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J. Biol. Chem., Vol. 282, Issue 20, 15170-15178, May 18, 2007

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Association of Protein-tyrosine Phosphatase MEG2 via Its Sec14p Homology Domain with Vesicle-trafficking Proteins^*

Kan Saito, Scott Williams, Anna Bulankina, Stefan Höning, and Tomas Mustelin¹

From the Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute for Medical Research, La Jolla, California 92037 and the Institute of Biochemistry I, University of Cologne, Joseph-Steizmann-Strasse 52, 50931 Cologne, Germany

The protein-tyrosine phosphatase PTPMEG2 is located on the cytoplasmic face of the enclosing membrane of secretory vesicles, where it regulates vesicle size by promoting homotypic vesicle fusion by dephosphorylating N-ethylmaleimide-sensitive factor, a key regulator of vesicle fusion. Here we address the question of how PTPMEG2 is targeted to this subcellular location. Using a series of deletion mutants, we pinpointed the N-terminal Sec14p homology (SEC14) domain of PTPMEG2, residues 1-261, as the region containing the secretory vesicle targeting signal. This domain, alone or appended to a heterologous protein, was localized to intracellular vesicle membranes. Yeast two-hybrid screening identified a number of secretory vesicle proteins that interacted directly with the SEC14 domain of PTPMEG2, providing a mechanism for PTPMEG2 targeting to secretory vesicles. Two such proteins, mannose 6-phosphate receptor-interacting protein TIP47 and Arfaptin2, were found to alter PTPMEG2 localization when overexpressed, and elimination of TIP47 resulted in loss of PTPMEG2 function. We conclude that the N terminus of PTPMEG2 is necessary for the targeting of this phosphatase to the secretory vesicle compartment by association with other proteins involved in intracellular transport.

Received for publication, September 8, 2006 , and in revised form, February 16, 2007.

^* This work was supported by National Institutes of Health Grant AI55741. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 858-713-6270; E-mail: tmustelin{at}burnham-inst.org.

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