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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3736-3743. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-10-3566. This Article Full Text (PDF) All Versions of this Article: 2003-10-3566v1 103/10/3736    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lannutti, B. J Articles by Drachman, J. G Search for Related Content PubMed PubMed Citation Articles by Lannutti, B. J Articles by Drachman, J. G Social Bookmarking                   What's this? Submitted October 20, 2003 Accepted January 8, 2004 Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors Brian J Lannutti* and Jonathan G Drachman Puget Sound Blood Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA * Corresponding author; email: brianl{at}psbc.org. In this study we demonstrate that thrombopoietin (TPO)-stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors PP1 and PP2, we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyn-deficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Tyr112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of JAK2, Shc, STAT5, or STAT3. In contrast, pretreatment of cells with PP2 increased Erk1/2 (MAPK) phosphorylation and in vitro kinase activity, particularly after prolonged TPO stimulation. Taken together, our results show that Mpl stimulation results in the activation of Lyn kinase, which appears to limit the proliferative response through a signaling cascade that regulates MAPK activity. These data suggest that SFKs modify the rate of TPO-induced proliferation and are likely to affect cell cycle regulation during megakaryocytopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Verhagen, M. E. Wallace, A. Goradia, S. A. Jones, H. A. 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