Engagement of T-cell antigen receptors (TCRs) on resting T cells triggers a rapid increase in intracellular protein tyrosine phosphorylation due to the activation of Src and Syk family tyrosine kinases. These tyrosine phosphorylation events, in turn, provoke the release of second messengers that increase intracellular free Ca2+ concentrations and activate protein kinase C (PKC). Dr. Altman's laboratory has focused on the roles of the Src family kinase, Lck, and the Syk family members, Syk and ZAP-70, in the initiation of signal output from the TCR. In addition a novel PKC isoform, PKC-theta, has been discovered and was found to be expressed primarily in hematopoietic cells and skeletal muscle. Preliminary evidence suggests that this PKC isoform may specifically mediate the coupling of cell surface receptors, such as the TCR, to the transriptional activation of the AP-1 complex in T cells.
The Specific Aims of this project are: (1) To further characterize the function of PKC-theta in T-cell activation by identifying proteins that interact with and serve as substrates for this protein kinase.
This aim will also include functional studies with transgenic mice expressing either wild-type or a kinase-inactive version of PKC-theta under the control of the thymocyte-specific lck proximal promoter. (2) To understand the regulatory mechanisms that control the activities of Syk family kinases, and to further define the interactions of Syk with two potential substrates, Vav and HS1. The proposed studies are intended to fill some important gaps in our understanding of signal transduction through the TCR.
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