The small GTPase, Rap1, mediates CD31-induced integrin adhesion.
The small GTPase, Rap1, mediates CD31-induced integrin adhesion.
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DOI：
10.1083/jcb.148.6.1151
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发表时间：
2000-03-20
期刊：
影响因子：
--
通讯作者：
Bos JL
中科院分区：
文献类型：
--
作者：
Reedquist KA;Ross E;Koop EA;Wolthuis RM;Zwartkruis FJ;van Kooyk Y;Salmon M;Buckley CD;Bos JL
整合素介导的白细胞粘附是白细胞功能的一个重要方面，其受到多种刺激的严格调节，包括趋化因子、抗原受体和粘附受体。来自CD 31和其他粘附放大器的细胞信号如何与来自经典促有丝分裂刺激的信号整合以调节白细胞功能仍然知之甚少。在这里，我们表明，CD 31的胞质尾，一个重要的整合素粘附放大器，传播信号，诱导T细胞粘附通过β1（VLA-4）和β2（LFA-1）整合素。我们确定了小GTdR，Rap 1，作为这种效果的关键调解人。重要的是，CD 31选择性激活小Ras相关的GT3，Rap 1，而不是Ras，R-Ras或Rap 2。激活的Rap 1突变体刺激T淋巴细胞粘附细胞间粘附分子（ICAM）和血管细胞粘附分子（VCAM），Rap 1鸟嘌呤核苷酸交换因子C3 G和RapGAP的催化失活突变体。相反，Rap 1信号的负调节剂阻断CD 31依赖性粘附。这些发现确定了一个新的重要作用Rap 1在调节配体诱导的细胞粘附，并建议Rap 1可能发挥更广泛的作用，在白细胞迁移和外渗过程中的协调粘附依赖性信号。我们的研究结果还表明了一种替代机制，与Ras近端信号干扰不同，Rap 1可能通过这种机制介导转化逆转。
Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte function that is tightly regulated by diverse stimuli, including chemokines, antigen receptors, and adhesion receptors. How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogenic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion amplifier, propagates signals that induce T cell adhesion via β1 (VLA-4) and β2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a critical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1, but not Ras, R-Ras, or Rap2. An activated Rap1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guanine nucleotide exchange factor C3G and a catalytically inactive mutant of RapGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-dependent adhesion. These findings identify a novel important role for Rap1 in regulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte migration and extravasation. Our findings also suggest an alternative mechanism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.
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20.3
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