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Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2.

Publication ,  Journal Article
Richardson, RM; Pridgen, BC; Haribabu, B; Snyderman, R
Published in: J Biol Chem
March 31, 2000

To investigate the regulation of the CCR1 chemokine receptor, a rat basophilic leukemia (RBL-2H3) cell line was modified to stably express epitope-tagged receptor. These cells responded to RANTES (regulated upon activation normal T expressed and secreted), macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-2 to mediate phospholipase C activation, intracellular Ca(2+) mobilization and exocytosis. Upon activation, CCR1 underwent phosphorylation and desensitization as measured by diminished GTPase stimulation and Ca(2+) mobilization. Alanine substitution of specific serine and threonine residues (S2 and S3) or truncation of the cytoplasmic tail (DeltaCCR1) of CCR1 abolished receptor phosphorylation and desensitization of G protein activation but did not abolish desensitization of Ca(2+) mobilization. S2, S3, and DeltaCCR1 were also resistant to internalization, mediated greater phosphatidylinositol hydrolysis and sustained Ca(2+) mobilization, and were only partially desensitized by RANTES, relative to S1 and CCR1. To study CCR1 cross-regulation, RBL cells co-expressing CCR1 and receptors for interleukin-8 (CXCR1, CXCR2, or a phosphorylation-deficient mutant of CXCR2, 331T) were produced. Interleukin-8 stimulation of CXCR1 or CXCR2 cross-phosphorylated CCR1 and cross-desensitized its ability to stimulate GTPase activity and Ca(2+) mobilization. Interestingly, CCR1 cross-phosphorylated and cross-desensitized CXCR2, but not CXCR1. Ca(2+) mobilization by S3 and DeltaCCR1 were also cross-desensitized by CXCR1 and CXCR2 despite lack of receptor phosphorylation. In contrast to wild type CCR1, S3 and DeltaCCR1, which produced sustained signals, cross-phosphorylated and cross-desensitized responses to CXCR1 as well as CXCR2. Taken together, these results indicate that CCR1-mediated responses are regulated at several steps in the signaling pathway, by receptor phosphorylation at the level of receptor/G protein coupling and by an unknown mechanism at the level of phospholipase C activation. Moreover selective cross-regulation among chemokine receptors is, in part, a consequence of the strength of signaling (i.e. greater phosphatidylinositol hydrolysis and sustained Ca(2+) mobilization) which is inversely correlated with the receptor's susceptibility to phosphorylation. Since many chemokines activate multiple chemokine receptors, selective cross-regulation among such receptors may play a role in their immunomodulation.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

March 31, 2000

Volume

275

Issue

13

Start / End Page

9201 / 9208

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Receptors, Interleukin-8B
  • Receptors, Interleukin-8A
  • Receptors, Interleukin
  • Receptors, Chemokine
  • Receptors, CCR1
  • Receptor Cross-Talk
  • Rats
  • Phosphorylation
  • Phospholipase C beta
 

Citation

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Richardson, R. M., Pridgen, B. C., Haribabu, B., & Snyderman, R. (2000). Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2. J Biol Chem, 275(13), 9201–9208. https://doi.org/10.1074/jbc.275.13.9201
Richardson, R. M., B. C. Pridgen, B. Haribabu, and R. Snyderman. “Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2.J Biol Chem 275, no. 13 (March 31, 2000): 9201–8. https://doi.org/10.1074/jbc.275.13.9201.
Richardson RM, Pridgen BC, Haribabu B, Snyderman R. Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2. J Biol Chem. 2000 Mar 31;275(13):9201–8.
Richardson, R. M., et al. “Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2.J Biol Chem, vol. 275, no. 13, Mar. 2000, pp. 9201–08. Pubmed, doi:10.1074/jbc.275.13.9201.
Richardson RM, Pridgen BC, Haribabu B, Snyderman R. Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2. J Biol Chem. 2000 Mar 31;275(13):9201–9208.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

March 31, 2000

Volume

275

Issue

13

Start / End Page

9201 / 9208

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Receptors, Interleukin-8B
  • Receptors, Interleukin-8A
  • Receptors, Interleukin
  • Receptors, Chemokine
  • Receptors, CCR1
  • Receptor Cross-Talk
  • Rats
  • Phosphorylation
  • Phospholipase C beta