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，这些信号对细胞存活和代谢都很重要。启动脂质信息以促进葡萄糖摄取进入细胞并促进细胞存活的中心细胞内信号传导酶是由PI 3-激酶产生的。这种酶在许多癌症中具有增加的活性，并且当酶可能被抑制时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，该酶在细胞内起作用以对抗PI 3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已被鉴定为一种称为米勒-迪克尔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大脑异常有关。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PI 3激酶信号分子中去除磷酸分子。SKIP已被证明通过破坏PI 3-激酶信号来防止葡萄糖摄取到细胞中。我们最近证明SKIP磷酸酶活性可以通过与另一种称为死亡结构域抑制因子（SODD）的蛋白质结合来抑制。我们计划研究这种复合物对SKIP酶活性的影响，以及这种复合物如何在调节促进葡萄糖摄取的PI 3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（基因敲除小鼠）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的功能意义和这种酶调节的分子途径。

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.