Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture.
Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture.
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DOI：
10.1084/jem.187.5.801
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发表时间：
1998-03-02
期刊：
影响因子：
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通讯作者：
Gershengorn MC
中科院分区：
文献类型：
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作者：
Geras-Raaka E;Arvanitakis L;Bais C;Cesarman E;Mesri EA;Gershengorn MC
卡波西肉瘤相关疱疹病毒（KSHV）/人疱疹病毒8，始终存在于卡波西肉瘤和原发性渗出性淋巴瘤患者的组织中，含有编码G蛋白偶联受体（KSHV-GPCR）的基因。我们最近发现，KSHV-GPCR通过激活磷酸肌醇特异性磷脂酶C表现出组成型信号传导，并刺激细胞增殖和转化。在这项研究中，我们确定是否正常的细胞机制可以抑制组成型信号KSHV-GPCR，从而KSHV-GPCR刺激的增殖。我们发现，在COS-1猴肾细胞和小鼠NIH 3 T3细胞中，GPCR特异性激酶（GRKs）的共表达和蛋白激酶C的激活抑制了KSHV-GPCR的组成性信号传导。此外，GRK-5而不是GRK-2抑制KSHV-GPCR刺激的啮齿动物成纤维细胞增殖。这些数据提供的证据表明，受体脱敏的细胞调节途径可能是涉及组成型活性受体的人类疾病的治疗靶点。
Kaposi's sarcoma–associated herpesvirus (KSHV)/human herpesvirus 8, which is consistently present in tissues of patients with Kaposi's sarcoma and primary effusion lymphomas, contains a gene that encodes a G protein–coupled receptor (KSHV-GPCR). We recently showed that KSHV-GPCR exhibits constitutive signaling via activation of phosphoinositide-specific phospholipase C and stimulates cell proliferation and transformation. In this study, we determined whether normal cellular mechanisms could inhibit constitutive signaling by KSHV-GPCR and thereby KSHV-GPCR–stimulated proliferation. We show that coexpression of GPCR-specific kinases (GRKs) and activation of protein kinase C inhibit constitutive signaling by KSHV-GPCR in COS-1 monkey kidney cells and in mouse NIH 3T3 cells. Moreover, GRK-5 but not GRK-2 inhibits KSHV-GPCR–stimulated proliferation of rodent fibroblasts. These data provide evidence that cell regulatory pathways of receptor desensitization may be therapeutic targets in human diseases involving constitutively active receptors.