The Journal of Experimental Medicine
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Published 5 December 2005. doi:10.1084/jem.20051108
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1587-1597
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ARTICLE

 Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function

Yingchun Wang1, Eric Vachon1, Jinyi Zhang2, Vera Cherepanov1, Joshua Kruger1, Jun Li1, Kan Saito3, Patrick Shannon4, Nunzio Bottini3, Huong Huynh3, Heyu Ni5, Hong Yang5, Colin McKerlie6, Sue Quaggin2,8, Zhizhuang Joe Zhao7, Philip A. Marsden8, Tomas Mustelin3, Katherine A. Siminovitch2, and Gregory P. Downey1

1 Division of Respirology, Department of Medicine, and the McLaughlin Center for Molecular Medicine, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario M5S 1A8, Canada
2 Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
3 Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute, La Jolla, CA 92037
4 Department of Laboratory Medicine and Pathobiology, Toronto Western Hospital of the University Health Network, Toronto, Ontario M5G 2M9, Canada
5 St. Michael's Hospital Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto and Canadian Blood Services, Toronto, Ontario M5B 1W8, Canada
6 Research Institute of the Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
7 Hematology/Oncology Division, Department of Medicine, Department of Veterans Affairs Medical Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37235
8 Division of Nephrology, Department of Medicine, and Research Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada

CORRESPONDENCE Gregory P. Downey: gregory.downey{at}utoronto.ca

MEG2, a protein tyrosine phosphatase with a unique NH2-terminal lipid-binding domain, binds to and is modulated by the polyphosphoinositides PI(4,5)P2 and PI(3,4,5)P3. Recent data implicate MEG2 in vesicle fusion events in leukocytes. Through the genesis of Meg2-deficient mice, we demonstrate that Meg2–/– embryos manifest hemorrhages, neural tube defects including exencephaly and meningomyeloceles, cerebral infarctions, abnormal bone development, and >90% late embryonic lethality. T lymphocytes and platelets isolated from recombination activating gene 2–/– mice transplanted with Meg2–/– embryonic liver–derived hematopoietic progenitor cells showed profound defects in activation that, in T lymphocytes, was attributable to impaired interleukin 2 secretion. Ultrastructural analysis of these lymphocytes revealed near complete absence of mature secretory vesicles. Taken together, these observations suggest that MEG2-mediated modulation of secretory vesicle genesis and function plays an essential role in neural tube, vascular, and bone development as well as activation of mature platelets and lymphocytes.

Abbreviations used: ES, embryonic stem; NSF, N-ethylmaleimide sensitive factor; PTP, protein tyrosine phosphatase; SNAP, soluble NSF attachment protein; SNARE, soluble NSF attachment protein receptor; VAMP, vesicle-associated membrane protein.


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