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The N Terminus of the Non-T Cell Activation Linker (NTAL) Confers Inhibitory Effects on Pre-B Cell Differentiation¹

Institute for Biology III, Albert-Ludwigs University of Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany

SLP-65 and the linker for activation of T cells (LAT) are central adaptor proteins that link the activated pre-BCR to downstream events in pre-B cells. Recently, a new transmembrane adaptor called NTAL/LAB/LAT2 (hereafter called NTAL for non-T cell activation linker) with striking functional and structural similarity to LAT has been identified in B cells. In this study, we compare the function of NTAL and LAT in pre-BCR signaling and show that, in contrast to LAT, NTAL does not induce pre-BCR down-regulation, calcium flux, or pre-B cell differentiation. To test whether differences between NTAL-mediated and LAT-mediated signaling are caused by the missing phospholipase C (PLC)- binding motif in NTAL, we inserted the PLC-1/2 binding motif of LAT into NTAL. This insertion rendered NTAL capable of activating pre-BCR down-regulation and calcium flux. Unexpectedly however, the ability of NTAL to induce calcium flux was not sufficient to promote pre-B cell differentiation, suggesting that the PLC- binding motif has only partial effects on NTAL-mediated pre-BCR signaling. By generating chimeric swap mutants, we identified the N terminus of NTAL as an inhibitory domain that prevents pre-B cell differentiation while allowing pre-BCR down-regulation and receptor-mediated calcium flux. Our data suggest that, in addition to the missing PLC-1/2 binding motif, the N terminus is responsible for the functional differences between NTAL and LAT in pre-B cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 620.

² Address correspondence and reprint requests to Dr. Hassan Jumaa, Max Planck Institute for Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany. E-mail address: jumaa{at}immunbio.mpg.de

³ Abbreviations used in this paper: PLC, phospholipase C; LAT, linker for activation of T cells; NTAL, non-T cell activation linker; PLCBM, PLC- binding motif; TL, tailless; WT, wild type.