Summary of the probe development effort to identify inhibitors of ADP-ribosylation factor GTPase activating protein 1 (ARFGAP1)
Name: Summary of the probe development effort to identify inhibitors of ADP-ribosylation factor GTPase activating protein 1 (ARFGAP1). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: University of North Carolina at Chapel Hill
Assay Provider: Qisheng Zhang, University of North Carolina at Chapel Hill
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1R21NS073041 (Fast Track)
Grant Proposal PI: Qisheng Zhang, University of North Carolina at Chapel Hill
External Assay ID: ARFGAP1_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of ADP-ribosylation factor GTPase activating protein 1 (ARFGAP1).
The low molecular weight ADP-ribosylation factors (Arfs) regulate actin remodeling, vesicle trafficking, membrane lipid composition, and phospholipid metabolism (1). Arfs are members of the Ras family of GTP-binding proteins, switching between the GTP- and GDP-bound forms (2). Arf GTP binding and GTP hydrolysis is regulated by ARFGAPs (ARF GTPase-activating proteins) which associate with the Golgi apparatus and possess a conserved zinc-finger GAP catalytic domain. ARFGAPs such as ARFGAP1 and ASAP1 are found in cell structures involved in vesicle production and trafficking, adhesion, migration, and development (3, 4). ARFGAP1 promotes hydrolysis of ARF1-bound GTP and is required for dissociation of coat proteins from Golgi-derived membranes and vesicles. ARFGAP1 is stimulated by phosphoinosides and inhibited by phosphatidylcholine (4). Dysfunctional regulation of ARFGAPs has been implicated in various diseases, including cancer, alzheimer disease, and autism (3). However, the catalytic mechanism and specific disease-associated roles of ARFGAPs are unclear (2), but recent studies suggest a role for Ca2+ in stimulating ARFGAP-mediated GTP hydrolysis (2). As a result the identification of modulators of ARFGAPs would provide useful tools to elucidate ARFGAP biology (4,5).
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of ADP-ribosylation factor GTPase activating protein 1 (ARFGAP1). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Donaldson, J.G. and C.L. Jackson, ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol, 2011. 12(6): p. 362-75.
2. Ismail, S.A., I.R. Vetter, B. Sot, and A. Wittinghofer, The structure of an Arf-ArfGAP complex reveals a Ca2+ regulatory mechanism. Cell, 2010. 141(5): p. 812-21.
3. Sabe, H., Y. Onodera, Y. Mazaki, and S. Hashimoto, ArfGAP family proteins in cell adhesion, migration and tumor invasion. Curr Opin Cell Biol, 2006. 18(5): p. 558-64.
4. Hashimoto, S., A. Hashimoto, A. Yamada, Y. Onodera, and H. Sabe, Assays and properties of the ArfGAPs, AMAP1 and AMAP2, in Arf6 function. Methods Enzymol, 2005. 404: p. 216-31.
5. Sun, W., J.L. Vanhooke, J. Sondek, and Q. Zhang, High-Throughput Fluorescence Polarization Assay for the Enzymatic Activity of GTPase-Activating Protein of ADP-Ribosylation Factor (ARFGAP). J Biomol Screen, 2011.
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