Role of clathrin-mediated endocytosis in CXCR2 sequestration, resensitization, and signal transduction.

Yang W, Wang D, Richmond A
J Biol Chem. 1999 274 (16): 11328-33

PMID: 10196223 · DOI:10.1074/jbc.274.16.11328

CXCR2 is a seven-transmembrane receptor that transduces intracellular signals in response to the chemokines interleukin-8, melanoma growth-stimulatory activity/growth-regulatory protein, and other ELR motif-containing CXC chemokines by coupling to heterotrimeric GTP-binding proteins. In this study, we explored the mechanism responsible for ligand-induced CXCR2 endocytosis. Here, we demonstrate that dynamin, a component of clathrin-mediated endocytosis, is essential for CXCR2 endocytosis and resensitization. In HEK293 cells, dynamin I K44A, a dominant-negative mutant of dynamin that inhibits the clathrin-mediated endocytosis, blocks the ligand-stimulated CXCR2 sequestration. Furthermore, co-expression of dynamin I K44A significantly delays dephosphorylation of CXCR2 after ligand stimulation, suggesting that clathrin-mediated endocytosis plays an important role in receptor dephosphorylation and resensitization. In addition, ligand-mediated receptor down-regulation is attenuated when receptor internalization is inhibited by dynamin I K44A. Interestingly, inhibition of receptor endocytosis by dynamin I K44A does not affect the CXCR2-mediated stimulation of mitogen-activated protein kinase. Most significantly, our data indicate that the ligand-stimulated receptor endocytosis is required for CXCR2-mediated chemotaxis in HEK293 cells. Taken together, our findings suggest that clathrin-mediated CXCR2 internalization is crucial for receptor endocytosis, resensitization, and chemotaxis.

MeSH Terms (22)

Calcium-Calmodulin-Dependent Protein Kinases Cell Line Chemokine CXCL1 Chemokines, CXC Chemotactic Factors Chemotaxis Clathrin Down-Regulation Dynamin I Dynamins Endocytosis Enzyme Activation Growth Substances GTP Phosphohydrolases Humans Intercellular Signaling Peptides and Proteins Interleukin-8 Phosphorylation Receptors, Chemokine Receptors, Interleukin Receptors, Interleukin-8B Signal Transduction

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