Prof. Dr. Bettina Warscheid

Abteilung für Biochemie und Funktionelle Proteomik
Institut für Biologie II und BIOSS Centre for Biological Signalling Studies
Albert-Ludwigs-Universität Freiburg
Schänzlestr. 1
79108 Freiburg

Prof. Dr. Michael Reth

Molekulare Immunologie
Fakultät für Biologie
Albert-Ludwigs-Universität Freiburg
und MPI-IE
Stübeweg 51    
79108 Freiburg    

Tel. +49 (0) 761 5108 420    

Project summary:

The role of phosphatases in B cell autoimmunity

B cell activation is mediated by multiple tyrosine phosphorylation events that are tightly controlled by protein tyrosine phosphatases (PTPs). The majority of these enzymes have a negative regulatory role and thus their dysfunction can lead to hyperactivity and auto-reactivity of B cells. We generated mice with a B-cell-specific deficiency for the protein tyrosine phosphatase 1B (PTP1B, encoded by the Ptpn1 gene). We observed that aged animals develop systemic autoimmunity. Our ex vivo studies showed that the PTP1B inhibits TNFR family receptors (CD40, BAFFR) and TLR4 signalling in B cells. We also observed reduced Ptpn1 mRNA levels in human rheumatoid arthritis patients. Other PTPs such as SHP-1 and CD148 are also connected to autoimmunity. These PTPs can have different subcellular locations. For example, SHP-1 is a cytoplasmic enzyme, CD148 is a receptor PTP at the plasma membrane, while PTP1B is localized to the cytoplasmic surface of the endoplasmic reticulum (ER). Using large-scale quantitative phosphoproteomics assays, we will comprehensively identify the substrates of these three different PTPs in B cells. Moreover, purifying cellular fractions (ER, plasma membrane) and analysing the compartment-specific substrates of the PTPs will allow us to determine key signalling events at these intracellular locations. We will then functionally validate the found substrates in mouse and in human samples. These results will help to clarify the key distinctions and redundancies in the tyrosine phosphatase network in B cells and may lead to a better understanding of the molecular mechanisms of B cell autoimmunity.

Fig. 1. Establishment of the protein tyrosine phosphatase (PTP)-substrate network in B cells.
Publications P 05:

Hobeika, E., Nielsen, P.J., and D. Medgyesi. (2015). Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med 93, 143-158.

Wiese, H., Gelis, L., Wiese, S., Reichenbach, C., Jovancevic, N., Osterloh, M., Meyer, H.E., Neuhaus, E.M., Hatt, H.H., Radziwill, G., and Warscheid, B. (2015). Quantitative phosphoproteomics reveals the protein tyrosine kinase Pyk2 as a central effector of olfactory receptor signaling in prostate cancer cells. Biochim Biophys Acta 1854, 632-640.

Wiese, H., Kuhlmann, K., Wiese, S., Stoepel, N.S., Pawlas, M., Meyer, H.E., Stephan, C., Eisenacher, M., Drepper, F., and Warscheid, B. (2014). Comparison of alternative MS/MS and bioinformatics approaches for confident phosphorylation site localization. J Proteome Res 13, 1128-1137.

Alsadeq, A., Hobeika, E., Medgyesi, D., Kläsener, K., and Reth, M. (2014). The role of the Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and signaling. J Immunol 193, 268-276.

Medgyesi, D., Hobeika, E., Biesen, R., Kollert, F., Taddeo, A., Voll, R.E., Hiepe, F. and Reth, M. (2014). The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity. J Exp Med 211, 427-440.