Defective Chemokine Signal Integration in Leukocytes Lacking Activator of G Protein Signaling 3 ( AGS3)

Background: Roles for AGS3/Gpsm1 in the immune system are not defined. Results: Loss of AGS3 expression results in defective leukocyte chemotaxis, calcium mobilization, and ERK1/2 and Akt activation. Conclusion: AGS3 is required for efficient chemokine receptor signal integration. Significance: These studies extend the functional repertoire for AGS3 in the immune system, providing unexpected regulatory mechanisms for immune function. Activator of G-protein signaling 3 (AGS3, gene name G-protein signaling modulator-1, Gpsm1), an accessory protein for G-protein signaling, has functional roles in the kidney and CNS. Here we show that AGS3 is expressed in spleen, thymus, and bone marrow-derived dendritic cells, and is up-regulated upon leukocyte activation. We explored the role of AGS3 in immune cell function by characterizing chemokine receptor signaling in leukocytes from mice lacking AGS3. No obvious differences in lymphocyte subsets were observed. Interestingly, however, AGS3-null B and T lymphocytes and bone marrow-derived dendritic cells exhibited significant chemotactic defects as well as reductions in chemokine-stimulated calcium mobilization and altered ERK and Akt activation. These studies indicate a role for AGS3 in the regulation of G-protein signaling in the immune system, providing unexpected venues for the potential development of therapeutic agents that modulate immune function by targeting these regulatory mechanisms.