Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor.
Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor.
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DOI：
10.4049/jimmunol.163.4.2017
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发表时间：
1999-08
影响因子：
4.4
通讯作者：
M. Burger;J. Burger;R. C. Hoch;Z. Oades;H. Takamori;I. Schraufstatter
中科院分区：
文献类型：
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作者：
M. Burger;J. Burger;R. C. Hoch;Z. Oades;H. Takamori;I. Schraufstatter
趋化因子受体CXCR 2是与卡波西肉瘤疱疹病毒-G蛋白偶联受体（KSHV-GPCR）最接近的同源物，已知KSHV-GPCR被组成性激活并能够引起致癌转化。在G蛋白偶联受体中，第二胞内环中的DRY序列是高度保守的。然而，KSHV-GPCR却显示了VRY序列。在本研究中，我们将CXCR 2中DRY序列的Asp 138与KSHV-GPCR中相应的氨基酸瓦尔（D138 V）或Gln（D138 Q）交换，并研究了这些突变的功能后果。在NIH 3 T3细胞中的焦点形成和软琼脂生长测定中，D138 V突变体表现出与KSHV-GPCR相似的转化潜力。令人惊讶的是，CXCR 2野生型本身显示出转化活性，尽管由于连续的自分泌刺激而没有那么强，而D138 Q突变体没有形成病灶。与这些结果一致的是在D138 V突变体和KSHV-GPCR中高水平的肌醇磷酸积累，表明组成型活性。这些数据强调了DRY序列对于CXCR 2的G蛋白偶联信号传导的重要性。CXCR 2的组成性激活或持续性自分泌刺激引起类似于KSHV-GPCR转染细胞的转化，可能激活可以废除正常生长控制机制的相同信号转导级联。
The chemokine receptor CXCR2 is the closest homologue to Kaposi's sarcoma herpesvirus-G protein-coupled receptor (KSHV-GPCR), which is known to be constitutively activated and able to cause oncogenic transformation. Among G protein-coupled receptors, a DRY sequence in the second intracellular loop is highly conserved. However, the KSHV-GPCR shows a VRY sequence instead. In this study, we exchanged Asp138 of the DRY sequence in the CXCR2 with a Val (D138V), the corresponding amino acid in KSHV-GPCR, or with a Gln (D138Q), and investigated the functional consequences of these mutations. In focus formation and soft agar growth assays in NIH 3T3 cells, the D138V mutant exhibited transforming potential similar to the KSHV-GPCR. Surprisingly, the CXCR2 wild type itself showed transforming activity, although not as potently, due to continuous autocrine stimulation, whereas the D138Q mutant formed no foci. In agreement with these results were high levels of inositol phosphate accumulation in the D138V mutant and the KSHV-GPCR, indicating constitutive activity. These data emphasize the importance of the DRY sequence for G protein-coupled signaling of the CXCR2. Either constitutive activation or persistent autocrine stimulation of the CXCR2 causes transformation similar to KSHV-GPCR-transfected cells, probably activating the same signal transduction cascade that can abrogate normal growth control mechanisms.