ARF GTPases and their GEFs and GAPs: concepts and challenges

Mol Biol Cell. 2019 May 15;30(11):1249-1271. doi: 10.1091/mbc.E18-12-0820.

Elizabeth Sztul ¹, Pei-Wen Chen ², James E Casanova ³, Jacqueline Cherfils ⁴, Joel B Dacks ⁵, David G Lambright ⁶, Fang-Jen S Lee ⁷, Paul A Randazzo ⁸, Lorraine C Santy ⁹, Annette Schürmann ¹⁰, Ilka Wilhelmi ¹⁰, Marielle E Yohe ¹¹, Richard A Kahn ¹²

Affiliations

1 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
2 Department of Biology, Williams College, Williamstown, MA 01267.
3 Department of Cell Biology, University of Virginia, Charlottesville, VA 22908.
4 Laboratoire de Biologie et Pharmacologie Appliquée, CNRS and Ecole Normale Supérieure Paris-Saclay, 94235 Cachan, France.
5 Division of Infectious Disease, Department of Medicine, University of Alberta, Edmonton, AB T6G 2H7, Canada.
6 Program in Molecular Medicine and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Amherst, MA 01605.
7 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
8 Laboratory of Cellular and Molecular Biology and.
9 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802.
10 German Institute of Human Nutrition, 85764 Potsdam-Rehbrücke, Germany.
11 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
12 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322-3050.

PMID: 31084567 DOI: 10.1091/mbc.E18-12-0820

Abstract

Detailed structural, biochemical, cell biological, and genetic studies of any gene/protein are required to develop models of its actions in cells. Studying a protein family in the aggregate yields additional information, as one can include analyses of their coevolution, acquisition or loss of functionalities, structural pliability, and the emergence of shared or variations in molecular mechanisms. An even richer understanding of Cell Biology can be achieved through evaluating functionally linked protein families. In this review, we summarize current knowledge of three protein families: the ARF GTPases, the guanine nucleotide exchange factors (ARF GEFs) that activate them, and the GTPase-activating proteins (ARF GAPs) that have the ability to both propagate and terminate signaling. However, despite decades of scrutiny, our understanding of how these essential proteins function in cells remains fragmentary. We believe that the inherent complexity of ARF signaling and its regulation by GEFs and GAPs will require the concerted effort of many laboratories working together, ideally within a consortium to optimally pool information and resources. The collaborative study of these three functionally connected families (≥70 mammalian genes) will yield transformative insights into regulation of cell signaling.

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