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Nature Immunology 10, 880–888 (1 August 2009) | doi:10.1038/ni.1749

Essential function for the GTPase TC21 in homeostatic antigen receptor signaling

Pilar Delgado , Beatriz Cubelos , Enrique Calleja , Nuria Mart|[iacute]|nez-Mart|[iacute]|n , Angel Cipr|[eacute]|s , Isabel M|[eacute]|rida , Carmen Bellas , Xos|[eacute]| R Bustelo & Balbino Alarc|[oacute]|n

T cell antigen receptors (TCRs) and B cell antigen receptors (BCRs) transmit low-grade signals necessary for the survival and maintenance of mature cell pools. We show here that TC21, a small GTPase encoded by Rras2, interacted constitutively with both kinds of receptors. Expression of a dominant negative TC21 mutant in T cells produced a rapid decrease in cell viability, and Rras2|[minus]|/|[minus]| mice were lymphopenic, possibly as a result of diminished homeostatic proliferation and impaired T cell and B cell survival. In contrast, TC21 was overexpressed in several human lymphoid malignancies. Finally, the p110|[delta]| catalytic subunit of phosphatidylinositol-3-OH kinase (PI(3)K) was recruited to the TCR and BCR in a TC21-dependent way. Consequently, we propose TC21 directly links antigen receptors to PI(3)K-mediated survival pathways.