biostudies-literatureSztul ENIDDK NIH HHSNIGMS NIH HHSNational Science Foundation1249-1271https://www.ebi.ac.uk/biostudies/studies/S-EPMC6724607biostudies-literatureUnknown30(11)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 <i>three</i> 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. HMolecular biology of the cellARF GTPases and their GEFs and GAPs: concepts and challenges.PMC6724607R01 GM122802R01 GM056324R01 DK093729P30 DK079626R35 GM122568R01 GM090158R01 GM127361MCB-1615607Chen PWCasanova JESztul ELee FSCherfils JLambright DGRandazzo PAWilhelmi IKahn RAYohe MEDacks JBSchurmann ASanty LCfalseARF GTPases and their GEFs and GAPs: concepts and challenges.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 <i>three</i> 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. H2019-01-01T00:00:00Z2019 May2025-04-05T13:19:45.7Z2019-09-12T07:05:18ZS-EPMC67246073108456710.1091/mbc.E18-12-0820