RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes

Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth fact ors, including cytokines, and chemokines that bind to G-protein-coupled rec eptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein fam ily that can act as GTPase-activating proteins for G(alphai)- and G(alphaq) -class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues , which are characteristic of an amphipathic helix within its first 33 amin o acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was als o detected specifically in haematopoietic progenitor and myeloerythroid lin eage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. R GS18 was also highly expressed in mouse embryonic 15-day livers, livers bei ng the principal organ for haematopoiesis at this stage of fetal developmen t. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the G(alphai-3) subun it in membranes from K562 cells. Furthermore, over-expression of RGS18 inhi bited mitogen-activated-protein kinase activation in HEK-293/chemokine rece ptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, R GS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GP CR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might h ave an important role in the regulation of megakaryocyte differentiation an d chemotaxis.