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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2470-2477. Prepublished online as a Blood First Edition Paper on October 7, 2008; DOI 10.1182/blood-2008-05-157073. This Article Full Text (PDF) All Versions of this Article: blood-2008-05-157073v1 113/11/2470    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 Park, I.-K. Articles by Caligiuri, M. A. Search for Related Content PubMed PubMed Citation Articles by Park, I.-K. Articles by Caligiuri, M. A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 13, 2008 Accepted September 15, 2008 The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development Il-Kyoo Park, Chiara Giovenzana, Tiffany L Hughes, Jianhua Yu, Rossana Trotta, and Michael A. Caligiuri* Human Cancer Genetics Program, The Ohio State University, Columbus, OH, United States Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, United States Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, United States The Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, United States * Corresponding author; email: michael.caligiuri{at}osumc.edu. IL-15 is essential for natural killer (NK) cell differentiation. In this study, we assessed whether the receptor tyrosine kinase Axl and its ligand, Gas6, are involved in IL-15-mediated human NK differentiation from CD34+ hematopoietic progenitor cells (HPC). Blocking the Axl-Gas6 interaction with a soluble Axl fusion protein (Axl-Fc) or the vitamin K inhibitor warfarin significantly diminished the absolute number and percentage of CD3-CD56+ NK cells derived from human CD34+ HPC cultured in the presence of IL-15, likely due in part to reduced phosphorylation of STAT5. In addition, CD3-CD56+ NK cells derived from culture of CD34+ HPC with IL-15 and Axl-Fc had a significantly diminished capacity to express IFN- or its master regulator, T-BET. Culture of CD34+ HPC in the presence of c-Kit ligand and Axl-Fc resulted in a significant decrease in the frequency of NK precursor cells responding to IL-15, likely due to reduced c-Kit phosphorylation. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK cell development at least in part via its regulatory effects on both the IL-15 and c-Kit signaling pathways in CD34+ HPC, and to functional NK cell maturation via an effect on the master regulatory transcription factor T-BET. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. C McCann and B. N Ames Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am. J. Clinical Nutrition, October 1, 2009; 90(4): 889 - 907. [Abstract] [Full Text] [PDF] S. Scutera, T. Fraone, T. Musso, P. Cappello, S. Rossi, D. Pierobon, Z. Orinska, R. Paus, S. Bulfone-Paus, and M. Giovarelli Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-{alpha}-Inducible Axl/Gas6 Pathway J. Immunol., September 1, 2009; 183(5): 3004 - 3013. [Abstract] [Full Text] [PDF]

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