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Review
, 70 (1), 1-11

RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer

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Review

RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer

Chao Yan et al. Pharmacol Rev.

Abstract

More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being the commonly mutated in tumors. These RAS mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, RALA and RALB, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.

Figures

Fig. 1.
Fig. 1.
Structure comparison between human RALA and RALB proteins. Structure models of RALA-GDP, RALA-GNP, RALB-GDP, RALB-GNP are shown in ribbon representation. GDP and GNP (nonhydrolyzable form of GTP) is shown in yellow, Mg is shown as a green sphere, α-helices are shown in red, and β-sheets are shown in cyan. Models were generated with Accelrys Discovery Studio software (San Diego, CA) using published structures.
Fig. 2.
Fig. 2.
(A) The three most characterized effector signaling pathways downstream of RAS. (B) The GDP-GTP cycle of RAL small GTPases. Upstream signals stimulate binding of RALGEF that triggers GDP-GTP exchange, resulting in the activation of RAL. RAL-GTP can then bind to its downstream effector proteins such as RALBP1. Finally, RALGAPs bind to RAL-GTP and hydrolyze GTP to GDP, cycling RAL back to its inactive GDP-bound form.
Fig. 3.
Fig. 3.
Targeting the allosteric site of RAL. Structure of inactive (A) and active (B) RALA, red sphere represents the allosteric site that is only exposed in the GDP-bound form. GNP: nonhydrolyzable form of GTP used in X-ray crystallography. (C) Chemical structure of the first small molecule inhibitor of RAL, BQU57. (D) BQU57 binds to the allosteric site of RALA-GDP.

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