Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcε receptor type 1 stimulation of mast cells

TY - JOUR

T1 - Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcε receptor type 1 stimulation of mast cells

AU - Turner, Helen

AU - Gomez, Manuel

AU - McKenzie, Edward

AU - Kirchem, Antje

AU - Lennard, Andrew

AU - Cantrell, Doreen A.

PY - 1998/8/3

Y1 - 1998/8/3

N2 - 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 Fcε receptor type 1 (FcεR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcεR1 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 FcεR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcεR1 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.

AB - 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 Fcε receptor type 1 (FcεR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcεR1 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 FcεR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcεR1 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.

KW - Fcε receptor type 1

KW - Mast cells

KW - Nuclear factor of activated T cells

KW - Rac-1

KW - Ras

UR - https://www.scopus.com/pages/publications/0032479870

U2 - 10.1084/jem.188.3.527

DO - 10.1084/jem.188.3.527

M3 - Article

C2 - 9687530

AN - SCOPUS:0032479870

SN - 0022-1007

VL - 188

SP - 527

EP - 537

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 3

ER -