Summary
Phosphorylation is the most important post translational modification in signal transduction controlling growth, differentiation and most other cell biological processes. 528 Kinases transfer such phosphate groups and about 120 phosphates reverse this modification, a relative large part (107) of which control tyrosine phosphate ester hydrolysis. The equilibrium of these processes is tightly controlled but the exact mechanisms are poorly understood.
Kinases are best understood, in part because reasonable chemical inhibitors have been made and used in research. Kinase inhibitors have proven useful in cancer therapy, the best known being Gleevec/Imatinib, an inhibitor of the kinase ABL that is used to treat CML patients. Other kinase inhibitors act on PKB/Akt, PI3 kinase and other kinases for similar purposes. Phosphatases are less understood with CD45 and PTEN forming notable exceptions. This is in large part due to the lack of chemical inhibitors with defined action and in part due to lack of defined model systems and tools to identify, inhibit and place phosphatases in signaling networks, despite the fact that nature frequently relies on broad spectrum phosphatase inhibition in defense mechanisms evidenced by the agents okadaic acid, calyculin and FK-506.
This defines the goal of this proposal: development and application of tyrosine phosphatase inhibitors, baits and ABPs to identify the role of phosphatases in tumor- and infection- as well as developmental models in cultured cells and zebrafish.
Results of this project will strengthen and profit from the parallel NPC projects NPC E2.5 “Kinome and phosphatasome knock-down libraries and infections”, NPC E2.2 “Serine/ threonine kinase inhibitors, baits and ABPs” as well as project NPC E2.3 “Tyrosine phosphatase peptide arrays”.