We have data indicating that the interleukin-2 receptor (IL-2R) -beta, but not the alpha- or gamma-, chain is enriched in rafts and that it associates with cytoskeletal tubulin. These findings are in keeping with the growing recognition that both rafts and cytoskeletal proteins participate in and influence the function of various receptors on T cells. Further work, within an ongoing mentored training experience for the applicant, is thus proposed to test the hypothesis that the IL-2R beta-chain is critical for the interface of the IL-2R with rafts and the cytoskeleton and that this interface is functionally important. Standard molecular biological andmorphological techniques (e.g., immunoprecipitation and immunoblotting, internalization assays, confocal microscopy) will be used to address the following specific aims:1. Identification of mechanisms responsible for the raft-targeting of the IL-2R beta-chain;2. Further characterization of the dynamic relationship between the IL-2R beta-chain, rafts and the tubulin cytoskeleton;3. Investigation of the association of the IL-2/15R beta-chain with rafts and the cytoskeleton in antigen-specific T cells.The results derived from these studies characterizing the relationship between the IL-2R, especially its beta-chain, and rafts as well as the cytoskeleton will provide new insights into of cytokine receptor structure, function and turnover and thus provide for a more comprehensive understanding of processes critically involved in T cell function. The applicant's training towards becoming an independent scientist with a focus in transplantation immunology will be fostered in the process through continued mentoring by two established immunologists and participation in several didactic courses.
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| Goebel, Jens; Forrest, Kathy; Wills-Karp, Marsha et al. (2006) Tubulin polymerization modulates interleukin-2 receptor signal transduction in human T cells. J Recept Signal Transduct Res 26:87-106 |
| Goebel, Jens; Logan, Barbara; Forrest, Kathy et al. (2005) Atorvastatin affects interleukin-2 signaling by altering the lipid raft enrichment of the interleukin-2 receptor beta chain. J Investig Med 53:322-8 |
| Rao, Rakesh; Logan, Barbara; Forrest, Kathy et al. (2004) Lipid rafts in cytokine signaling. Cytokine Growth Factor Rev 15:103-10 |
