Mechanismen der Inostitol (1,4,5) trisphosphate 3-kinase B (ltpkB) Upstream-Reguation in Thymozyten

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Dr. Sauer's lab recently published in Science that Inositol(1,4,5)trisphosphate 3-kinase B (ItpkB) is essential for thymocyte positive selection by producing the novel, soluble "third" messenger molecule Inositol-tetrakisphosphate (IP4). Inability to produce sufficient IP4 in ItpkB-/- thymocytes impaired T cell receptor (TCR) signaling and positive selection, resulting in T cell immunodeficiency. It is unclear how ItpkB is activated by the TCR. In nonlymphoid tissue culture cells, ItpkB may be activated via Ca2+-dependent interactions with Calmodulin. Limited evidence suggests modulation of this interaction by protein kinase C isoenzymes (PKCs). Based on Dr. Sauer's preliminary data, I hypothesize that Ca2+/Calmodulin binding is required for TCR induced ItpkB activation in thymocytes and that this interaction is negatively regulated by PKC phosphorylation of the Calmodulin binding domain in ItpkB. In this project I will determine the role of Ca2+/Calmodulin binding and its modulation by PKCs in regulating ItpkB activity and function in thymocytes. The results of this study will unveil new components of the molecular circuitry regulating positive selection through ItpkB and help to elucidate the still unclear functions of PKCs in thymocyte development. Moreover, they will provide important insights into the mechanisms regulating soluble inositol-polyphosphate signaling in vivo - a very exciting, highly innovative, emerging field of research.