The RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules of 21 kd. They act as an on/off switch linking receptor and non-receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.

The RAS proto-oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP-hydrolysing ability of the proteins causing constitutive activation [7], which leads to increased cell proliferation and decreased apoptosis [15]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [1].

* Key recommended reading is highlighted with an asterisk

* Chen H, Smaill JB, Liu T, Ding K, Lu X. (2020) Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. J Med Chem, 63 (23): 14404-14424. [PMID:33225706]

* Dorard C, Vucak G, Baccarini M. (2017) Deciphering the RAS/ERK pathway in vivo. Biochem Soc Trans, 45 (1): 27-36. [PMID:28202657]

* Kattan WE, Hancock JF. (2020) RAS Function in cancer cells: translating membrane biology and biochemistry into new therapeutics. Biochem J, 477 (15): 2893-2919. [PMID:32797215]

* Keeton AB, Salter EA, Piazza GA. (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res, 77 (2): 221-226. [PMID:28062402]

Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J. (2016) Ras Conformational Ensembles, Allostery, and Signaling. Chem Rev, 116 (11): 6607-65. [PMID:26815308]

Ostrem JM, Shokat KM. (2016) Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov, 15 (11): 771-785. [PMID:27469033]

* Papke B, Der CJ. (2017) Drugging RAS: Know the enemy. Science, 355 (6330): 1158-1163. [PMID:28302824]

* Quah SY, Tan MS, Teh YH, Stanslas J. (2016) Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs. Pharmacol Ther, 162: 35-57. [PMID:27016467]

* Simanshu DK, Nissley DV, McCormick F. (2017) RAS Proteins and Their Regulators in Human Disease. Cell, 170 (1): 17-33. [PMID:28666118]

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10. Xie Y, Zhang W, Peng T, Wang X, Lian X, He J, Wang C, Xie N. (2024) TBC1D15-regulated mitochondria-lysosome membrane contact exerts neuroprotective effects by alleviating mitochondrial calcium overload in seizure. Sci Rep, 14 (1): 23782. [PMID:39390030]

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