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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2001-12-0180. This Article Full Text (PDF) All Versions of this Article: 2001-12-0180v1 101/8/3240    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 Zhong, B. Articles by Wei, S. Search for Related Content PubMed PubMed Citation Articles by Zhong, B. Articles by Wei, S. Social Bookmarking                   What's this? Submitted December 6, 2001 Accepted November 10, 2002 Human neutrophils utilize a Rac/Cdc42-dependent MAPK pathway to direct intracellular granule mobilization towards ingested microbial pathogens Bin Zhong, Kun Jiang, Danielle L Gilvary, P K Epling-Burnette, Connie Ritchey, Jinhong Liu, Rosalind J Jackson, Elizabeth Hong-Geller, and Sheng Wei* Immunology Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Los Alamos National Laboratories,, Los Alamos, NM, USA * Corresponding author; email: wei{at}moffitt.usf.edu. Elevated levels of mitogen-activated protein kinase (MAPK/ERK) activity are frequently found in some cancer cells. In efforts to reduce tumor growth, attempts have been made to develop cancer therapeutic agents targeting the MAPK. Here, by use of biological, biochemical, and gene manipulation methods in human PMN, we have identified a key pathway important in normal cell function involving MAPK/ERK in PMN for growth inhibition of C. albicans. Contact with C. albicans triggered MAPK/ERK activation in PMN within 5 min, and blocking of MAPK/ERK activation, either by the pharmacological reagent PD098059 or by dominant-negative MEK expression via vaccinia viral delivery, suppressed anti-microbial activity. Rac and Cdc42, but not Ras or Rho, were responsible for this MAPK/ERK activation. Expression of dominant-negative Rac (N17Rac) or Cdc42 (N17Cdc42) eliminated not only C. albicans-mediated ERK phosphorylation but also phagocytosis and granule migration towards the ingested microbes, whereas dominant-negative Ras (N17Ras) and Rho (N19Rho) did not. PAK1 activation is induced by C. albicans suggesting that PAK1 may also be involved in the Rac1 activation of MAPK/ERK. We conclude from these data that Rac-, Cdc42-dependent activation of MAPK/ERK is a critical event in the immediate phagocytic response of PMN to microbial challenge. Therefore, use of MAPK pharmacological inhibitors for the treatment of cancer may result in the interruption of normal neutrophil function. A balance between therapeutic outcome and undesirable side effects must be attained to achieve successful and safe anti-cancer therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X. Chen, F. Bai, L. Sokol, J. Zhou, A. Ren, J. S. Painter, J. Liu, D. A. Sallman, Y. A. Chen, J. A. Yoder, et al. A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia Blood, April 2, 2009; 113(14): 3226 - 3234. [Abstract] [Full Text] [PDF] K. P. Sundararaj, D. J. Samuvel, Y. Li, A. Nareika, E. H. Slate, J. J. Sanders, M. F. Lopes-Virella, and Y. 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