The Role of Arrestins in CCR7 Trafficking

描述（由申请人提供）：G蛋白偶联趋化因子受体（GPCR），CCR 7在由CD 4 + T淋巴细胞介导的迟发型超敏反应中起重要作用。 缺乏这种趋化因子受体的小鼠在受到攻击时不能产生迟发型超敏反应。 令人惊讶的是，对CCR 7受体的调控知之甚少。 更好地了解调节CCR 7受体功能的机制可以为靶向治疗提供基础，以调节T细胞反应并减少或预防迟发型超敏反应造成的进一步损害。 CCR 7在祖T细胞上表达，ve B细胞和成熟树突状细胞。 这种受体是免疫系统中淋巴细胞和树突细胞迁移的主要调节因子，在配体结合时被激活。 通常，配体结合诱导构象变化，从而允许通过GDP-GTP交换激活偶联的异源三聚体G蛋白。 释放的、活化的G蛋白启动信号转导级联。 由于GPCR的磷酸化，反应迅速脱敏。 我们的目标是在分子水平上了解控制响应于CCR 7 GPCR刺激的信号事件的调节机制。 虽然很明显，GPCR信号被受体磷酸化减弱，但控制这种减弱的机制仍然是一个谜。 例如，在原型GPCR（β-肾上腺素能受体）的情况下，抑制蛋白与受体的磷酸化C-末端的结合下调该信号级联。 这种结合通过网格蛋白包被的凹坑介导受体内化，并阻止G蛋白的进一步结合。 相反，我们发现，尽管活化的N-甲酰肽GPCR在不存在抑制蛋白的情况下被磷酸化和内化，但受体被错误运输并且不能再循环。 我们建议研究arrestin如何调节CCR 7的信号转导和内化。

DESCRIPTION (provided by applicant): 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, nave 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.