RGS14, a GTPase-Activating Protein for Giα, Attenuates Giα- and G13α-Mediated Signaling Pathways
- 1B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (H.C., K.T., J.H.K.); 2Section de Recherche, Institut Curie, Paris, France (J.D.G.); and 3Department of Pharmacology, University of Illinois, Chicago, Illinois (T.K.)
Abstract
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 Gα subunits and as effector antagonists for Gqα. 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 Giα subfamily members and it attenuates interleukin-8 receptor-mediated mitogen-activated protein kinase activation. However, RGS14 does not exhibit GAP activity toward Gsα or Gqα nor does it regulate Gsα- or Gqα-mediated signaling pathways. Although RGS14 does not act as a GAP for G12/13α, it impairsc-fos serum response element activation induced by either a constitutively active mutant of G13α (G13αQ226L) or by carbachol stimulation of muscarinic type 1 receptors. An RGS14 mutant (EN92/93AA), which does not block Giα-linked signaling, also inhibits serum response element activation. RGS14 localizes predominantly in the cytosol, but it can be recruited to membranes by expression of G13αQ226L. 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 Giα- or G13α-mediated cellular processes in lymphocytes, such as adhesion and migration.
Footnotes
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Send reprint requests to: John H. Kehrl, National Institute of Allergy and Infectious Diseases, Bldg.10, Rm. 11B-13, 10 Center Dr., MSC 1876, Bethesda, MD 20892-1876. E-mail: jkehrl{at}niaid.nih.gov
- Abbreviations:
- RGS
- regulator of G protein signaling
- GAP
- GTPase-activating protein
- GPCR
- G protein-coupled receptor
- FCS
- fetal calf serum
- IL
- interleukin
- HA
- hemagglutinin
- ERK
- extracellular signal-related kinase
- MAP
- mitogen-activated protein
- MBP
- myelin basic protein
- PAGE
- polyacrylamide gel electrophoresis
- M1
- muscarinic type 1
- PLC
- phospholipase C
- CREB
- cAMP response element-binding protein
- TCR
- T cell receptor
- BCR
- B cell receptor
- PAF
- platelet-activating factor
- SRE
- serum response element
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- Received February 15, 2000.
- Accepted June 12, 2000.
- U.S. Government
