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.
Turner
H
H
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.
Gomez
M
M
McKenzie
E
E
Kirchem
A
A
Lennard
A
A
Cantrell
D A
DA
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