The Journal of Experimental Medicine
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Published 17 June 2002. doi:10.1084/jem.20011883
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© Rockefeller University Press, 0022-1007/2002/6/1599/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 12, June 17, 2002 1599-1611

Cytokine Signaling and Hematopoietic Homeostasis Are Disrupted in Lnk-deficient Mice

Laura Velazquez1, Alec M. Cheng3, Heather E. Fleming4,5, Caren Furlonger4, Shirly Vesely1, Alan Bernstein1,2,6, Christopher J. Paige4,5 and Tony Pawson1,2

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital
2 Department of Medical and Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada
3 Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110
4 Ontario Cancer Institute, Princess Margaret Hospital, University Health Network
5 Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada
6 The Canadian Institutes of Health Research, Ottawa, Ontario K1A 0W9, Canada

Address correspondence to T. Pawson, Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. Phone: 416-586-8262; Fax: 416-586-8869; E-mail: pawson{at}mshri.on.ca

The adaptor protein Lnk, and the closely related proteins APS and SH2B, form a subfamily of SH2 domain-containing proteins implicated in growth factor, cytokine, and immunoreceptor signaling. To elucidate the physiological function of Lnk, we derived Lnk-deficient mice. Lnk-/- mice are viable, but display marked changes in the hematopoietic compartment, including splenomegaly and abnormal lymphoid and myeloid homeostasis. The in vitro proliferative capacity and absolute numbers of hematopoietic progenitors from Lnk-/- mice are greatly increased, in part due to hypersensitivity to several cytokines. Moreover, an increased synergy between stem cell factor and either interleukin (IL)-3 or IL-7 was observed in Lnk-/- cells. Furthermore, Lnk inactivation causes abnormal modulation of IL-3 and stem cell factor–mediated signaling pathways. Consistent with these results, we also show that Lnk is highly expressed in multipotent cells and committed precursors in the erythroid, megakaryocyte, and myeloid lineages. These data implicate Lnk as playing an important role in hematopoiesis and in the regulation of growth factor and cytokine receptor–mediated signaling.

Key Words: knockout • hematopoiesis • cell proliferation • growth factors • signal transduction


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