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.
Cytokine Signaling and Hematopoietic Homeostasis Are Disrupted in Lnk-deficient Mice
Abbreviations used in this paper: BCR, B cell receptor; BMMC, bone marrow–derived mast cell; EMH, extramedullary hematopoiesis; EPO, erythropoietin; ES, embryonic stem; FACS, flow cytometric analysis; IL-3Rβ, IL-3 receptor β chain; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; pBCR, pre-B cell receptor; PH, pleckstrin domain; PI3K, phosphoinositide 3-kinase; SCF, stem cell factor; SH2, src homology 2; STAT, signal transducer and activator of transcription.
Laura Velazquez, Alec M. Cheng, Heather E. Fleming, Caren Furlonger, Shirly Vesely, Alan Bernstein, Christopher J. Paige, Tony Pawson; Cytokine Signaling and Hematopoietic Homeostasis Are Disrupted in Lnk-deficient Mice . J Exp Med 17 June 2002; 195 (12): 1599–1611. doi: https://doi.org/10.1084/jem.20011883
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