生物谷报道：最近，一项可能帮助为移植患者设计免疫抑制药物的新研究发现，一个帮助新的免疫细胞从脾脏和淋巴结进入身体的循环系统的强有力的信号发生分子有两个不同的来源。统称为淋巴细胞的免疫系统T细胞、B细胞、和自然杀伤细胞在胸腺、脾脏、和淋巴结中发育后进入血液和淋巴循环。这项研究发表在3月15日的《科学》杂志上。
一个叫S1P的分子帮助淋巴细胞进入循环，是目前正在临床试验的免疫抑制和自身免疫药物的靶标。Rajita Pappu和同事现在揭示，帮助淋巴细胞进入血液的S1P分子来自红血细胞，而帮助淋巴细胞进入淋巴系统的S1P另有来源。这些供给使淋巴细胞跟随一个淋巴组织和两个循环系统之间的梯度。该发现也许能帮助改进免疫抑制和S1P路径激活的方法。
原文出处：
Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate
Rajita Pappu, Susan R. Schwab, Ivo Cornelissen, João P. Pereira, Jean B. Regard, Ying Xu, Eric Camerer, Yao-Wu Zheng, Yong Huang, Jason G. Cyster, and Shaun R. Coughlin
Published online 15 March 2007 [DOI: 10.1126/science.1139221] (in Science Express Reports)
Abstract » PDF » Supporting Online Material »
作者简介：
Shaun R.
Coughlin, M.D., Ph.D.
Director, Cardiovascular Research Institute (CVRI); Professor of Medicine and Cellular and Molecular Pharmacology
Signaling by proteases and G protein-coupled receptors, and role of protease-activated receptors in vivo
Protease Signaling.
Thrombin, the effector protease for the coagulation cascade, elicits a host of cellular response. How does thrombin, a protease, behave like a hormone to activate cells? We have characterized a family of protease-activated G protein-coupled receptors (PARs) that are activated by an unusual mechanism. Thrombin cleaves PAR1's amino terminal exodomain to unmask a new amino terminus that then serves as a tethered peptide ligand, binding intramolecularly to the body of the receptor to cause transmembrane signaling. PAR1 is the prototype for a small family of PARs. PAR2 is activated by trypsin-like proteases. PAR3 and PAR4 are newly identified thrombin receptors.
Current work focuses on:
PAR activation. We are examining possible PAR-PAR interactions and novel cofactor mechanisms.
Receptor trafficking. The irreversibility of PAR1's proteolytic activation mechanism raises the question of how its signaling is terminated. We are using biochemical and somatic cell genetic approaches to identify how activated PAR1 is internalized and sorted to lysosomes.
PARs and platelets. To define the roles of PARs in vivo, we generated mice deficient in PAR1, PAR2, and PAR3; a PAR4 knockout is in progress. We are testing a model in which PAR3 and PAR4 mediate activation of mouse platelets and PAR1 and PAR4 activate human platelets.
PARs in embryonic development. Thrombin's not just for coagulation anymore? Approximately half of PAR1-deficient mouse embryos die at ~E9.5, apparently from bleeding. It appears that the "coagulation" system plays an unanticipated role in embryonic development that is unrelated to hemostasis in the usual sense. We are testing the hypothesis that the coagulation cascade functions as a "leak detector" that monitors and regulates vascular development, and that defective thrombin signaling in endothelial cells impairs blood vessel formation.
Other collaborative projects focus on the structural basis of GPCR signaling.
Publications
相关基因：
CACYBP
Official Symbol: CACYBP and Name: calcyclin binding protein [Homo sapiens]
Other Aliases: GIG5, MGC87971, PNAS-107, RP1-102G20.6, S100A6BP, SIP
Other Designations: Siah-interacting protein (SIP); growth-inhibiting gene 5 protein; siah-interacting protein
Chromosome: 1; Location: 1q24-q25
MIM: 606186
GeneID: 27101
