Editorial
Copyright ©2012 Baishideng. All rights reserved.
World J Pharmacol. Aug 9, 2012; 1(4): 55-64
Published online Aug 9, 2012. doi: 10.5497/wjp.v1.i4.55
Small inhibitors of ADP-ribosylation factor activation and function in mammalian cells
Sylvain G Bourgoin, Mohammed-Amine El Azreq
Sylvain G Bourgoin, Mohammed-Amine El Azreq, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ-CHUL, Quebec G1V 4G2, Canada
Sylvain G Bourgoin, Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec G1V 4G2, Canada
Author contributions: Bourgoin SG and El Azreq MA contributed equally to this paper.
Supported by A Grant from the Canadian Institutes of Health Research (MOP-14790) to Bourgoin SG
Correspondence to: Sylvain G Bourgoin, PhD, Professor, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUL, 2705 boul. Laurier, local T1-49, Quebec G1V 4G2, Canada. sylvain.bourgoin@crchul.ulaval.ca
Telephone: +1-418-6564141-46136 Fax: +1-418-6542765
Received: October 9, 2011
Revised: February 18, 2012
Accepted: July 12, 2012
Published online: August 9, 2012
Abstract

Small GTP-binding proteins of the ADP-ribosylation factor (Arf) family control various cell functional responses including protein transport and recycling between different cellular compartments, phagocytosis, proliferation, cytoskeletal remodelling, and migration. The activity of Arfs is tightly regulated. GTPase-activating proteins (GAPs) inactivate Arfs by stimulating GTP hydrolysis, and guanine nucleotide exchange factors (GEFs) stimulate the conversion of inactive GDP-bound Arf to the active GTP-bound conformation. There is increasing evidence that Arf small GTPases contribute to cancer growth and invasion. Increased expression of Arf6 and of Arf-GEPs, or deregulation Arf-GAP functions have been correlated with enhanced invasive capacity of tumor cells and metastasis. The spatiotemporal specificity of Arf activation is dictated by their GEFs that integrate various signals in stimulated cells. Brefeldin A (BFA), which inactivates a subset of Arf-GEFs, has been very useful for assessing the function of Golgi-localized Arfs. However, specific inhibitors to investigate the individual function of BFA-sensitive and insensitive Arf-GEFs are lacking. In recent years, specific screens have been developed, and new inhibitors with improved selectivity and potency to study cell functional responses regulated by BFA-sensitive and BFA-insensitive Arf pathways have been identified. These inhibitors have been instrumental for our understanding of the spatiotemporal activation of Arf proteins in cells and demonstrate the feasibility of developing small molecules interfering with Arf activation to prevent tumor invasion and metastasis.

Keywords: Golgi; Vesicular transport; Migration; Adhesion; Actin