Article abstract
Nature Cell Biology 6, 831 - 839 (2004)
Published online: 22 August 2004 | doi:10.1038/ncb1164
Control of vesicle fusion by a tyrosine phosphatase
Huong Huynh1,5, Nunzio Bottini1,5, Scott Williams1, Vera Cherepanov2, Lucia Musumeci1, Kan Saito1, Shane Bruckner1, Eric Vachon2, Xiaodong Wang1, Joshua Kruger2, Chung-Wai Chow2, Maurizio Pellecchia1, Edvard Monosov1, Peter A. Greer3, William Trimble4, Gregory P. Downey2 & Tomas Mustelin1
Abstract
The tyrosine phosphatase PTP-MEG2 is targeted by its amino-terminal Sec14p homology domain to the membrane of secretory vesicles. There it regulates vesicle size by promoting homotypic vesicle fusion by a mechanism that requires its catalytic activity. Here, we identify N-ethylmaleimide-sensitive factor (NSF), a key regulator of vesicle fusion, as a substrate for PTP-MEG2. PTP-MEG2 reduced the phosphotyrosine content of NSF and co-localized with NSF and syntaxin 6 in intact cells. Furthermore, endogenous PTP-MEG2 co-immunoprecipitated with endogenous NSF. Phosphorylation of NSF at Tyr 83, as well as an acidic substitution at the same site, increased its ATPase activity and prevented 
SNAP binding. Conversely, expression of a Y83F mutant of NSF caused spontaneous fusion events. Our results suggest that the molecular mechanism by which PTP-MEG2 promotes secretory vesicle fusion involves the local release of NSF from a tyrosine-phosphorylated, inactive state. This represents a novel mechanism for localized regulation of NSF and the first demonstrated role for a protein tyrosine phosphatase in the regulated secretory pathway.
- Program of Inflammation, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
- Division of Respirology, Department of Medicine, University of Toronto, Rm 6264 Medical Sciences Building, Clinical Sciences, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
- Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, ON, Canada.
- Program in Cell Biology, Hospital for Sick Children, and Department of Biochemistry, University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada.
- These authors contributed equally to this work.
Correspondence to: Tomas Mustelin1 e-mail: tmustelin@burnham-inst.org
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