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P 7 - Prof. Dr. Michael Reth

Modifications and adaptor function of the B cell signaling proteins Syk and SHP-1




Prof. Dr. Michael Reth 

Institut für Biologie III, Universität Freiburg

Stübeweg 51, 79108 Freiburg

Phone: +49 761 5108-421

Fax: +49 761 5108-423



Project Summary


The B cell antigen receptor (BCR) is required for the proper development and activation of B lymphocytes. Signals emitted from this receptor are processed by the spleen tyrosine kinase (Syk) and are controlled by the protein tyrosine phosphatase SHP-1. Using a new version of the proximity ligation assay (PLA), we found in the last funding period that Syk is not only a downstream signaling element but also opens and activates the BCR via an inside-out signaling mechanism. We now want to study the molecular requirement for this novel signaling process. Specifically, we will test whether the membrane-binding and dimerization domains in the interdomain B sequence of Syk are required for the inside-out signaling function of this kinase. Using a proteomic screen, we identified several novel substrates of Syk and SHP-1 in the nucleus. Specifically, we found that the transcription factor Foxp1 is a target of both enzymes. Syk phosphorylates several tyrosines in Foxp1, thus promoting the degradation of this transcription factor. As Foxp1 is an important driver of pre-B cell expansion and is associated with tumor development, we want to study the functional specificity of this modification through knock-in of Foxp1 mutants and biochemical experiments. We also will continue our study of the sumoylated form of SHP-1, with the intent of identifying further substrates of this phosphatase. Our studies on the regulation and function of the arginine methyl transferase PRMT1 in B cells showed that the adaptor protein BTG2 regulates the activity of this enzyme. The PRMT1/BTG2 complex stops the expansion of pre-B cells and acts as a tumor suppressor. In line with this, we have found that the CyclinD3/CDK4 complex is a target of this methyl transferase. We now want to identify further substrates of the PRMT1/BTG2 module and test whether BTG2 constructs can be employed for a new anticancer therapy.

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