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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-07-2250. This Article Full Text (PDF) All Versions of this Article: 2003-07-2250v1 103/2/571    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 Aarts, L. H Articles by Touw, I. P Search for Related Content PubMed PubMed Citation Articles by Aarts, L. H Articles by Touw, I. P Social Bookmarking                   What's this? Submitted July 7, 2003 Accepted September 15, 2003 Receptor activation and two distinct COOH-terminal motifs control G-CSF receptor distribution and internalization kinetics Lambertus H Aarts, Onno Roovers, Alister C Ward, and Ivo P Touw* Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands * Corresponding author; email: i.touw{at}erasmusmc.nl. We have studied the intracellular distribution and internalization kinetics of the granulocyte colony-stimulating factor receptor (G-CSF-R) in living cells using fusion constructs of wild type or mutant G-CSF-R and enhanced green fluorescent protein (EGFP). Under steady-state conditions the G-CSF-R localized predominantly to the Golgi apparatus, late endosomes and lysosomes, with only low expression on the plasma membrane, resulting from spontaneous internalization. Internalization of the G-CSF-R was significantly accelerated by addition of G-CSF. This ligand-induced switch from slow to rapid internalization required the presence of G-CSF-R residue Trp650, previously shown to be essential for its signaling ability. Both spontaneous and ligand-induced internalization depended on two distinct amino acid stretches in the G-CSF-R COOH-terminus: 749-755, containing a di-leucine internalization motif, and 756-769. Mutation of Ser749 at position -4 of the di-leucine motif to Ala significantly reduced the rate of ligand-induced internalization. In contrast, mutation of Ser749 did not affect spontaneous G-CSF-R internalization, suggesting the involvement of a serine-threonine kinase specifically in ligand-accelerated internalization of the G-CSF-R. COOH-terminal truncation mutants of G-CSF-R, found in severe congenital neutropenia, lack the internalization motifs and were completely defective in both spontaneous and ligand-induced internalization. As a result, these mutants showed constitutively high cell surface expression. 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] Y. Tanaka, N. Tanaka, Y. Saeki, K. Tanaka, M. Murakami, T. Hirano, N. Ishii, and K. Sugamura c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130 Mol. Cell. Biol., August 1, 2008; 28(15): 4805 - 4818. [Abstract] [Full Text] [PDF] H. S. Ramshaw, M. A. Guthridge, F. C. Stomski, E. F. Barry, L. Ooms, C. A. Mitchell, C. G. Begley, and A. F. Lopez The Shc-binding site of the {beta}c subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis Blood, November 15, 2007; 110(10): 3582 - 3590. [Abstract] [Full Text] [PDF] E. M. Sloand, A. S. M. Yong, S. Ramkissoon, E. Solomou, T. C. Bruno, S. Kim, M. Fuhrer, S. Kajigaya, A. J. Barrett, and N. S. Young Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor PNAS, September 26, 2006; 103(39): 14483 - 14488. [Abstract] [Full Text] [PDF] A. Wolfler, S. J. Erkeland, C. Bodner, M. Valkhof, W. Renner, C. Leitner, W. Olipitz, M. Pfeilstocker, C. Tinchon, W. Emberger, et al. A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome Blood, May 1, 2005; 105(9): 3731 - 3736. [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] G.-J. M. van de Geijn, J. Gits, L. H. J. Aarts, C. Heijmans-Antonissen, and I. P. Touw G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact Blood, August 1, 2004; 104(3): 667 - 674. [Abstract] [Full Text] [PDF]

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