The role of Ephrin-A2 receptor-tyrosinkinase in Kaposi sarcoma-associated herpesvirus infection

卡波西肉瘤相关疱疹病毒（Kaposi sarcoma-associated herpesvirus，KSHV），又称人类疱疹病毒8型（human herpesvirus 8，HHV-8），是卡波西肉瘤（Kaposi sarcoma，KS）和两种淋巴系统恶性肿瘤的病原体。疱疹病毒进入细胞是一个多步骤的过程，涉及几种病毒糖蛋白和细胞受体。最近，我们鉴定了KSHV糖蛋白H和L（gH/gL）的第一个受体：Ephrin受体-酪氨酸激酶A2（EphA 2）。EphA 2是至关重要的，如果不是绝对必要的感染内皮细胞的起源KS。EphA 2不仅是KSHV的受体;还已知其有助于肿瘤发生和新血管形成。其中，EphA 2与分子相互作用并触发已知参与KSHV进入的信号级联。EphA 2在许多实体瘤中高度表达。我们发现KS也是如此。有趣的是，尽管EphA 2在潜伏性KSHV感染的KS组织中上调，但KSHV裂解性复制的再激活伴随着EphA 2表达的显著降低。EphA 2表达调控的机制基本上是未知的。我们表明，KSHV转录因子RTA足以在KSHV再活化后下调EphA 2。总之，EphA 2可能是KSHV感染中的关键分子，有助于KS发病机制。然而，到目前为止，涉及EphA 2的KSHV条目的步骤定义得很差。 识别EphA 2，2监管的进入过程中的步骤。参与KSHV进入/感染的EphA 2的细胞内结构域的解剖，3.鉴定与KSHV进入相关的由EphA 2触发的信号传导途径。4.通过RTA鉴定EphA 2表达调节的机制（转录或转录后）。EphA 2参与KSHV进入及其受KSHV调节的分析可能不仅对于理解KSHV生物学和KS发病机制很重要，而且还将揭示EphA 2在癌症中的功能。

Kaposi sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus 8 (HHV-8), is the causative agent of Kaposi sarcoma (KS) and two lymphoid malignancies. Entry of a herpesvirus into a cell is a multi-step process involving several viral glycoproteins and cellular receptors. Recently, we identified the first receptor for KSHV glycoprotein H and L (gH/gL): Ephrin receptor-tyrosinkinase A2 (EphA2). EphA2 is crucial if not absolutely essential for the infection of endothelial cells which are the origin of KS. EphA2 is not only a receptor for KSHV; it is also known to contribute to oncogenesis and neo-vascularization. Amongst others, EphA2 interacts with molecules and triggers signaling cascades that are known to be involved in KSHV entry. EphA2 is highly expressed in many solid tumors. We showed that this is the case in KS, too. Interestingly, whereas EphA2 is upregulated in latently KSHV infected KS tissues, reactivation of KSHV lytic replication is accompanied by a marked reduction of EphA2 expression. The mechanism(s) of EphA2 expression regulation are essentially unknown. We showed that the KSHV transcription factor RTA is sufficient for EphA2 downregulation upon KSHV reactivation. In summary, EphA2 is likely to be a key molecule in KSHV infection that contributes to KS pathogenesis. However, the step(s) of KSHV entry in which EphA2 is involved have been poorly defined so far The goals of this project are: 1. Identification of the steps in the entry process that are regulated by EphA2, 2. Dissection of the intracellular domains of EphA2 involved in KSHV entry/infection, 3. identification of the signaling pathways triggered by EphA2 which are relevant for KSHV entry. 4. Identification of the mechanisms (transcriptional or post-transcriptional) of EphA2 expression-regulation by RTA. It is likely that the analysis of EphA2 involvement in KSHV entry and its regulation by KSHV will not only be important for the understanding of KSHV biology and KS pathogenesis but will also shed light on the functions of EphA2 in cancer in general.