Mechanisms of cross talk between insulin and adiponectin signaling pathways

项目描述 脂联素是一种主要由脂肪细胞产生的肽类激素， 被认为是一种胰岛素增敏剂，具有抗糖尿病、抗炎和 心脏保护特性。然而，脂联素的分子机制， 增敏胰岛素信号传导和作用仍然在很大程度上未知。我们最近 鉴定了普列克底物蛋白同源性（PH）和磷酸酪氨酸结合（PTB）结构域- 含蛋白质APPL 1，与脂联素受体AdipoR 1直接相互作用 AdipoR2通过RNAi抑制APPL 1不仅抑制脂联素信号传导， 胰岛素刺激的Akt磷酸化，提示APPL 1可能在胰岛素刺激的Akt磷酸化中起作用。 在脂联素和胰岛素信号通路之间的串扰中起重要作用 (Mao等人，2006，Nat. Cell Biol，8，516-523）。根据这一观点，我们的初步 数据显示APPL 1直接与胰岛素受体相互作用， 有趣的是，脂联素刺激增强了这种相互作用。另外我们有 发现APPL 1在Ser 430处经历脂联素刺激的磷酸化; 提示了脂联素调节 APPL 1和胰岛素受体。此外，我们发现APPL 2，APPL 1 在蛋白质序列上与APPL 1共享54%同一性的同种型，与 APPL 1在细胞中过表达时抑制脂联素信号传导。基于这些 新的发现，我们假设APPL异构体和信号传导之间的相互作用， 脂联素和胰岛素信号通路中的分子可能在 这两个重要信号通路之间的串扰。为了验证这个假设，我们 将：1）表征APPL 1和信号分子之间的相互作用， 胰岛素受体（IR）信号通路及其相互作用在胰岛素抵抗中的作用 阐明APPL 2在脂联素和胰岛素信号转导中的作用 3）确定APPL 1是否在胰岛素信号传导中起作用，以及APPL 1是否在胰岛素信号传导中起作用。 脂联素体内胰岛素增敏作用

Project Description Adiponectin, a peptide hormone mainly produced by adipocytes, is now widely recognized as an insulin sensitizer that possesses anti-diabetic, anti-inflammatory and cardioprotective properties. However, the molecular mechanisms by which adiponectin sensitizes insulin signaling and action remain largely unknown. We have recently identified a pleckstrin homology (PH) and phosphotyrosine binding (PTB) domain- containing protein, APPL1 that interacts directly with the adiponectin receptors AdipoR1 and AdipoR2. Suppression of APPL1 by RNAi not only inhibits adiponectin signaling but also insulin-stimulated Akt phosphorylation, suggesting that APPL1 may play an essential role in the crosstalk between the adiponectin and insulin signaling pathways (Mao et al, 2006, Nat. Cell Biol, 8, 516-523). Consistent with this view, our preliminary data have shown that APPL1 interacts directly with the insulin receptor and more interestingly, this interaction is enhanced by adiponectin stimulation. In addition, we have found that APPL1 undergoes adiponectin-stimulated phosphorylation at Ser430; this suggests a potential mechanism by which adiponectin regulates the interaction between APPL1 and the insulin receptor. Furthermore, we have found that APPL2, an APPL1 isoform which shares 54% identity in protein sequence with APPL1, dimerizes with APPL1 and inhibits adiponectin signaling when overexpressed in cells. Based on these novel findings, we hypothesize that the interaction between APPL ispforms and signaling molecules in the adiponectin and insulin signaling pathways may play a key role in the crosstalk between these two important signaling pathways. To test this hypothesis, we will: 1) Characterize the interaction between APPL1 and signaling molecules in the insulin receptor (IR) signaling pathway and the roles of the interaction in insulin signaling; 2) Elucidate the roles of APPL2 in regulating adiponectin and insulin signaling and function; and 3) Determine whether APPL1 plays a role in insulin signaling and the insulin sensitizing effect of adiponectin in vivo.