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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI057966-10
Application #
8431997
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mallia, Conrad M
Project Start
2004-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$261,188
Indirect Cost
$53,896
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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-β in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener 10:12
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
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 154:1036-46
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
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
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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