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The regulation of SHP-1 tyrosine phosphatase in B cell antigen receptor signaling


Antigen specific activation of B cells is mediated by the B cell receptor complex (BCR). Signal transduction of this receptor is regulated by the equilibrium of kinase and phosphatase activity. Syk protein tyrosine kinase and Src homology 2 domain containing protein tyrosine phosphatase 1 (SHP-1) has prominent role in the establishment of this equilibrium.

The aim of this proposal is to study the regulation of SHP-1 function. SHP-2 belongs to the same family of phosphatases, have high structural and sequence homology to SHP-1 but in contrast play mostly positive regulatory role in cell functions. The main goal of the project is to identify the modifications; molecular interactions that control the activity and intracellular localization of these enzymes and to compare the mechanisms of their regulations.

The major sequence differences of these phosphatases are in their C-terminal tail and probably this part is responsible for their functional divergence. This part of the protein contains two tyrosine and one-serine residues in SHP-1 and also two tyrosines and two serines in SHP-2. These amino acids are phosphorylation targets. My goal is to identify the kinase/kinases that phosphorylates them and other interacting molecules that can bind them and may regulate the phosphatases. For this purpose I will use the S2 Schneider cell reconstitution method that was developed in the host laboratory.

By the inducible and transient co-transfection of signalling molecules this method allows the rebuilding of signalling pathways in an evolutionary distant system and also to exclude the redundancy that is typical for molecules in mammalian signalling networks. SHP1 deficiency can lead to autoimmunity therefore revealing the molecular mechanisms of the regulation of this phosphata se may help to understand the development of certain autoimmune diseases.

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