The phosphatase Shp2 is required for signaling by the Kaposi's sarcoma-associated herpesvirus viral GPCR in primary endothelial cells.
The phosphatase Shp2 is required for signaling by the Kaposi's sarcoma-associated herpesvirus viral GPCR in primary endothelial cells.
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DOI：
10.1016/j.virol.2009.11.030
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发表时间：
2010-02-20
期刊：
影响因子：
3.7
通讯作者：
Cannon, Mark L.
中科院分区：
文献类型：
--
作者：
Bakken, Thomas;He, Meilan;Cannon, Mark L.
关键词：
卡波西肉瘤相关疱疹病毒(KSHV)是卡波西肉瘤(KS)的病原体，KS是一种与艾滋病相关的内皮细胞恶性肿瘤，是非洲中部和南部最常见的癌症。KSHV病毒G蛋白偶联受体(VGPCR)是一种病毒癌基因，它向内皮细胞传递生存优势，并在小鼠模型中引起KS样瘤。在本研究中，我们研究了蛋白酪氨酸磷酸酶Shp2在vGPCR信号转导中的作用。Shp2在许多细胞因子诱导的信号通路中起着至关重要的作用，并且在各种感染和恶性肿瘤中调节失调。最近，它还被认为与血管生成有关。我们发现vGPCR活性导致Shp2中调节性酪氨酸的磷酸化，反过来，Shp2是vGPCR介导的MEK、NFκB和AP-1激活所必需的。此外，Shp2的遗传和化学抑制均可阻断vGPCR诱导的内皮细胞迁移。这使得Shp2成为KSHV vGPCR信号的重要汇聚点，并成为设计抗KSHV治疗方案的潜在分子靶点。
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-related endothelial cell malignancy that is the most common cancer in central and southern Africa. The KSHV viral G protein-coupled receptor (vGPCR) is a viral oncogene that conveys a survival advantage to endothelial cells and causes KS-like tumors in mouse models. In this study we investigate the role of Shp2, a protein tyrosine phosphatase in vGPCR signaling. Shp2 is vital to many cytokine-induced signaling pathways and is dysregulated in various infections and malignancies. It has also recently been implicated in angiogenesis. We find that vGPCR activity results in phosphorylation of regulatory tyrosines in Shp2 and that in turn, Shp2 is required for vGPCR-mediated activation of MEK, NFκB, and AP-1. Furthermore, both genetic and chemical inhibition of Shp2 abrogate vGPCR-induced enhancement of endothelial cell migration. This establishes Shp2 as an important point of convergence of KSHV vGPCR signaling and a potential molecular target in the design of an anti-KSHV therapeutic regimen.
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