Regulation of Ras Signaling by S-Nitrosylation

Abstract

Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in different types of cancers. After translation, Ras proteins can be targets of post-translational modifications (PTM), which can alter the intracellular dynamics of the protein. In this review, we will focus on how S-nitrosylation of Ras affects the way these proteins interact with membranes, its cellular localization, and its activity. S-Nitrosylation occurs when a nitrosyl moiety of nitric oxide (NO) is covalently attached to a thiol group of a cysteine residue in a target protein. In Ras, the conserved Cys118 is the most surface-exposed Cys and the preferable residue for NO action, leading to the initiation of transduction events. Ras transduces the mitogen-activated protein kinases (MAPK), the phosphoinositide-3 kinase (PI3K) and the RalGEF cellular pathways. S-Nitrosylation of elements of the RalGEF cascade remains to be identified. On the contrary, it is well established that several components of the MAPK and PI3K pathways, as well as different proteins associated with these cascades, can be modified by S-nitrosylation. Overall, this review presents a better understanding of Ras S-nitrosylation, increasing the knowledge on the dynamics of these proteins in the presence of NO and the underlying implications in cellular signaling.

Far-reaching effects of tyrosine64 phosphorylation on Ras revealed with BeF3– complexes

“…Furthermore, the utility of 19 F NMR is extended to elucidate the underlying molecular basis of conformational changes induced by PTMs, which might not be captured by high-resolution structures. It serves as a precedent for its application to the investigation of other PTMs, such as S-nitrosylation on C118 44 . Indeed, utilising 19 F NMR on BeF 3 – GSA complexes reveals that Switch I predominantly adopts a “closed” conformation ( ~ 90% occupancy) in solution.…”