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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 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 Citation Map 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. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors Brian J. Lannutti, and Jonathan G. Drachman From the Puget Sound Blood Center, Seattle, WA; and Division of Hematology, University of Washington Medical Center, Seattle. In this study we demonstrate that thrombopoietin (TPO)–stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, 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 Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2), Shc, signal transducer and activator of transcription (STAT)5, or STAT3. In contrast, pretreatment of cells with PP2 increased Erk1/2 (mitogen-activated protein kinase [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. Croom, D. Metcalf, J. E. Collinge, M. J. Maxwell, M. L. Hibbs, W. S. Alexander, et al. A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency J. Immunol., February 15, 2009; 182(4): 2020 - 2029. [Abstract] [Full Text] [PDF] N. K. Williams, I. S. Lucet, S. P. Klinken, E. Ingley, and J. Rossjohn Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State J. Biol. 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McLemore, F. Liu, S. Pereira, J. Woloszynek, C. A. Lowell, and D. C. Link Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis Blood, October 15, 2006; 108(8): 2562 - 2568. [Abstract] [Full Text] [PDF] Y. Zhao, D. He, B. Saatian, T. Watkins, E. Wm. Spannhake, N. J. Pyne, and V. Natarajan Regulation of Lysophosphatidic Acid-induced Epidermal Growth Factor Receptor Transactivation and Interleukin-8 Secretion in Human Bronchial Epithelial Cells by Protein Kinase C{delta}, Lyn Kinase, and Matrix Metalloproteinases J. Biol. Chem., July 14, 2006; 281(28): 19501 - 19511. [Abstract] [Full Text] [PDF] T. Pertel, D. Zhu, R. A. Panettieri, N. Yamaguchi, C. W. Emala, and C. A. Hirshman Expression and muscarinic receptor coupling of Lyn kinase in cultured human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L492 - L500. [Abstract] [Full Text] [PDF] B. J. Lannutti, N. Blake, M. J. Gandhi, J. A. Reems, and J. G. 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