Review
Ral small GTPase signaling and oncogenesis: More than just 15 minutes of fame

https://doi.org/10.1016/j.bbamcr.2014.09.004Get rights and content
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Highlights

  • Ral proteins are members of the Ras superfamily of small GTPases.

  • Ral functions as GTP–GDP regulated binary on–off switch in signaling.

  • Ral proteins are key downstream effectors of Ras oncoprotein-mediated oncogenesis.

  • Ral regulates vesicular transport and actin organization.

Abstract

Since their discovery in 1986, Ral (Ras-like) GTPases have emerged as critical regulators of diverse cellular functions. Ral-selective guanine nucleotide exchange factors (RalGEFs) function as downstream effectors of the Ras oncoprotein, and the RalGEF–Ral signaling network comprises the third best characterized effector of Ras-dependent human oncogenesis. Because of this, Ral GTPases as well as their effectors are being explored as possible therapeutic targets in the treatment of RAS mutant cancer. The two Ral isoforms, RalA and RalB, interact with a variety of downstream effectors and have been found to play key and distinct roles in both normal and neoplastic cell physiology including regulation of vesicular trafficking, migration and invasion, tumor formation, metastasis, and gene expression. In this review we provide an overview of Ral biochemistry and biology, and we highlight recent discoveries.

Abbreviations

CAAX
cysteine-aliphatic-aliphatic-terminal amino acid
DMBA
7,12-dimethylbenz[α]anthracene
EGF
epidermal growth factor
EH
Eps homology
ER
endoplasmic reticulum
GAP
GTPase activating protein
GEF
guanine nucleotide exchange factor
ICMT
isoprenylcysteine carboxyl methyltransferase
NSCLC
non-small cell lung cancer
PDAC
pancreatic ductal adenocarcinoma
PH
pleckstrin homology domain
PKA
protein kinase A
PKC
protein kinase C
RA
Ras-association domain
RBD
Ral-binding domain
RCE1
Ras converting enzyme 1
REM
Ras exchanger motif
SI/II
SwitchI/II
SCC
squamous cell carcinoma
SH3
Src homology 3 domain

Keywords

Exocyst
GTPase activating protein
Guanine nucleotide exchange factor
Ras
Rho
Small GTPase

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