VCAM-1 activation of endothelial cell protein tyrosine phosphatase 1B
VCAM-1 activation of endothelial cell protein tyrosine phosphatase 1B
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DOI：
10.4049/jimmunol.178.6.3865
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Cook-Mills, Joan M.
中科院分区：
文献类型：
--
作者：
Deem, Tracy L.;Abdala-Valencia, Hiam;Cook-Mills, Joan M.
淋巴细胞通过与内皮细胞结合并迁移穿过内皮细胞，从血液迁移到组织中。 VCAM-1 是介导淋巴细胞结合的内皮细胞粘附分子之一。我们已经报道，与 VCAM-1 的结合会激活内皮细胞 NADPH 氧化酶，从而产生活性氧 (ROS)。 ROS 氧化并刺激蛋白激酶 C (PKC)α 活性增加。此外，这些信号是 VCAM-1 依赖性淋巴细胞迁移所必需的。在本报告中，我们确定了蛋白酪氨酸磷酸酶 1B (PTP1B) 在 VCAM-1 信号通路中的作用。在内皮细胞和内皮细胞系的原代培养物中，VCAM-1 的抗体交联刺激 PTP1B（PTP1B 的活性形式）丝氨酸磷酸化的增加。 VCAM-1 的抗体交联也增加了 PTP1B 的活性。通过药理学抑制剂和反义方法确定，PTP1B 的激活位于 VCAM-1 信号通路中 NADPH 氧化酶和 PKC α 的下游。此外，在VCAM-1信号传导过程中，ROS不会氧化内皮细胞PTP1B。相反，PTP1B 是通过丝氨酸磷酸化激活的。重要的是，抑制 PTP1B 活性可阻止 VCAM-1 依赖性淋巴细胞跨内皮细胞迁移。综上所述，VCAM-1激活内皮细胞NADPH氧化酶产生ROS，导致PKCa氧化激活，进而导致PTP1B丝氨酸磷酸化。这种 PTP1B 活性对于 VCAM-1 依赖性跨内皮淋巴细胞迁移是必需的。这些数据首次显示 PTP1B 在 VCAM-1 依赖性淋巴细胞迁移中的功能。
Lymphocytes migrate from the blood into tissue by binding to and migrating across endothelial cells. One of the endothelial cell adhesion molecules that mediate lymphocyte binding is VCAM-1. We have reported that binding to VCAM-1 activates endothelial cell NADPH oxidase for the generation of reactive oxygen species (ROS). The ROS oxidize and stimulate an increase in protein kinase C (PKC)alpha activity. Furthermore, these signals are required for VCAM-1-dependent lymphocyte migration. In this report, we identify a role for protein tyrosine phosphatase 1B (PTP1B) in the VCAM-1 signaling pathway. In primary cultures of endothelial cells and endothelial cell lines, Ab cross-linking of VCAM-1 stimulated an increase in serine phosphorylation of PTP1B, the active form of PTP1B. Ab cross-linking of VCAM-1 also increased activity of PTP1B. This activation of PTP1B was downstream of NADPH oxidase and PKC alpha in the VCAM-1 signaling pathway as determined with pharmacological inhibitors and antisense approaches. In addition, during VCAM-1 signaling, ROS did not oxidize endothelial cell PTP1B. Instead PTP1B was activated by serine phosphorylation. Importantly, inhibition of PTP1B activity blocked VCAM-1-dependent lymphocyte migration across endothelial cells. In summary, VCAM-1 activates endothelial cell NADPH oxidase to generate ROS, resulting in oxidative activation of PKCa and then serine phosphorylation of PTP1B. This PTP1B activity is necessary for VCAM-1-dependent transendothelial lymphocyte migration. These data show, for the first time, a function for PTP1B in VCAM-1-dependent lymphocyte migration.