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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-07-2250.
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.
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