SEARCH:   Advanced

Blood, 1 August 2004, Vol. 104, No. 3, pp. 667-674. Prepublished online as a Blood First Edition Paper on April 6, 2004; DOI 10.1182/blood-2003-08-2913. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2913v1 104/3/667    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 van de Geijn, G.-J. M. Articles by Touw, I. P. Search for Related Content PubMed PubMed Citation Articles by van de Geijn, G.-J. M. Articles by Touw, I. P. Related Collections Hematopoiesis and Stem Cells Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact Gert-Jan M. van de Geijn, Judith Gits, Lambertus H. J. Aarts, Claudia Heijmans-Antonissen, and Ivo P. Touw From the Institute of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands. Truncated granulocyte colony-stimulating factor receptors (G-CSF-Rs) are implicated in severe congenital neutropenia (SCN) and the consecutive development of acute myeloid leukemia (AML). Mice expressing G-CSF-R truncation mutants (gcsfr-d715) show defective receptor internalization, an increased signal transducer and activator of transcription 5 (STAT5)/STAT3 activation ratio, and hyperproliferative responses to G-CSF treatment. We determined whether a lack of negative feedback by suppressor of cytokine signaling (SOCS) proteins contributes to the signaling abnormalities of G-CSF-R–d715. Expression of SOCS3 transcripts in bone marrow cells from G-CSF–treated gcsfr-d715 mice was approximately 60% lower than in wild-type (WT) littermates. SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays. In contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R–d715, STAT5 activation was no longer affected. This was due mainly to loss of the SOCS3 recruitment site Tyr729, with an additional contribution of the internalization defects of G-CSF-R–d715. Because Tyr729 is also a docking site for the Src homology 2–containing protein tyrosine phosphatase-2 (SHP-2), which binds to and inactivates STAT5, we suggest a model in which reduced SOCS3 expression, combined with the loss of recruitment of both SOCS3 and SHP-2 to the activated receptor complex, determine the increased STAT5/STAT3 activation ratio and the resulting signaling abnormalities projected by truncated G-CSF-R mutants. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Liongue, C. J. Hall, B. A. O'Connell, P. Crosier, and A. C. Ward Zebrafish granulocyte colony-stimulating factor receptor signaling promotes myelopoiesis and myeloid cell migration Blood, March 12, 2009; 113(11): 2535 - 2546. [Abstract] [Full Text] [PDF] M. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. Salipante Neutrophil elastase in cyclic and severe congenital neutropenia Blood, March 1, 2007; 109(5): 1817 - 1824. [Abstract] [Full Text] [PDF] A. D. Panopoulos, L. Zhang, J. W. Snow, D. M. Jones, A. M. Smith, K. C. El Kasmi, F. Liu, M. A. Goldsmith, D. C. Link, P. J. Murray, et al. STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils Blood, December 1, 2006; 108(12): 3682 - 3690. [Abstract] [Full Text] [PDF] J. Piessevaux, D. Lavens, T. Montoye, J. Wauman, D. Catteeuw, J. Vandekerckhove, D. Belsham, F. Peelman, and J. Tavernier Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling J. Biol. Chem., November 3, 2006; 281(44): 32953 - 32966. [Abstract] [Full Text] [PDF] C. H. Mermel, M. L. 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] J. Staerk, C. Lacout, T. Sato, S. O. Smith, W. Vainchenker, and S. N. Constantinescu An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor Blood, March 1, 2006; 107(5): 1864 - 1871. [Abstract] [Full Text] [PDF] D. Zhuang, Y. Qiu, S. J. Haque, and F. Dong Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1 J. Leukoc. Biol., October 1, 2005; 78(4): 1008 - 1015. [Abstract] [Full Text] [PDF] E. van den Akker, Y. Vankan-Berkhoudt, P. J. M. Valk, B. Lowenberg, and R. Delwel The Common Viral Insertion Site Evi12 Is Located in the 5'-Noncoding Region of Gnn, a Novel Gene with Enhanced Expression in Two Subclasses of Human Acute Myeloid Leukemia J. Virol., May 1, 2005; 79(9): 5249 - 5258. [Abstract] [Full Text] [PDF] V. Moucadel and S. N. Constantinescu Differential STAT5 Signaling by Ligand-dependent and Constitutively Active Cytokine Receptors J. Biol. Chem., April 8, 2005; 280(14): 13364 - 13373. [Abstract] [Full Text] [PDF] L. J. Druhan, J. Ai, P. Massullo, T. Kindwall-Keller, M. A. Ranalli, and B. R. Avalos Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia Blood, January 15, 2005; 105(2): 584 - 591. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020