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Vol. 14, Issue 12, 4835-4845, December 2003

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A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen

Sigrid A. Rajasekaran ^*, Gopalakrishnapillai Anilkumar ^*, Eri Oshima ^*, James U. Bowie , He Liu , Warren Heston , Neil H. Bander , and Ayyappan K. Rajasekaran ^* ||

^* Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; Department of Chemistry and Biochemistry, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; Department of Urology, Weill Medical College of Cornell University, New York, New York 10021; and Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Submitted November 13, 2002; Revised July 9, 2003; Accepted July 28, 2003
Monitoring Editor: Keith Mostov

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostate cancer and in tumor-associated neovasculature. In this study, we report that PSMA is internalized via a clathrin-dependent endocytic mechanism and that internalization of PSMA is mediated by the five N-terminal amino acids (MWNLL) present in its cytoplasmic tail. Deletion of the cytoplasmic tail abolished PSMA internalization. Mutagenesis of N-terminal amino acid residues at position 2, 3, or 4 to alanine did not affect internalization of PSMA, whereas mutation of amino acid residues 1 or 5 to alanine strongly inhibited internalization. Using a chimeric protein composed of Tac antigen, the -chain of interleukin 2-receptor, fused to the first five amino acids of PSMA (Tac-MWNLL), we found that this sequence is sufficient for PSMA internalization. In addition, inclusion of additional alanines into the MWNLL sequence either in the Tac chimera or the full-length PSMA strongly inhibited internalization. From these results, we suggest that a novel MXXXL motif in the cytoplasmic tail mediates PSMA internalization. We also show that dominant negative µ2 of the adaptor protein (AP)-2 complex strongly inhibits the internalization of PSMA, indicating that AP-2 is involved in the internalization of PSMA mediated by the MXXXL motif.

Abbreviations used: NAALDase, N-acetylated -linked acidic dipeptidase; PSMA, prostate-specific membrane antigen.

^|| Corresponding author. E-mail address: arajasekaran{at}mednet.ucla.edu.

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