RasGRF2, a guanosine nucleotide exchange factor for Ras GTPases, participates in T-cell signaling responses.
The Ras pathway is critical for the development and function of T lymphocytes. The stimulation of this GTPase in T cells occurs primarily through the Vav1- and phospholipase C-gamma1-dependent activation of RasGRP1, a diacylglycerol-responsive Ras GDP/GTP exchange factor. Here, we show that a second exchange factor, RasGRF2, also participates in T-cell signaling. RasGRF2 is expressed in T cells, translocates to immune synapses, activates Ras, and stimulates the transcriptional factor NF-AT (nuclear factor of activated T cells) through Ras- and phospholipase C-gamma1-dependent routes. T-cell receptor-, Vav1-, and Ca2+-elicited pathways synergize with RasGRF2 for NF-AT stimulation. The analysis of RasGRF2-deficient mice indicates that this protein is required for the induction of bona fide NF-AT targets such as the cytokines tumor necrosis factor alpha and interleukin 2, while it plays minor roles in Ras activation itself. The comparison of lymphocytes from Vav1-/-, Rasgrf2-/-, and Vav1-/-; Rasgrf2-/- mice demonstrates that the RasGRF2 pathway cooperates with the Vav1/RasGRP1 route in the blasting transformation and proliferation of mature T cells. These results identify RasGRF2 as an additional component of the signaling machinery involved in T-cell receptor- and NF-AT-mediated immune responses.
Ruiz
Sergio
S
Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain.
Santos
Eugenio
E
Bustelo
Xosé R
XR
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D050778:NFATC Transcription Factors; D051567:Proto-Oncogene Proteins c-vav; C504490:RASGRF2 protein, human; C504491:Rasgrf2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors; D051966:Phospholipase C gamma; D018631:ras Proteins; D002118:Calcium