ClipR-59: a novel regulator of Akt signaling

总结 ClipR-59是Clip-170蛋白家族的成员，其特征在于存在三个锚蛋白重复序列， 两个胞浆素相关蛋白-富含甘氨酸（CAP-Gly）结构域（也称为微管结合 域（MTB）。然而，与其他与微管结合的Clip-17蛋白家族成员不同， 调节微管动力学，ClipR-59与细胞膜相关，推测在 膜相关事件。我们最近分离出ClipR-59，其表达在脂肪细胞增殖过程中升高， 分化，作为Akt相互作用蛋白ClipR-59。我们目前的研究表明，ClipR-59与 Akt并调节Akt细胞区室化。此外，ClipR-59还与AS 160底物相互作用 Akt在胰岛素调节的葡萄糖转运脂肪细胞。目前的建议是调查 ClipR-59在脂肪细胞中的功能。我们提出三个具体目标：1。我们将确定 ClipR-59表达的机制。具体地，我们将表征小鼠ClipR-59启动子和 鉴定在脂肪细胞和分化过程中介导ClipR-59诱导的顺式作用元件; 2. 我们将确定ClipR-59细胞定位受蛋白调节的机制， 棕榈酰化具体来说，我们将描述ClipR-59棕榈酰转移酶的特征，并确定其在细胞凋亡中的作用。 调节Akt细胞区室化; 3.我们将确定 ClipR-59和AS 160之间的相互作用。具体来说，我们将确定AS 160 与ClipR-59相互作用，并研究AS 160和ClipR-59之间的相互作用如何调节Akt依赖性 AS 160磷酸化及其对葡萄糖转运的后续影响。总的来说，这里提出的研究将 证明ClipR-59是Akt信号传导的一种新的调节剂，并可能提供关于 Akt信号是如何指定的。

Summary ClipR-59 is a member of Clip-170 protein family, characterized by presence of three ankyrin repeats and two cytoskeleton-associated protein-Glycine rich (CAP-Gly) domains (also referred as microtubule binding domain (MTB). However, unlike othor members of Clip-17 protein family, which bind to microtubules and regulate microtubule dynamics, ClipR-59 is associated with cell membrane and speculated to play a role in membrane related events. We have recently isolated ClipR-59, whose expression is elevated during adipocyte differentiation, as an Akt interacting protein ClipR-59. Our current studies indicate that ClipR-59 interacts with Akt and regulates Akt cellular compartmentalization. Moreover, ClipR-59 also interacts with AS160 a substrate for Akt in insulin-regulated glucose transport in the adipocyte. The current proposal is to investigate the function of ClipR-59 in adipocyte. We propose three specific aims: 1. We will determine the molecular mechanism under which ClipR-59 expression. Specifically, we will characterize mouse ClipR-59 promoter and identify the cis-acting-element that mediates the induction of ClipR-59 during adipocyte and differentiation; 2. We will determine the mechanism under which ClipR-59 cellular localization is regulated by protein palmitoylation. Specifically, we will characterize the ClipR-59 palmitoyltransferase and determine its role in the regulation of Akt cellular compartmentalization; 3. We will determine the functional importance of the interaction between ClipR-59 and AS160. Specifically, we will determine the relevant domains by which AS160 interacts with ClipR-59 and examine how interaction between AS160 and ClipR-59 regulates Akt dependent AS160 phosphorylation and its subsequent impact on glucose transport. Overall, the studies proposed here will demonstrate that ClipR-59 is a novel regulator of Akt signaling and may provide insight knowledge regarding how Akt signaling is specified.