Inverted signaling hierarchy between RAS and RAC in T-lymphocytes

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Abstract
In order to generate coherent biological responses to extracellular stimuli, cells have established synergistic and antagonistic crosstalk between pathways with similar or opposing functions, respectively. Two routes cooperating in the generation of mitogenic and cytoskeletal functions are those induced by Ras and Rho/Rac GTPases. In these signaling interactions, Rho/Rac proteins have been always placed in a downstream position respect to Ras in all cell systems analysed so far. In this report, we describe that such signaling hierarchy does not apply to T-lymphocytes. Thus, we show that both Rac1 GDP/GTP exchange factors such as Vav and constitutively active versions of Rac1 can promote the effective stimulation of the Ras pathway in T-lymphocytes. The molecular link for this new type of pathway interconnectivity is RasGRP1, a diacylglycerol-dependent GDP/GTP exchange factor for Ras that translocates to the plasma membrane in a Vav- and Rac1-dependent manner. The effect of the Vav/Rac1 pathway on the Ras pathway is highly dependent on the activity of phospliolipase C-γ, the key cellular supplier of intracellular diacylglycerol. Signaling experiments suggest that this crosstalk represents a signaling strategy used by the T-cell receptor to promote robust biological responses of both the Rac/Rho and Ras pathways upon antigen engagement.We thank M Blázquez for technical assistance. This work was supported by the US National Cancer Institute (CA7373501), the Programa General del Conocimiento of the Spanish Ministry of Science and Technology (PM99-0093), and a grant from the Ministry of Education and Culture of the Autonomous Government of Castilla- León (SA051/02). MJC and JLZ are investigators of the Ramón y Cajal Program (Spanish Ministry of Science and Technology) associated to the University of Salamanca. The Centro de Investigación del Cáncer is supported by endowments from the CSIC, University of Salamanca, Castilla-León Autonomous Government, the Spanish National Network of Cancer Centers (Carlos III Institute, Spanish Ministry of Health), the Foundation for Cancer Research of Salamanca (FICUS), and the Solórzano and Moraza Foundations.Peer Reviewe