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Antibodies 2017, 6(4), 23; https://doi.org/10.3390/antib6040023

Modulation of BCR Signaling by the Induced Dimerization of Receptor-Associated SYK

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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Received: 26 October 2017 / Revised: 27 November 2017 / Accepted: 2 December 2017 / Published: 7 December 2017
(This article belongs to the Special Issue B Cell Antigen Receptor: Structure and Function)
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Abstract

Clustering of the B cell antigen receptor (BCR) by polyvalent antigens is transmitted through the SYK tyrosine kinase to the activation of multiple intracellular pathways that determine the physiological consequences of receptor engagement. To explore factors that modulate the quantity and quality of signals sent by the crosslinked BCR, we developed a novel chemical mediator of dimerization to induce clustering of receptor-associated SYK. To accomplish this, we fused SYK with E. coli dihydrofolate reductase (eDHFR), which binds the small molecule trimethoprim (TMP) with high affinity and selectivity and synthesized a dimer of TMP with a flexible linker. The TMP dimer is able to induce the aggregation of eDHFR-linked SYK in live cells. The induced dimerization of SYK bound to the BCR differentially regulates the activation of downstream transcription factors, promoting the activation of Nuclear Factor of Activated T cells (NFAT) without affecting the activation of NFκB. The dimerization of SYK enhances the duration but not the amplitude of calcium mobilization by enhancing the extent and duration of its interaction with the crosslinked BCR at the plasma membrane. View Full-Text
Keywords: BCR signaling; SYK; chemical inducer of dimerization; NFAT; calcium mobilization BCR signaling; SYK; chemical inducer of dimerization; NFAT; calcium mobilization
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Westbroek, M.L.; Geahlen, R.L. Modulation of BCR Signaling by the Induced Dimerization of Receptor-Associated SYK. Antibodies 2017, 6, 23.

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