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

Journal of Experimental Medicine - Tập 195 Số 12 - Trang 1599-1611 - 2002
Laura Evelia Torres Velázquez1, Alec M. Cheng2, Heather E. Fleming3,4, Caren Furlonger3, Shirly M. Vesely5, Alan Bernstein5,6,7, Christopher J. Paige3,4, Tony Pawson5,6
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
2Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110
34Ontario Cancer Institute, Princess Margaret Hospital, University Health Network
45Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada
51Samuel Lunenfeld Research Institute, Mount Sinai Hospital
62Department of Medical and Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada
76The Canadian Institutes of Health Research, Ottawa, Ontario K1A 0W9, Canada

Tóm tắt

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.

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Journal of Experimental Medicine

Tập 195 Số 12

1599-1611

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