AbstractThe regulator of G-protein signaling (RGS) negatively regulates the α subunit of G proteins by accelerating their intrinsic guanosine triphosphatase (GTPase) activity. Here are reported the isolation and characterization of a novel mouse RGS, termed RGS18, which is a new member of RGS subfamily B. Northern blot analysis showed that RGS18 messenger RNA was detected predominantly in spleen and hematopoietic cells, and immunohistochemical studies demonstrated that RGS18 was expressed in megakaryocytes, platelets, granulocytes/monocytes, and, weakly, in hematopoietic stem cells, but not in lymphocytes or erythrocytes. Although various subcellular localizations of RGS have been reported, RGS18 was found to be localized in cytoplasm in megakaryocytes. In vitro binding assays of RGS18 with megakaryocyte cell lysates with or without AlF4− treatment demonstrated that RGS18 specifically binds to 2 α subunits of the G protein, Gαi and Gαq. Furthermore, RGS18 clearly exhibited GTPase-activating protein (GAP) activity for Gαi and Gαq but not for Gαs or Gα12. In addition, chemokine stromal-derived factor 1 (SDF-1), which has been reported to stimulate megakaryocyte colony formation in the presence of thrombopoietin, affected the binding of RGS18 to Gαi but not to Gαq. Therefore, the newly isolated RGS18 turned out to be a new member of the RGS family bearing GAP activity for Gαi, which might be stimulated by SDF-1 in megakaryocytes, as well as for Gαq. Thus, RGS18 may play an important role in proliferation, differentiation, and/or migration of megakaryocytes.