Abstract
Adaptor protein interaction with specific peptide motifs found within the intracellular, carboxyl terminus of chemokine receptor CXCR2 has been shown to modulate intracellular trafficking and receptor function. Efficient ligand-induced internalization of this receptor is dependent on the binding of adaptor protein 2 to the specific LLKIL motif found within the carboxyl terminus (1). In this study we show that the carboxyl-terminal type 1 PDZ ligand motif (-STTL) of CXCR2 plays an essential role in both proper intracellular receptor trafficking and efficient cellular chemotaxis. First, we show that CXCR2 is sorted to and degraded in the lysosome upon long-term ligand stimulation. We also show that receptor degradation is not dependent upon receptor ubiquitination, but is instead modulated by the carboxyl-terminal type I PDZ ligand of CXCR2. Deletion of this ligand results in increased degradation, earlier co-localization with the lysosome, and enhanced sorting to the Rab7-positive late endosome. We also show that deletion of this ligand effects neither receptor internalization nor receptor recycling. Furthermore, we demonstrate that deletion of the PDZ ligand motif results in impaired chemotactic response. The data presented here demonstrate that the type I PDZ ligand of CXCR2 acts to both delay lysosomal sorting and facilitate proper chemotactic response.
Highlights
Adaptor protein interaction with specific peptide motifs found within the intracellular, carboxyl terminus of chemokine receptor CXCR2 has been shown to modulate intracellular trafficking and receptor function
In this study we show that the carboxylterminal type 1 PDZ ligand motif (-STTL) of CXCR2 plays an essential role in both proper intracellular receptor trafficking and efficient cellular chemotaxis
Upon ligand engagement of CXCR2, two interrelated processes occur: a conformational change that initiates several signal transduction cascades linked to cell motility and proliferation, and a phosphorylation event that facilitates the binding of adaptor proteins essential for receptor endocytosis and subsequent intracellular trafficking
Summary
Adaptor protein interaction with specific peptide motifs found within the intracellular, carboxyl terminus of chemokine receptor CXCR2 has been shown to modulate intracellular trafficking and receptor function. B.), Vanderbilt-Ingram Cancer Center Support Grant CA68485, and a Senior Career Scientist Award from the Department of Veterans Affairs Upon ligand engagement of CXCR2, two interrelated processes occur: a conformational change that initiates several signal transduction cascades linked to cell motility and proliferation, and a phosphorylation event that facilitates the binding of adaptor proteins essential for receptor endocytosis and subsequent intracellular trafficking (see Ref. 4 for review). Like many GPCRs, CXCR2 undergoes clathrin-mediated endocytosis subsequent to agonist-induced activation by its cognate ligands that include CXCL1–3 and 5– 8 [5,6,7] This endocytic event initiates intracellular trafficking of the receptor that results in either a re-localization of the receptor on the plasma membrane, or a down-regulation and degradation of internalized receptor [8]. The interruption of this process can result in the disregulation of both signaling and functional outcomes
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