The role of TCTP in regulating adiponectin signaling

 描述（由申请方提供）：脂联素已被公认为抑制葡萄糖生成和调节肝脏脂质代谢的胰岛素增敏剂。然而，脂联素作用的分子机制仍不清楚。我们的实验室首次鉴定了脂联素受体相互作用蛋白APPL1，其在脂联素信号传导中起重要作用。随后，我们发现APPL2，APPL1的一种异构体，作为与APPL1整合的阴阳调节机制来调节细胞中的脂联素信号。为了阐明APPL异构体调节脂联素信号转导的机制，我们以APPL 2为诱饵筛选了酵母双杂交cDNA文库。该筛选导致TCTP被鉴定为与APPL同种型相互作用的结合蛋白。基于我们的初步研究，我们假设TCTP是肝脏中脂联素信号传导的关键调节因子，其与APPL亚型的相互作用可能提供了肥胖诱导的脂联素信号传导下调的潜在机制。肥胖和2型糖尿病患者脂联素信号通路受损和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调控脂联素信号传导的机制可能会导致识别新的和有效的治疗策略，用于预防和治疗代谢紊乱。

 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.