Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells.
Transcription factors of the nuclear factor of activated T cells (NFAT) family play a key role in antigen receptor-mediated responses in lymphocytes by controlling induction of a wide variety of cytokine genes. The GTPases Ras and Rac-1 have essential functions in regulation of NFAT transcriptional activity in the mast cell system, where Fcepsilon receptor type 1 (FcepsilonR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcepsilonR1 activation of NFAT in mast cells. We are able to place Rac-1 in two positions in the signaling network that regulates the assembly and activation of NFAT transcriptional complexes in lymphocytes. First, we show that activity of Rac-1 is required for FcepsilonR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcepsilonR1 is a Rac-dependent but Ras-independent process. This novel signaling role for Rac-1 is distinct from its established regulation of the actin cytoskeleton. Our data also reveal a second GTPase signaling pathway regulating NFAT transcriptional activity, in which Rac-1 mediates a Ras signal. These data illustrate that the GTPase Rac-1 should now be considered as a component of the therapeutically important pathways controlling NFATC1 subcellular localization. They also reveal that GTPases may serve multiple functions in cellular responses to antigen receptor ligation.
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.
H
H
Turner
M
M
Gomez
E
E
McKenzie
A
A
Kirchem
A
A
Lennard
D A
DA
Cantrell
D000199:Actins / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008407:Mast Cells / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000378:metabolism*
D000199:Actins; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D008164:Luminescent Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011506:Proteins; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; D018631:ras Proteins