Regulation der „spleen tyrosine kinase“ Syk im B-Zell-Antigen-Rezeptor-Signalweg

Regulation of the "spleen tyrosine kinase" Syk in the B-cell antigen receptor signaling pathway

by Hanibal Bohnenberger
Doctoral thesis
Date of Examination:2014-01-14
Date of issue:2013-11-25
Advisor:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Tomas Pieler
Persistent Address: http://dx.doi.org/10.53846/goediss-4170

 

 

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Abstract

English

The “spleen tyrosine kinase” Syk offers transducer functions for a number of ITAM-based immune cell receptors and is critical for the development and activation of B lymphocytes. Furthermore Syk has been implicated in the pathogenesis of several forms of leukemia. Its catalytic activity and the capacity to interact with other signaling elements depend on its phosphorylation status. In this thesis the full spectrum of phosphoacceptor sites in human Syk and its complex dynamics in response to B-Cell antigen receptor stimulation was determined by high resolution mass spectrometry. One of the most frequently detected phosphoacceptor sites was serine 297. By elucidating the Syk interactome in resting and activated B cells, consisting of more than 25 interacting proteins, the 14-3-3 family of adapter proteins was discovered as one new group of interacting partners, which bind directly to phospho serine 297 after BCR stimulation. The latter complex weakens inducible plasma membrane recruitment of Syk and inhibits the B-cell antigen receptor signaling pathway. Collectively, the established ligand and phosphoacceptor site library offers a basis to comprehend the complexity of the Syk signaling network. The described regulation of Syk by 14-3-3 is the first reported serine dependent inhibition of Syk.
Keywords: B cell antigen receptor; SILAC; Mass spectrometry; Syk; Proteomics
Schlagwörter: B Zell Antigen Rezeptor; Massenspektrometrie; Proteomik
 
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