Ras superfamily small GTPases (Ras superfamily)

The Ras superfamily of small GTPases consists of over 150 monomeric proteins that act as molecular switches to regulate a vast array of cellular signaling pathways [1]. These proteins cycle between an active GTP-bound state and an inactive GDP-bound state, a process tightly controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [2]. The superfamily is categorized into five main families: Ras, which regulates cell growth and survival; Rho, which governs cytoskeletal dynamics; Rab, which manages vesicle docking and fusion; Arf, involved in vesicle formation; and Ran, which controls nucleocytoplasmic transport [1,3]. Dysregulation of these proteins, particularly through gain-of-function mutations in Ras isoforms, is a primary driver in approximately 30% of all human cancers [2]. Although long considered undruggable due to their high affinity for GTP and lack of traditional binding pockets, recent therapeutic advances have successfully targeted specific mutations like KRAS G12C using allele-specific covalent inhibitors [4]. Current research also explores the inhibition of post-translational modifications, such as farnesylation, which are required for the membrane association and functional activity of these GTPases [4]. (Sources: [1] Wennerberg K, et al. J Cell Sci. 2005; [2] Colicelli J. Sci STKE. 2004; [3] Homma Y, et al. FEBS J. 2021; [4] Canon J, et al. Nature. 2019).

Other names

Small GTP-binding proteinsMonomeric GTPasesRas-like GTPasesRab GTPasesRas-related proteins

Covalent inhibition of specific mutant alleles (e.g., KRAS G12C), inhibition of post-translational prenylation via farnesyltransferase or geranylgeranyltransferase inhibitors, and disruption of guanine nucleotide exchange factor (GEF) interactions.