PT  - JOURNAL ARTICLE
AU  - A.O. Helbig
AU  - M. Kofler
AU  - E. Petsalaki
AU  - G. Gish
AU  - K. Lorenzen
AU  - M. Tucholska
AU  - C. Zhang
AU  - F.P. Roth
AU  - K. Colwill
AU  - T. Pawson
TI  - The Fes tyrosine kinase guides CD19 receptor fate in B-cells by shaping regulatory Src phosphorylation networks
AID  - 10.1101/125088
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 125088
4099  - http://biorxiv.org/content/early/2017/04/07/125088.short
4100  - http://biorxiv.org/content/early/2017/04/07/125088.full
AB  - 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.