Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling

Chimaerins are GTPase-activating proteins that inactivate the GTP-hydrolase Rac1 in a diacylglycerol-dependent manner. To date, the study of chimaerins has been done mostly in neuronal cells. Here, we show that α2- and β2-chimaerin are expressed at different levels in T-cells and that they participate in T-cell receptor signaling. In agreement with this, we have observed that α2- and β2-chimaerins translocate to the T-cell/B-cell immune synapse and, using both gain- and loss-of-function approaches, demonstrated that their catalytic activity is important for the inhibition of the T-cell receptor- and Vav1-dependent stimulation of the transcriptional factor NF-AT. Mutagenesis-based approaches have revealed the molecular determinants that contribute to the biological program of chimaerins during T-cell responses. Unexpectedly, we have found that the translocation of chimaerins to the T-cell/B-cell immune synapse does not rely on the canonical binding of diacylglycerol to the C1 region of these GTPase-activating proteins. Taken together, these results identify chimaerins as candidates for the downmodulation of Rac1 in T-lymphocytes and, in addition, uncover a novel regulatory mechanism that mediates their activation in T-cells. © 2007 Elsevier Inc. All rights reserved.This work was supported by grants to MJC from the Spanish Ministry of Health (PI052096), the Castilla-León Autonomous Government (SA051/04), the Mutua Madrileña Medical Foundation, and the Solórzano Foundation, to XRB from the US National Cancer Institute/NIH (5R01-CA73735-11), the Spanish Ministry of Education and Science (MES) (SAF2006-01789), the Castilla-León Autonomous Government (SA053A05), and the Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD06/0020/0001, Spanish Ministry of Health), and to BA from the Spanish Ministry of Education and Science (SAF2005- 00937). MJC is an investigator of the Ramón y Cajal Program of the Spanish Ministry of Education and Science who is associated to the University of Salamanca.Peer Reviewe