The Journal of Experimental Medicine
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Published online 30 August 2004 doi:10.1084/jem.20040762
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 5, 569-580
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Lnk Inhibits Tpo–mpl Signaling and Tpo-mediated Megakaryocytopoiesis

Wei Tong1 and Harvey F. Lodish1,2

1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142
2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139

Address correspondence to Harvey F. Lodish, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142. Phone: (617) 258-5216; Fax: (617) 258-6768; email: lodish{at}wi.mit.edu

Thrombopoietin (Tpo) is the primary cytokine regulating megakaryocyte development and platelet production. Tpo signaling through its receptor, c-mpl, activates multiple pathways including signal transducer and activator of transcription (STAT)3, STAT5, phosphoinositide 3-kinase–Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor and immunoreceptor signaling. Here, we show that Lnk overexpression negatively regulates Tpo-mediated cell proliferation and endomitosis in hematopoietic cell lines and primary hematopoietic cells. Lnk attenuates Tpo-induced S-phase progression in 32D cells expressing mpl, and Lnk decreases Tpo-dependent megakaryocyte growth in bone marrow (BM)–derived megakaryocyte culture. Consistent with this result, we found that in both BM and spleen, Lnk-deficient mice exhibited increased numbers of megakaryocytes with increased ploidy compared with wild-type mice. In addition, Lnk-deficient megakaryocytes derived from BM and spleen showed enhanced sensitivity to Tpo during culture. The absence of Lnk caused enhanced and prolonged Tpo induction of STAT3, STAT5, Akt, and MAPK signaling pathways in CD41+ megakaryocytes. Furthermore, the Src homology 2 domain of Lnk is essential for Lnk's inhibitory function. In contrast, the conserved tyrosine near the COOH terminus is dispensable and the pleckstrin homology domain of Lnk contributes to, but is not essential for, inhibiting Tpo-dependent 32D cell growth or megakaryocyte development. Thus, Lnk negatively modulates mpl signaling pathways and is important for Tpo-mediated megakaryocytopoiesis in vivo.

Key Words: hematopoiesis • megakaryocytes • cytokine receptors • cell proliferation • endomitosis

Abbreviations used in this paper: AGM, aorta-gonad-mesonephros; IRES, internal ribosomal entry site; Lin–, lineage negative; MAPK, mitogen-activated protein kinase; MIG, MSCV-IRES-GFP; PH, pleckstrin homology; PI, propidium iodide; SCF, stem cell factor; SH2, Src homology 2; Tpo, thrombopoietin.


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