Characterization of the phosphoinositide 5-phosphatase SKIP.

生长因子和胰岛素刺激细胞内一系列复杂的信号，这对细胞存活和代谢都很重要。pi3激酶是一种中枢细胞内信号转导酶，它可以启动脂质信息，促进葡萄糖进入细胞并促进细胞存活。这种酶在许多癌症中都增加了活性，当这种酶被抑制时，它在糖尿病中也很重要。我们的资助计划研究另一种称为SKIP的酶的功能，这种酶在细胞内起作用，反对pi3激酶的功能。一些证据表明SKIP可能在发育和癌症中都很重要。SKIP已被确定为一种被称为米勒-迪克综合征的发育障碍的假定候选基因。这种疾病与面部和显著的脑部异常有关。此外，SKIP基因位于乳腺癌和结肠癌中经常缺失的染色体上。SKIP是一种酶，其功能是从pi3激酶信号分子中去除磷酸分子。SKIP已被证明通过分解pi3激酶信号来阻止葡萄糖进入细胞。我们最近证明SKIP磷酸酶的活性可以通过与另一种称为死亡结构域抑制因子（SODD）的蛋白质结合而被抑制。我们计划研究该复合物对SKIP酶活性的影响，以及该复合物如何在调节促进葡萄糖摄取的pi3激酶信号中发挥作用。其次，我们计划通过制造缺乏SKIP的小鼠（敲除小鼠）来研究SKIP在完整动物中的功能。鉴于SKIP与发育综合征和胰岛素信号传导有关，我们可以描述SKIP的功能意义以及该酶调节的分子途径。

Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional significance of SKIP and the molecular pathways regulated by this enzyme.