Bi-directional vesicular traffic is required to secrete proteins, to internalize proteins, and to generate the asymmetries in lipid and protein composition that underlie organellogenesis, cell growth and differentiation. Membrane traffic is a complex process that requires integration with virtually every other cell function, including the cell cycle, protein synthesis, ribosome assembly, and lipid metabolism. While a complete loss of such a highly integrated process would damage cells irreparably, more subtle defects in membrane traffic impact a number of human diseases, including Alzheimer's disease, cystic fibrosis, and others. The recruitment of distinct protein coat complexes is a first step in the construction of specific vesicles involved in membrane traffic. ADP-ribosylation factors (ARFs) are GTPases and regulators of vesicular traffic, though the molecular mechanisms are still only incompletely understood. We discuss a model to explain the role of ARF in a homologous vesicle budding reactions that reinforces the idea that the recruitment of soluble proteins to the bud is the initiating and/or rate-limiting step in vesicle biogenesis in membrane traffic. We propose that a minimum of three components (ARF, a transmembrane docking site, and an adaptor or coat complex) are required for formation of vesicles emanating from the Golgi/TGN. Seven of these ARF-dependent coat complexes have been described. Because all of these adaptors are recruited to Golgi/TGN membranes by ARF we sought a regulatory mechanism that could provide added levels of regulation and specificity of vesicle budding from a common membrane source. We further propose that protein phosphorylation acts in concert with cycles of ARF activation/inactivation through regulated GTP binding to regulate vesicle biogenesis or specificity. We propose to test the hypothesis that MlNTs represent a novel family of ARF-dependent adaptors involved in vesicle budding from the Golgi/TGN and that the Alzheimer's protein (amyloid precursor protein; APP) is the transmembrane protein that docks the ARF-MINT complex to membranes. This provides a model for the physiological role of APP in our cells and is likely to lead to a better understanding of the pathophysiology resulting from the secretion of proteolytic products of APP that occurs in Alzheimer's disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Development and Function Integrated Review Group (CDF)
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Shapiro, Bert I
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Emory University
Schools of Medicine
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Caster, Amanda H; Kahn, Richard A (2013) Recruitment of the Mint3 adaptor is necessary for export of the amyloid precursor protein (APP) from the Golgi complex. J Biol Chem 288:28567-80
Caster, Amanda H; Sztul, Elizabeth; Kahn, Richard A (2013) A role for cargo in Arf-dependent adaptor recruitment. J Biol Chem 288:14788-804
Herskowitz, Jeremy H; Offe, Katrin; Deshpande, Aniruddha et al. (2012) GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-? production. Mol Biol Cell 23:2645-57
East, Michael P; Kahn, Richard A (2011) Models for the functions of Arf GAPs. Semin Cell Dev Biol 22:3-9
Herskowitz, Jeremy H; Seyfried, Nicholas T; Gearing, Marla et al. (2011) Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA alters amyloid-beta production. J Biol Chem 286:6117-27
Jian, Xiaoying; Cavenagh, Margaret; Gruschus, James M et al. (2010) Modifications to the C-terminus of Arf1 alter cell functions and protein interactions. Traffic 11:732-42
Ben-Tekaya, Houchaima; Kahn, Richard A; Hauri, Hans-Peter (2010) ADP ribosylation factors 1 and 4 and group VIA phospholipase A? regulate morphology and intraorganellar traffic in the endoplasmic reticulum-Golgi intermediate compartment. Mol Biol Cell 21:4130-40
Kahn, Richard A (2009) Toward a model for Arf GTPases as regulators of traffic at the Golgi. FEBS Lett 583:3872-9
Kahn, Richard A; Bruford, Elspeth; Inoue, Hiroki et al. (2008) Consensus nomenclature for the human ArfGAP domain-containing proteins. J Cell Biol 182:1039-44
Shrivastava-Ranjan, Punya; Faundez, Victor; Fang, Guofu et al. (2008) Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network. Mol Biol Cell 19:51-64

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