GTPase Ras (Ras)

p21Ras refers to the 21 kDa protein products of the Ras gene family, including HRAS, KRAS, and NRAS, which function as binary molecular switches in signal transduction pathways [1, 3]. These small GTPases cycle between an active GTP-bound state and an inactive GDP-bound state to regulate fundamental cellular processes such as growth, proliferation, and survival [7]. Mutations in Ras genes are among the most common drivers in human cancers, particularly in pancreatic, colorectal, and lung malignancies, where they lead to constitutive signaling and uncontrolled cell growth [2, 7]. Historically considered 'undruggable' due to the lack of deep binding pockets, recent therapeutic breakthroughs have led to the development of allele-specific covalent inhibitors, such as those targeting the KRAS G12C mutation [7]. Beyond direct inhibition, strategies also include targeting Ras membrane localization via farnesyltransferase inhibitors or disrupting interactions with exchange factors like SOS1 [2, 8]. Additionally, germline mutations in the Ras pathway cause a group of developmental disorders known as RASopathies, such as Noonan syndrome [13, 14].

Other names

p21Rasp21Ras proteinTransforming protein p21HRASKRASNRAS

Covalent inhibition of mutant forms (e.g., G12C) to trap the protein in an inactive GDP-bound state, or inhibition of post-translational farnesylation to prevent essential membrane localization [2, 7].