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(Received for publication, August 27, 1997)
From the Departments of Members of the chemokine receptor family CCR5 and
CXCR4 have recently been shown to be involved in the entry of human
immunodeficiency virus (HIV) into target cells. Here, we investigated
the regulation of CXCR4 in rat basophilic leukemia cells (RBL-2H3)
stably transfected with wild type (Wt CXCR4) or a cytoplasmic tail
deletion mutant (
Volume 272, Number 45,
Issue of November 7, 1997
pp. 28726-28731
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Regulation of Human Chemokine Receptors CXCR4
ROLE OF PHOSPHORYLATION IN DESENSITIZATION AND
INTERNALIZATION
,
,
,
,
and§§
Medicine and
§§ Immunology, Duke University Medical Center,
Durham, North Carolina 27710, the ¶ Instuito di Ricerche
Farmacologiche, "Mario Negri," Milan, Italy, the ** James Graham
Brown Cancer Center, Louisville, Kentucky 40292, and the
Department of Immunology, Berlex
Biosciences, Richmond, California 94804
Cyto CXCR4) of CXCR4. The ligand, stromal cell
derived factor-1 (SDF-1) stimulated higher G-protein activation,
inositol phosphate generation, and a more sustained calcium elevation
in cells expressing Cyto CXCR4 relative to Wt CXCR4. SDF-1 and
phorbol 12-myristate 13-acetate (PMA), but not a membrane permeable
cAMP analog induced rapid phosphorylation as well as desensitization of
Wt CXCR4. Phosphorylation of Cyto CXCR4 was not detected under any
of these conditions. Despite lack of receptor phosphorylation, calcium mobilization by SDF-1 in Cyto CXCR4 cells was partially desensitized by prior treatment with SDF-1. Of interest, the rapid release of
calcium was inhibited without affecting the sustained calcium elevation, indicating independent regulatory pathways for these processes. PMA completely inhibited phosphoinositide hydrolysis and
calcium mobilization in Wt CXCR4 but only partially inhibited these
responses in Cyto CXCR4. cAMP also partially inhibited these
responses in both Wt CXCR4 and Cyto CXCR4. SDF-1, PMA, and cAMP
caused phosphorylation of phospholipase C
3 in Wt and Cyto CXCR4
cells. Both SDF-1 as well as PMA induced rapid internalization of Wt
CXCR4. SDF-1 but not PMA induced internalization of Cyto CXCR4
albeit at reduced levels relative to Wt CXCR4. These results indicate
that signaling and internalization of CXCR4 are regulated by receptor
phosphorylation dependent and independent mechanisms. Desensitization
of CXCR4 signaling, independent of receptor phosphorylation, appears to
be a consequence of the phosphorylation of phospholipase C3.
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