4B is drawn, which contains the G domain and hyper variable region (HVR). To distinguish KRAS4A and KRAS4B, different colors are utilized, and the amino acid sequence of the HVR is indicated with abbreviations. For the G domain, the PTMs between KRAS4A and KRAS4B are similar, including ubiquitination, glycosylation, sumoylation, phosphorylation, acetylation, nitrosylation, and ADP-ribosylation. Within the HVR, specific modifications and related residues share the same color.

Fig. 2. PTMs regulate the activation and carcinogenesis of KRAS.

A series of modifications occur during the activation or inactivation of KRAS. Each known enzyme that is responsible for a particular process is exhibited. KRAS proteins undergo consecutive modifications to assure their attachment to the plasma membrane and subsequent activation. Meanwhile, there are other modifications that regulate their activation and carcinogenic potency. These processes are indicated by three font colors, where red represents anticancer, green denotes pro-cancer, and brown indicates unconfirmed processes. In addition, the consequence of each modification is also depicted by lines with different colors, where the purple line represents the impact on the level of the GTP-bound state, the yellow line indicates the impact on protein stability, and the pink line denotes the impact on interactions with effectors. GEF guanine nucleotide exchange factors, GAP GTPase-activating proteins, FTase farnesyltransferase, NO nitric oxide, PIAS4 protein inhibitor of activated STAT 4, RCE1 RAS-converting enzyme 1, ICMT isoprenylcysteine carboxyl methyltransferase, PKC protein kinase C, APT acyl protein thioesterase, and PAT protein acetyltransferases.