Different N-Terminal Motifs Determine Plasma Membrane Targeting of the Human Concentrative Nucleoside Transporter 3 in Polarized and Nonpolarized Cells

作者：Errasti Murugarren Ekaitz; Javier Casado F; Pastor Anglada Marcal^*

来源：Molecular Pharmacology, 2010, 78(5): 795-803.

DOI：10.1124/mol.110.065920

Human concentrative nucleoside transporter 3 ( hCNT3) is a broad-selectivity, high-affinity protein implicated in the uptake of most nucleoside-derived anticancer and antiviral drugs. Regulated trafficking of hCNT3 has been recently postulated as a suitable way to improve nucleoside-based therapies. Moreover, the recent identification of a putative novel hCNT3-type transporter lacking the first 69 amino acids and retained at the endoplasmic reticulum anticipated that the N terminus of hCNT3 contains critical motifs implicated in trafficking. In the current study, we have addressed this issue by using deletions and site-directed mutagenesis and plasma membrane expression and nucleoside uptake kinetic analysis. Data reveal that 1) a segment between amino acids 50 and 62 contains plasma membrane-sorting determinants in nonpolarized cells; 2) in particular, the Val(57)-Thr(58)-Val(59) tripeptide seems to be the core of the export signal, whereas acidic motifs upstream and downstream of it seem to be important for the kinetics of the process; and 3) in polarized epithelia, the beta-turn-forming motif (17)VGFQ(20) is necessary for proper apical expression of the protein.

• 出版日期2010-11