RGS14, a GTPase-activating protein for Giα, attenuates Giα- and G13α-mediated signaling pathways

Regulator of G protein signaling (RGS) proteins are a family of approximately 20 proteins that negatively regulate signaling through heterotrimeric G protein-coupled receptors. The RGS proteins act as GTPase-activating proteins (GAPs) for certain Ga subunits and as effector antagonists for Gq alpha. Mouse RGS14 encodes a 547-amino-acid protein with an N-terminal RGS domain, which is highly expressed in lymphoid tissues. In this study, we demonstrate that RGS14 is a GAP for Gi alpha subfamily members and it attenuates interleukin-8 receptor-mediated mitogen-activated protein kinase activation. However, RGS14 does not exhibit GAP activity toward Gs alpha or Gq alpha nor does it regulate Gs alpha- or Gq alpha-mediated signaling pathways. Although RGS14 does not act as a GAP for G12/13 alpha, it impairs c-fos serum response element activation induced by either a constitutively active mutant of G13 alpha (G13 alpha Q226L) or by carbachol stimulation of muscarinic type 1 receptors. An RGS14 mutant (EN92/93AA), which does not block Gi alpha-linked signaling, also inhibits serum response element activation. RGS14 localizes predominantly in the cytosol, but it can be recruited to membranes by expression of G13 alpha Q226L. Although RGS14 is constitutively expressed in lymphoid cells, agents that activate B or T lymphocytes further enhance its levels. Taken together, our results suggest that signals generated after lymphocyte activation may via RGS14 directly impinge on Gi alpha- or G13 alpha-mediated cellular processes in lymphocytes, such as adhesion and migration.