The role of TCTP in regulating adiponectin signaling

 描述(申请人提供)：脂联素已被公认为是一种胰岛素增敏剂，可以抑制葡萄糖的产生和调节肝脏的脂肪代谢。然而，脂联素作用的分子机制在很大程度上仍不清楚。我们的实验室首次发现了脂联素受体相互作用蛋白APPL1，它在脂联素信号转导中起着重要作用。随后，我们发现APPL1的异构体APPL2与APPL1一起作为整合的阴阳调节机制来调节细胞内的脂联素信号。为了阐明APPL异构体调控脂联素信号转导的机制，我们以APPL2为诱饵，筛选了酵母双杂交文库。这一筛选导致TCTP被鉴定为与APPL亚型相互作用的结合蛋白。根据我们的初步研究，我们假设TCTP是肝脏脂联素信号的关键调节因子，它与APPL亚型的相互作用可能为肥胖导致脂联素信号下调提供了一种机制。肥胖症和2型糖尿病患者脂联素信号转导功能受损，脂联素水平降低，在胰岛素抵抗的发生发展中起重要作用。了解TCTP调节脂联素信号的机制可能有助于确定预防和治疗代谢紊乱的新的有效治疗策略。

 DESCRIPTION (provided by applicant): Adiponectin has been well established as an insulin sensitizer to suppress glucose production and regulate hepatic lipid metabolism. However, the molecular mechanisms underlying adiponectin action remain largely unknown. Our laboratory identified for the first time an adiponectin receptor interactive protein, APPL1, which plays an essential role in adiponectin signaling. Subsequently, we showed that APPL2, an isoform of APPL1, acts as integrated Yin-Yang regulatory machinery with APPL1 to regulate adiponectin signaling in cells. To elucidate the mechanisms by which APPL isoforms regulate adiponectin signaling, we screened a yeast two-hybrid cDNA library using APPL2 as bait. This screening led to identification of TCTP as a binding protein that interacts with APPL isoforms. Based on our preliminary studies, we hypothesize that TCTP is a key regulator of adiponectin signaling in the liver and its interaction with APPL isoforms may provide a mechanism underlying obesity-induced down-regulation of adiponectin signaling. Impairment of adiponectin signaling together with reduced level of adiponectin in obesity and type 2 diabetes play important roles in development of insulin resistance. Understanding the mechanisms underlying TCTP-regulated adiponectin signaling may lead to identification of novel and effective therapeutic strategies for the prevention and treatment of metabolic disorders.