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bioRxiv · 10.1101/125088

The Fes tyrosine kinase guides CD19 receptor fate in B-cells by shaping regulatory Src phosphorylation networks

Helbig, A. O.·Kofler, M.·Petsalaki, E.·Gish, G.·Lorenzen, K.·Tucholska, M.·Zhang, C.·Roth, F. P.·Colwill, K.·Pawson, T.
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Abstract

The c-Fes protein tyrosine kinase is a proto-oncogene that can also act as a tumor suppressor. We implemented an unbiased phosphoproteomics-based analysis that establishes cognate kinase-substrate associations, and revealed that c-Fes directly phosphorylates Dok1, Ptpn18 and Sts1, facilitating recruitment of the Src inhibitory kinase Csk to these substrates. These interactions resulted in modulation of Src signaling following B-cell receptor (BCR) stimulation and subsequent alteration of the protein levels of CD19, a membrane-localized BCR co-receptor and emerging key protein affecting the development of B- and plasma cell-lymphoma. Strikingly, manipulating c-Fes expression levels drove opposing biological outcomes. Low-level exogenous c-Fes expression led to a strong increase in CD19 protein levels while high c-Fes expression abolished CD19 protein levels. Thus, we propose that a balance of c-Fes and Src signaling can regulate receptor maintenance, which may influence cellular outcome such as tumorigenesis or tumor suppression.

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Helbig, A. O., Kofler, M., Petsalaki, E., Gish, G., Lorenzen, K., Tucholska, M., Zhang, C., Roth, F. P., Colwill, K., Pawson, T.. 2017-04-07. The Fes tyrosine kinase guides CD19 receptor fate in B-cells by shaping regulatory Src phosphorylation networks. https://doi.org/10.1101/125088

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