Trapping Grb2 within immune cells: the role of transmembrane adaptor proteins. DFG FOR 521
We have successfully demonstrated that the transmembrane adaptor SIT (i) is a negative regulator of TCR-mediated signals, (ii) is required to set the signaling threshold during thymocyte selection, (iii) regulates peripheral T cell homeostasis and (iv) peripheral T cell functions. Moreover, we have shown that SIT and the structurally related molecule TRIM represent two redundant negative regulators that together control T cell fate by setting the signaling threshold for positive selection. We have also found that SIT negatively regulates BCR-mediated signals in B1 B cells and shares overlapping function with the transmembrane adaptor LAX to regulate the number of B1 B cells. In summary, our studies have demonstrated that transmembrane adaptor molecules represent critical regulators in lymphocyte biology and that redundancy could be a general feature among the adaptors. Interestingly, the adaptors NTAL, LAT and LAX might share redundant functions as together they possess 14 Grb2-binding site. Through our participation in the modeling project, it came to our attention that also the function of the cytoplasmic adaptor Grb2 in antigen receptor-mediated signaling is not clearly understood. On the basis of these findings, we propose (i) the characterization of Grb2 function in antigen receptor (in particular TCR) signalling and (ii) the investigation of the functional redundancy of Grb2-binding NTAL, LAT and LAX in immune cells.
ERK, Grb2, LAT, LAX, NTAL, TCR-mediated signalling, adaptor protein, knockout mice
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