The G-protein coupled chemokine receptor (GPCR), CCR7 plays an essential role in delayed type hypersensitivity mediated by CD4+ T lymphocytes. Mice lacking this chemokine receptor are unable to mount delayed type hypersensitivity responses when challenged. Surprisingly little is known about the regulation of the CCR7 receptor. A better understanding of the mechanisms regulating CCR7 receptor function could provide the basis for targeted therapies to regulate T-cell responses and reduce or prevent further damage resulting from delayed type hypersensitivity. CCR7 is expressed on progenitor T-cells, na?ve B-cells and mature dendritic cells. This receptor, a principal regulator of lymphocyte and dendritic cell migration in the immune system, is activated in response to ligand binding. In general, ligand binding induces a conformational change allowing activation of coupled heterotrimeric G-proteins through GDP-GTP exchange. The released, activated G-proteins initiate signal transduction cascades. The response is desensitized rapidly due to phosphorylation of the GPCR. Our goal is to understand, at the molecular level, the regulatory mechanisms that control the signaling events in response to stimulation of the CCR7 GPCR. While it is clear that GPCR signaling is attenuated by receptor phosphorylation, the mechanisms controlling this attenuation remain quite an enigma. For instance in the case of the prototypic GPCR, the beta-adrenergic receptor, binding of arrestins to the phosphorylated C-terminus of the receptor down regulates this signaling cascade. This binding mediates receptor internalization thorough clathrin-coated pits and prevents further association of G-proteins. In contrast we have found that although the activated N-formyl peptide GPCR is phosphorylated and internalized in the absence of arrestins, the receptor is mis-trafficked and cannot recycle. We propose to examine how arrestin regulates signaling and internalization of CCR7.
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| Chittasupho, Chuda; Shannon, Laura; Siahaan, Teruna J et al. (2011) Nanoparticles targeting dendritic cell surface molecules effectively block T cell conjugation and shift response. ACS Nano 5:1693-702 |
| Shannon, Laura A; Calloway, Psachal A; Welch, T Paul et al. (2010) CCR7/CCL21 migration on fibronectin is mediated by phospholipase Cgamma1 and ERK1/2 in primary T lymphocytes. J Biol Chem 285:38781-7 |
| Byers, Melissa A; Calloway, Psachal A; Shannon, Laurie et al. (2008) Arrestin 3 mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. J Immunol 181:4723-32 |
