Alternative titles; symbols
HGNC Approved Gene Symbol: ARFIP2
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:6,476,519-6,481,331 (from NCBI)
The RAC proteins (see RAC1; 602048) are members of the Rho subfamily of Ras-related proteins. Like all members of the Ras superfamily, RAC proteins act as molecular switches and are implicated in the regulation of a number of cellular processes, such as the organization of the actin cytoskeleton. Microinjection of activated RAC (V12Rac) results in rapid actin polymerization and membrane ruffling (Ridley et al., 1992). Van Aelst et al. (1996) used activated human RAC1 in a 2-hybrid screen to identify a protein they called POR1 for partner of RAC1. The POR1 protein binds directly to RAC1, and the interaction is GTP dependent. A mutation in RAC1 shown to abolish membrane ruffling also abolishes interaction with POR1. In addition, a truncated form of the POR1 protein inhibits the ability of activated RAC1 to induce membrane ruffling. The authors suggested a role for POR1 in RAC1-mediated signaling pathways.
ADP-ribosylation factors, or ARFs (e.g., ARF1; 103180), enhance the ADP ribosyltransferase activity of cholera toxin and are implicated in vesicle transport between endoplasmic reticulum and the Golgi complex. A gln71-to-leu (Q71L) or gln71-to-ile (Q71I) mutation in the ARF1 gene slows the rate of GTP hydrolysis, thereby making the mutant constitutively active (Teal et al., 1994). Using a yeast 2-hybrid screen of an HL60 cDNA library with an ARF3 (103190) Q71L mutant as bait, Kanoh et al. (1997) obtained cDNAs encoding arfaptin-1 (605928) and arfaptin-2 (the name arfaptin derives from ARF and the Greek word 'apto,' meaning 'I bind to'). Sequence analysis predicted that the 341-amino acid, hydrophilic arfaptin-2 protein, which is 60% identical to arfaptin-1, contains a leucine zipper motif and several potential phosphorylation sites. Northern blot analysis revealed ubiquitous expression of a 2.1-kb transcript that was relatively higher in liver, pancreas, and placenta. In vitro binding analysis showed that arfaptin-2 binds to nonmyristoylated GTP-bound ARF3, but not to GDP-bound ARF3, and also to ARF1, another class I ARF. It binds with lower affinity to ARF5 (103188), a class II ARF, and with very little affinity to ARF6 (600464), a class III ARF.
Arfaptin-2 (POR1) is a ubiquitously expressed protein implicated in mediating crosstalk between RAC and ARF small GTPases. Tarricone et al. (2001) showed that arfaptin-2 binds specifically to GTP-bound ARF1 and ARF6, but binds to Rac-GTP and Rac-GDP with similar affinities. The x-ray structure of arfaptin reveals an elongated, crescent-shaped dimer of 3-helix coiled-coils. Structures of arfaptin with Rac bound to either GDP or the slowly hydrolysable analog GMPPNP show that the switch regions adopt similar conformations in both complexes. Tarricone et al. (2001) concluded that their data highlighted fundamental differences between the molecular mechanisms of RHO and RAS family signaling, and suggested a model of arfaptin-mediated synergy between the ARF and RHO family signaling pathways.
Peters et al. (2002) demonstrated that expression of arfaptin-2/POR1 in cultured cells induced the formation of pericentriolar and nuclear aggregates, which morphologically resemble mutant huntingtin (613004) aggregates characteristic of Huntington disease (143100). Endogenous arfaptin-2 localizes to aggregates induced by expression of an abnormal amino-terminal fragment of huntingtin that contains polyglutamine expansions. A dominant inhibitory mutant of arfaptin-2 inhibited aggregation of mutant huntingtin, but not in the presence of proteasome inhibitors. Using cell-free biochemical assays, Peters et al. (2002) showed that arfaptin-2 inhibits proteasome activity and demonstrated that expression of arfaptin-2 is increased at sites of neurodegeneration and that the protein localizes to huntingtin aggregates in HD transgenic mouse brains. Peters et al. (2002) concluded that arfaptin-2 is involved in regulating huntingtin protein aggregation, possibly by impairing proteasome function.
Kanoh, H., Williger, B.-T., Exton, J. H. Arfaptin 1, a putative cytosolic target protein of ADP-ribosylation factor, is recruited to Golgi membranes. J. Biol. Chem. 272: 5421-5429, 1997. [PubMed: 9038142] [Full Text: https://doi.org/10.1074/jbc.272.9.5421]
Peters, P. J., Ning, K., Palacios, F., Boshans, R. L., Kazantsev, A., Thompson, L. M., Woodman, B., Bates, G. P., D'Souza-Schorey, C. Arfaptin 2 regulates the aggregation of mutant huntingtin protein. Nature Cell Biol. 4: 240-245, 2002. [PubMed: 11854752] [Full Text: https://doi.org/10.1038/ncb761]
Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D., Hall, A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70: 401-410, 1992. [PubMed: 1643658] [Full Text: https://doi.org/10.1016/0092-8674(92)90164-8]
Tarricone, C., Xiao, B., Justin, N., Walker, P. A., Rittinger, K., Gamblin, S. J., Smerdon, S. J. The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways. Nature 411: 215-219, 2001. [PubMed: 11346801] [Full Text: https://doi.org/10.1038/35075620]
Teal, S. B., Hsu, V. W., Peters, P. J., Klausner, R. D., Donaldson, J. G. An activating mutation in ARF1 stabilizes coatomer binding to Golgi membranes. J. Biol. Chem. 269: 3135-3138, 1994. [PubMed: 8106346]
Van Aelst, L., Joneson, T., Bar-Sagi, D. Identification of a novel Rac1-interacting protein involved in membrane ruffling. EMBO J. 15: 3778-3786, 1996. [PubMed: 8670882]