@article {Helbig125088, author = {A.O. Helbig and M. Kofler and E. Petsalaki and G. Gish and K. Lorenzen and M. Tucholska and C. Zhang and F.P. Roth and K. Colwill and T. Pawson}, title = {The Fes tyrosine kinase guides CD19 receptor fate in B-cells by shaping regulatory Src phosphorylation networks}, elocation-id = {125088}, year = {2017}, doi = {10.1101/125088}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The c-Fes protein tyrosine kinase is a proto-oncogene that can also act as a tumor suppressor. We implemented a novel 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 maintenance of CD19, which may influence cellular outcome of accelerated hematopoietic tumorigenesis or tumor suppression.}, URL = {https://www.biorxiv.org/content/early/2017/04/07/125088}, eprint = {https://www.biorxiv.org/content/early/2017/04/07/125088.full.pdf}, journal = {bioRxiv} }