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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2562-2568. Prepublished online as a Blood First Edition Paper on June 13, 2006; DOI 10.1182/blood-2006-05-024307. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-024307v1 108/8/2562    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 Mermel, C. H Articles by Link, D. C Search for Related Content PubMed PubMed Citation Articles by Mermel, C. H Articles by Link, D. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 19, 2006 Accepted May 31, 2006 Src-family kinases are important negative regulators of G-CSF dependent granulopoiesis Craig H Mermel, Morgan L McLemore, Fulu Liu, Shalini Pereira, Jill Woloszynek, Clifford A Lowell, and Daniel C Link* Division of Oncology, Washington University, Missouri, USA Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas Department of Laboratory Medicine, University of California, San Francisco, CA, USA * Corresponding author; email: dlink{at}im.wustl.edu. Granulocyte colony stimulating factor (G-CSF) is the principal cytokine regulating granulopoiesis. Truncation mutations of the G-CSF receptor (G-CSFR) are associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia. Though increased proliferative signaling by a representative G-CSFR truncation mutation (termed d715) has been documented, the molecular basis for this hyperproliferative phenotype has not been fully characterized. Given the accumulating evidence implicating Src-family kinases in the transduction of cytokine receptor signals, the role of these kinases in the regulation of G-CSF signaling was examined. We show that Hck and Lyn, Src-family kinases expressed in myeloid cells, are negative regulators of granulopoiesis that act at distinct stages of granulocytic differentiation. Whereas Hck regulates the G-CSF induced proliferation of granulocytic precursors, Lyn regulates the production of myeloid progenitors. Interestingly, d715 G-CSFR myeloid progenitors were resistant to the growth-stimulating effect of treatment with a Src kinase inhibitor. Together, these data establish Lyn and Hck as key negative regulators of granulopoiesis and raise the possibility that loss of Src-family kinase activation by the d715 G-CSFR may contribute to its hyperproliferative phenotype. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. D. Jack, L. Zhang, and A. D. Friedman M-CSF elevates c-Fos and phospho-C/EBP{alpha}(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification Blood, September 3, 2009; 114(10): 2172 - 2180. [Abstract] [Full Text] [PDF] M. P. Nelson, A. E. Metz, S. Li, C. A. Lowell, and C. Steele The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses to Pneumocystis murina Infect. Immun., May 1, 2009; 77(5): 1790 - 1797. [Abstract] [Full Text] [PDF] G. Zhu, M. M. Augustine, T. Azuma, L. Luo, S. Yao, S. Anand, A. C. Rietz, J. Huang, H. Xu, A. S. Flies, et al. B7-H4-deficient mice display augmented neutrophil-mediated innate immunity Blood, February 19, 2009; 113(8): 1759 - 1767. [Abstract] [Full Text] [PDF] S. Shivtiel, O. Kollet, K. Lapid, A. Schajnovitz, P. Goichberg, A. Kalinkovich, E. Shezen, M. Tesio, N. Netzer, I. Petit, et al. CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules J. Exp. Med., September 29, 2008; 205(10): 2381 - 2395. [Abstract] [Full Text] [PDF] C. Dos Santos, C. Demur, V. Bardet, N. Prade-Houdellier, B. Payrastre, and C. Recher A critical role for Lyn in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2269 - 2279. [Abstract] [Full Text] [PDF] M. Hiyoshi, S. Suzu, Y. Yoshidomi, R. Hassan, H. Harada, N. Sakashita, H. Akari, K. Motoyoshi, and S. Okada Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor Blood, January 1, 2008; 111(1): 243 - 250. [Abstract] [Full Text] [PDF] M. B. Miranda, R. L. Redner, and D. E. Johnson Inhibition of Src family kinases enhances retinoic acid induced gene expression and myeloid differentiation Mol. Cancer Ther., December 1, 2007; 6(12): 3081 - 3090. [Abstract] [Full Text] [PDF]

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