Structure, signaling and the drug discovery of the Ras oncogene protein

Abstract

Mutations in Ras GTPase are among the most common genetic alterations in human cancers. Despite extensive research investigating Ras proteins, their functions still remain a challenge over a long period of time. The currently available data suggests that solving the outstanding issues regarding Ras could lead to development of effective drugs that could have a significant impact on cancer treatment. Developing a better understanding of their biochemical properties or modes of action, along with improvements in their pharmacologic profiles, clinical design and scheduling will enable the development of more effective therapies. [BMB Reports 2017; 50(7): 355-360].

Fig. 1

Regulation of Ras membrane association. (A) Ras protein with a CAAX motif at the carboxyl terminus undergoes three posttranslational modifications (PTMs). The first modification step is addition of an isoprenyl group to the cysteine of the CAAX motif by farnesyltransferase (FTase). Next, the isoprenylated CAAX protein becomes a substrate for Ras converting enzyme 1 (RCE1), which removes the last three amino acids (the -AAX of the CAAX motif) by endoproteolysis. Finally, the newly exposed isoprenylated cysteine residue is methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). (B) After trafficking and association with the inner face of the plasma membrane, Ras proteins cycle between inactive GDP-bound and active GTP-bound states. Growth factors stimulate transient activation of Ras through activation of GEF. Ras-GTP binds preferentially to downstream effectors. GAP accelerates the intrinsic GTP hydrolysis activity, returning Ras to the inactive state.

Fig. 2

Regulating signaling downstream of Ras. In the active GTP-bound state, Ras interacts with several families of effector proteins, resulting in stimulation of their catalytic activities. Raf protein kinases activate mitogen-activated protein kinase kinases 1 and 2 (MEK1 and MEK2), which leads to ERK1/2 activation. Phosphoinositide 3-kinases (PI3Ks) generate second-messenger lipids and activate numerous target proteins, including the survival signaling kinase AkT/PDK1. Ras binding activates Ral specific guanine-nucleotide-exchange factors (Ral-GEFs) by targeting them to their substrates, Ral GTPases, which are present in the plasma membrane. Phospholipase Cɛ (PLCɛ) catalyses the activation of protein kinase C (PKC) and mobilization of calcium from intracellular stores.