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 alpha2- and beta2-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 alpha2- and beta2-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.
Caloca
María José
MJ
Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain. xbustelo@usal.es
Delgado
Pilar
P
Alarcón
Balbino
B
Bustelo
Xosé R
XR
D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D020848:Chimerin 1 / Q000378:metabolism; D020740:Chimerin Proteins / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D009154:Mutation; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D017252:CD3 Complex; D020848:Chimerin 1; D020740:Chimerin Proteins; D004075:Diglycerides; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D051567:Proto-Oncogene Proteins c-vav; C107953:RAC1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C496618:VAV1 protein, human; C079844:beta-chimaerin; D020830:rac1 GTP-Binding Protein