MDR/PGPs in both mammals and A. thaliana appear to be regulated by en-docytic cycling. Human MDR1 has been localized in DRMs that have been implicated in endocytic membrane trafficking and protein sorting (reviewed in Brown and London, 1998). Human MDR/PGPs in hepatic canalicular cells have been shown to cycle between a relatively large endomembrane pool and the PM in response to taurocholate or cyclic AMP stimulus (Kipp and Arias, 2002) and, in multidrug-resistant cancer cells, MDR1 is actively cycled between the PM and an endosomal membrane compartment via a clathrin-dependent mechanism (Kim et al., 1997). Cycling of MDR/PGPs was also found to be dependent on the action of phosphoinositol-3-kinases (PI3K), which are essential for vesicle trafficking in yeast, animal, and plant cells (Fruman et al., 1998). Additionally, MDR1 labeled with enhanced green fluorescent protein has been shown to undergo vesicular trafficking, dis ruption of which led to retention of PGP in Golgi bodies (Fu et al., 2004). Trafficking of human MDR1 was found to be dependent on a dileucine protein-protein interaction motif at the C-terminus of the protein, but was restored by treatment with cyclosporin A, suggesting an interaction with an immunophilin-like protein (Loo et al., 2005). Consistent with this hypothesis, the immunophilin-like protein FKBP12 has been shown to play an essential role in MDR/PGP function unrelated to FKBP12 enzymatic peptide-prolyl isomerase (PPIase) activity (Hemenway and Heitman, 1996; Mealey et al., 1999). It is likely that FKBP12 regulates MDR/PGP function via a proteinprotein interaction, which can be mimicked by treating C-terminally truncated MDR1 with cyclosporin A.
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