Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus
Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus
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DOI：
10.1073/pnas.0837136100
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发表时间：
2003-04-15
影响因子：
11.1
通讯作者：
Lerman, MI
中科院分区：
文献类型：
--
作者：
Danilkovitch-Miagkova, A;Duh, FM;Lerman, MI
候选肿瘤抑制基因透明质酸酶2（HYAL 2）编码一种糖基磷脂酰肌醇锚定的细胞表面蛋白，该蛋白可作为绵羊肺结核逆转录病毒的进入受体，绵羊肺结核逆转录病毒是一种导致绵羊传染性肺癌的病毒，在形态上与人类细支气管肺泡癌相似。单独的病毒包膜（Env）蛋白可以转化培养的细胞，我们假设Env可以结合和隔离HYAL 2受体，从而释放出一种潜在的致癌因子结合和负控制的HYAL 2。在这里，我们表明，HYAL 2受体蛋白与罗恩受体酪氨酸激酶（在小鼠中也称为MST 1 R或Stk）相关，使其功能沉默。在表达jaagsiekte绵羊逆转录病毒Env转基因的人细胞中，Env蛋白与HYAL 2物理缔合。从与HYAL 2的结合中释放的罗恩变得具有功能活性，并因此激活Akt和丝裂原活化蛋白激酶途径，导致永生化人支气管上皮细胞的致癌转化。我们在人细支气管肺泡癌肿瘤中发现了活化的罗恩，提示罗恩参与了这种类型的人肺癌。
The candidate tumor-suppressor gene hyaluroniclase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus, a virus that causes contagious lung cancer in sheep that is morphologically similar to human bronchioloalveolar carcinoma. The viral envelope (Env) protein alone can transform cultured cells, and we hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. Here we show that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent. In human cells expressing a jaagsiekte sheep retrovirus Env transgene, the Env protein physically associates with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells. We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.