The specific arrangement of proteins in the contact surface between the T cell and the APC is known as the immunological synapse. The exact function of the synapse is not clear but it has been proposed to function in the process of TCR signaling and also for TCR downregulation. Here we propose a model that suggests that there is a complex relationship between signaling, full receptor phosphorylation and downregulation. Recruitment to the center of the synapse facilitates full receptor phosphorylation, and fully phosphorylated receptors are targeted for degradation. The model also suggests that receptors that are unable to be recruited to the center of the synapse become only partially phosphorylated and are recycled to the plasma membrane after dephosphorylation. In this application, we propose a series of experiments to test this hypothesis using state of the art imaging techniques. Specifically, in Specific Aim # 1, we propose to analyze the relationship between synapse formation, receptor phosphorylation and receptor degradation.
In Specific Aim #2, we propose to determine the site ofphosphorylation of fully phosphorylated versus partially phosphorylated receptors.
In Specific Aim #3, we propose to examine the role of receptor downregulation in thymocyte signaling. Lastly, in Specific Aim #4, we propose to examine the role of CD28 and CD2 in TCR recycling and degradation.
|Raju, Saravanan; Kretzmer, Lena Z; Koues, Olivia I et al. (2016) NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo. J Immunol 196:4805-13|
|Le Borgne, Marie; Raju, Saravanan; Zinselmeyer, Bernd H et al. (2016) Real-Time Analysis of Calcium Signals during the Early Phase of T Cell Activation Using a Genetically Encoded Calcium Biosensor. J Immunol 196:1471-9|
|Hu, Jiancheng; Ahuja, Lalima G; Meharena, Hiruy S et al. (2015) Kinase regulation by hydrophobic spine assembly in cancer. Mol Cell Biol 35:264-76|
|Liao, Fan; Jiang, Hong; Srivatsan, Subhashini et al. (2015) Effects of CD2-associated protein deficiency on amyloid-? in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener 10:12|
|Taylor, Susan S; Shaw, Andrey; Hu, Jiancheng et al. (2013) Pseudokinases from a structural perspective. Biochem Soc Trans 41:981-6|
|Hu, Jiancheng; Stites, Edward C; Yu, Haiyang et al. (2013) Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154:1036-1046|
|Sandoval, Gabriel J; Graham, Daniel B; Gmyrek, Grzegorz B et al. (2013) Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL. Cancer Immunol Res 1:426-37|
|Zhao, Jianping; Bruck, Serawit; Cemerski, Saso et al. (2013) CD2AP links cortactin and capping protein at the cell periphery to facilitate formation of lamellipodia. Mol Cell Biol 33:38-47|
|Srivatsan, Subhashini; Swiecki, Melissa; Otero, Karel et al. (2013) CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. J Immunol 191:5933-40|
|Le Borgne, Marie; Filbert, Erin L; Shaw, Andrey S (2013) Kinase suppressor of Ras 1 is not required for the generation of regulatory and memory T cells. PLoS One 8:e57137|
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