Signaling in Anergy: from Fyn to Ras and beyond

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In peripheral T-cells, the phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) appears to function as a negative regulator of cellular activation by recruiting the C-terminal Src-kinase (Csk) to the plasma membrane. Via its association to PAG, Csk is able to inhibit the activity of the membrane-associated Src-kinases p56lck and p59fyn. Upon activation, PAG becomes dephosphorylated by an unidentified phosphatase and its association with Csk is lost, allowing for the subsequent activation of the Src-kinases and the induction of signaling. The aim of this project is to identify the phosphatase responsible for this activity, as it is a potential target for regulating the activity of Src-kinases and thereby regulating the activity of T-cells. The role of PAG in T-cell development, the induction of anergy, adhesion and migration shall also be explored, as these are processes in which Src-kinases are known to be involved. Additionally, we shall further explore the known protein associations (i.e. Csk, Fyn) and the function of palmitoylation in targeting PAG to the GEMs, while also looking for new proteins that may help us to fully understand the regulatory functions of this novel adaptor. We shall employ several strategies to observe the dynamics of these interactions, in particular the changes which occur upon activation. Finally, as data suggests that there may be another PAG-like molecule, we shall identify this protein.