Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice

• Published in: The Journal of experimental medicine Vol. 195; no. 12; pp. 1599 - 1611
• Main Authors: Velazquez, Laura, Cheng, Alec M, Fleming, Heather E, Furlonger, Caren, Vesely, Shirly, Bernstein, Alan, Paige, Christopher J, Pawson, Tony
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 17.06.2002; The Rockefeller University Press
• Subjects: Animals; Cytokines - metabolism; Flow Cytometry; Hematology; Hematopoiesis, Extramedullary; Hematopoietic Stem Cells - metabolism; Homeostasis; Human health and pathology; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Life Sciences; Mice; Mice, Knockout; Proteins - genetics; Proteins - physiology; Signal Transduction; EPO; FACS; flow cytometric analysis; signal transducer and activator of transcription; IL-3R; mitogen-activated protein kinase; extramedullary hematopoiesis; PI3K; Janus kinase; erythropoietin; EMH; stem cell factor; bone marrow-derived mast cell; MAPK; ES; embryonic stem; IL-3 receptor ␤ chain; pBCR; STAT; JAK; SCF; pre-B cell receptor; PH; pleckstrin domain; B cell receptor; SH2; src homology 2; BMMC; phosphoinositide 3-kinase
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20011883

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.