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Molecular and Cellular Biology, December 2007, p. 8127-8142, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00912-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RasGRF2, a Guanosine Nucleotide Exchange Factor for Ras GTPases, Participates in T-Cell Signaling Responses{triangledown}

Sergio Ruiz, Eugenio Santos, and Xosé R. Bustelo*

Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain

Received 23 May 2007/ Returned for modification 6 July 2007/ Accepted 18 September 2007

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-{gamma}1-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-{gamma}1-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.

* Corresponding author. Mailing address: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain. Phone: 34-923-294802. Fax: 34-923-294743. E-mail: xbustelo{at}usal.es

{triangledown} Published ahead of print on 8 October 2007.

Molecular and Cellular Biology, December 2007, p. 8127-8142, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00912-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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