Distinct sites within the vascular cell adhesion molecule-1 (VCAM-1) cytoplasmic domain regulate VCAM-1 activation of calcium fluxes versus Rac1 during leukocyte transendothelial migration.
Distinct sites within the vascular cell adhesion molecule-1 (VCAM-1) cytoplasmic domain regulate VCAM-1 activation of calcium fluxes versus Rac1 during leukocyte transendothelial migration.
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DOI：
10.1021/bi300925r
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发表时间：
2012-10-16
期刊：
影响因子：
2.9
通讯作者：
Cook-Mills JM
中科院分区：
文献类型：
--
作者：
Marchese ME;Berdnikovs S;Cook-Mills JM
血管黏附分子调节炎症期间白细胞从血液到组织的迁移。白细胞与血管细胞黏附分子-1(VCAM-1)结合可激活内皮细胞中的信号，包括rac1和钙流。这些VCAM-1信号是白细胞在VCAM-1上进行内皮迁移所必需的。然而，VCAM-1的胞质结构域是否对这些信号是必需的，目前还没有报道。有趣的是，VCAM-1细胞质结构域的19个氨基酸序列在许多哺乳动物中是100%保守的，这表明该结构域具有重要的功能。为了研究VCAM-1胞浆结构域的功能，我们在N724、S728、Y729、S730或S737位氨基酸上删除了VCAM-1胞质结构域或突变了胞质结构域。胞浆结构域和S728、Y729、S730或S737是白细胞内皮细胞迁移所必需的。S728和Y729是VCAM-1激活钙流所必需的，而S730或S737不是必需的。相反，S730和S737是Rac1激活VCAM-1所必需的，而不是S728或Y729。这些功能数据与我们的计算模型一致，即VCAM-1细胞质结构域的结构是一个α螺旋，S728/Y729和S730/S737在α螺旋的两侧。综上所述，这些数据表明S728/Y729和S730/S737是不同的功能位点，在白细胞内皮细胞迁移过程中协调VCAM-1激活钙离子通量和rac1。
Vascular adhesion molecules regulate the migration of leukocytes from the blood into tissue during inflammation. Leukocyte binding to vascular cell adhesion molecule-1 (VCAM-1) activates signals in endothelial cells, including Rac1 and calcium fluxes. These VCAM-1 signals are required for leukocyte transendothelial migration on VCAM-1. However, it has not been reported whether the cytoplasmic domain of VCAM-1 is necessary for these signals. Interestingly, the 19 amino acid sequence of the VCAM-1 cytoplasmic domain is 100% conserved among many mammalian species, suggesting an important functional role for the domain. To examine the function of the VCAM-1 cytoplasmic domain, we deleted the VCAM-1 cytoplasmic domain or mutated the cytoplasmic domain at amino acids N724, S728, Y729, S730 or S737. The cytoplasmic domain and S728, Y729, S730 or S737 were necessary for leukocyte transendothelial migration. The S728 and Y729, but not S730 or S737, were necessary for VCAM-1 activation of calcium fluxes. In contrast, the S730 and S737, but not S728 or Y729 were necessary for VCAM-1 activation of Rac1. These functional data are consistent with our computational model of the structure of the VCAM-1 cytoplasmic domain as an alpha helix with S728/Y729 and S730/S737 on opposite sides of the alpha helix. Together, these data indicate that S728/Y729 and S730/S737 are distinct functional sites that coordinate VCAM-1 activation of calcium fluxes and Rac1 during leukocyte transendothelial migration.
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