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Blood, 1 July 2004, Vol. 104, No. 1, pp. 73-80. Prepublished online as a Blood First Edition Paper on March 16, 2004; DOI 10.1182/blood-2003-04-1340. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1340v1 104/1/73    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 Chen, C. Articles by Sytkowski, A. J. Search for Related Content PubMed PubMed Citation Articles by Chen, C. Articles by Sytkowski, A. J. Related Collections Hematopoiesis and Stem Cells Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism Changmin Chen, and Arthur J. Sytkowski From the Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA. Stimulation of the erythropoietin (EPO) receptor triggers a cascade of signaling events. We reported that EPO upregulates c-myc expression through 2 pathways in BaF3-EpoR cells—a phosphatidylinositol 3-kinase (PI3K) pathway operating on transcriptional initiation and a Raf-1–mitogen-activated protein kinase (MAPK) pathway affecting elongation. We now show that EPO induces phosphorylation of Raf-1 at serine 338 and within the carboxy-terminal domain, resulting in an electrophoretic mobility change (hyperphosphorylation). Importantly, MEK 1 inhibitor PD98059 blocked only the hyperphosphorylation of Raf-1 but not the phosphorylation at serine 338. This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity. Deletion of the first 184 amino acids of Raf-1, which are involved in its interaction with Ras, had no effect on EPO-induced phosphorylation. Introducing the dominant-negative N17Ras or GAP had no effect on EPO-induced kinase activity of Raf-1 and ELK activation. N17Ras failed to inhibit ELK activation in another cell line—Rauscher murine erythroleukemia— which expresses the EPO receptor endogenously and differentiates in response to the hormone. These results indicate the presence of a Ras-independent mechanism for Raf-1 and MEK activation in these cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Grebien, M. A. Kerenyi, B. Kovacic, T. Kolbe, V. Becker, H. Dolznig, K. Pfeffer, U. Klingmuller, M. Muller, H. Beug, et al. Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2 Blood, May 1, 2008; 111(9): 4511 - 4522. [Abstract] [Full Text] [PDF] C. W. Dawson, L. Laverick, M. A. Morris, G. Tramoutanis, and L. S. Young Epstein-Barr Virus-Encoded LMP1 Regulates Epithelial Cell Motility and Invasion via the ERK-MAPK Pathway J. Virol., April 1, 2008; 82(7): 3654 - 3664. [Abstract] [Full Text] [PDF] S. M. Kumar, G. Acs, D. Fang, M. Herlyn, D. E. Elder, and X. Xu Functional Erythropoietin Autocrine Loop in Melanoma Am. J. Pathol., March 1, 2005; 166(3): 823 - 830. [Abstract] [Full Text] [PDF]

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