KAPOSI?S SARCOMA-ASSOCIATED HERPESVIRUS K1 SIGNALOSOME

卡波西肉瘤相关疱疹病毒 K1 信号体

• 批准号: 7349565
• 负责人: BOK-SOO LEE
• 金额: $ 6.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349565
• 关键词: KAPOSI; SARCOMA; ASSOCIATED; HERPESVIRUS; K1

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Kaposi's sarcoma (KS) is a multifocal angiogenic tumor and appears to be a hyperplastic disorder caused, in part, by local production of inflammatory cytokines. The K1 lymphocyte receptor-like protein of KS-associated herpesvirus (KSHV) efficiently transduces extracellular signals to elicit cellular activation events through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). To further delineate K1-mediated signal transduction, we purified K1 signaling complexes and identified its cellular components. Upon stimulation, the K1 ITAM was efficiently tyrosine phosphorylated and subsequently interacted with cellular Src homology 2 (SH2)-containing signaling proteins Lyn, Syk, p85, PLC2, RasGAP, Vav, SH2 domain-containing protein tyrosine phosphatase ¿, and Grab2 through its phosphorylated tyrosine residues. Mutational analysis demonstrated that each tyrosine residue of K1 ITAM contributed to the interactions with cellular signaling proteins in distinctive ways. Consequently, these interactions led to the marked augmentation of cellular signal transduction activity, evidenced by the increase of cellular tyrosine phosphorylation and intracellular calcium mobilization, the activation of NF-AT and AP0-1 transcription factor activities, and the production of inflammatory cytokines. These results demonstrate that KSHV K1 effectively recruits a set of cellular SH2-containing signaling molecules to form the K1 signalosome, which elicits downstream signal transduction and induces inflammatory cytokine production.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。卡波西肉瘤是一种多灶性血管生成性肿瘤，是一种增生性疾病，部分原因是局部产生炎性细胞因子。KS相关疱疹病毒（KSHV）的K1淋巴细胞受体样蛋白通过其胞质免疫受体酪氨酸激活基序（ITAM）有效地转导细胞外信号以引发细胞激活事件。为了进一步描述K1介导的信号转导，我们纯化了K1信号复合物并鉴定了其细胞组分。在刺激后，K1 ITAM被有效地酪氨酸磷酸化，随后通过其磷酸化的酪氨酸残基与含有细胞Src同源性2（SH 2）的信号传导蛋白林恩、Syk、p85、PLC 2、RasGAP、Vav、含有SH 2结构域的蛋白酪氨酸磷酸酶？和Grab 2相互作用。突变分析表明，K1 ITAM的每个酪氨酸残基以独特的方式与细胞信号蛋白相互作用。因此，这些相互作用导致细胞信号转导活性的显著增强，这通过细胞酪氨酸磷酸化和细胞内钙动员的增加、NF-AT和AP 0 -1转录因子活性的激活以及炎性细胞因子的产生来证明。这些结果表明，KSHV K1有效地招募了一组细胞内含有SH 2的信号分子，形成K1信号体，从而促进下游信号转导并诱导炎症细胞因子的产生。