MECHANISMS OF GLUCOSE SIGNAL TRANSDUCTION IN YEAST

描述（改编自申请人的摘要）：响应能力 细胞外环境的变化是所有细胞的基础。的 哺乳动物细胞的生长部分受细胞外细胞因子的控制 它与膜受体结合，膜受体反过来调节 细胞内蛋白激酶。在酿酒酵母中， 细胞外葡萄糖浓度的变化与 哺乳动物细胞因子信号通路。葡萄糖传感器蛋白由 SNF 3和RGT 2是结合细胞外葡萄糖的整合膜蛋白 并启动一个信号通路，最终导致基因的变化， 表情Snf 1丝氨酸/苏氨酸蛋白激酶在细胞凋亡中起重要作用。 信号葡萄糖限制，然而，葡萄糖 传感器调节Snf 1激酶的活性尚未阐明。 对一种名为Std 1的酵母蛋白的研究提供了一种合理而直接的 葡萄糖传感器和Snf 1激酶之间的连接。一种双杂交屏幕 对于Std 1相互作用蛋白，鉴定了 葡萄糖传感器，已经被证明对葡萄糖至关重要的结构域， 发信号。早期的研究表明，Std 1与Snf 1发生物理相互作用， 增加STD 1的基因剂量抑制了Snf 1激酶的突变， 复杂.其他数据记录了STD 1基因之间的遗传相互作用 (and它的同源物MTH 1）和编码葡萄糖传感器的基因， 响应细胞外葡萄糖水平变化的基因表达。 此外，Std 1/Mth 1和葡萄糖传感器之间的相互作用调节了葡萄糖代谢。 Snf 1激酶的活性。由于Std 1可以与葡萄糖和葡萄糖 传感器和Snf 1激酶，数据支持一个模型，即Std 1蛋白 作为膜受体和膜受体之间的信号传导中间体。 胞内蛋白激酶 这些研究的长期目标是确定所需的所有蛋白质 葡萄糖信号转导，并确定其序列 相互作用及其调控机制。三个具体目标是 本研究计划：（1）评估生物学意义。 Std 1和Mth 1蛋白与葡萄糖传感器之间的相互作用; 2） 确定Snf 1激酶信号通路的其他组分; 3） 鉴定与Std 1和Mth 1协同作用的其他蛋白质， 基因表达。

DESCRIPTION (adapted from the applicant's abstract): The ability to respond to changes in the extracellular environment is fundamental to all cells. The growth of mammalian cells is controlled in part by extracellular cytokines which bind to integral membrane receptors that in turn regulate the activity of intracellular protein kinases. In Saccharomyces cerevisiae, the response to changes in extracellular glucose concentration shares many similarities with mammalian cytokine signaling pathways. The glucose sensor proteins encoded by SNF3 and RGT2 are integral membrane proteins that bind extracellular glucose and initiate a signaling pathway that ultimately results in changes in gene expression. The Snf1 serine/threonine protein kinase plays an essential role in signaling glucose limitation, however the mechanism by which the glucose sensors regulate the activity of the Snf1 kinase has yet to be elucidated. Studies of a yeast protein called Std1 provide a plausible and direct connection between the glucose sensors and the Snf1 kinase. A two-hybrid screen for Std1 interacting proteins identified the C-terminal hydrophilic domains of the glucose sensors, domains that have been shown essential for glucose signaling. Earlier studies have shown that Std1 physically interacted with Snf1 and that increased gene dosage of STD1 suppressed a mutation in the Snf1 kinase complex. Additional data document genetic interactions between the STD1 gene (and its homologue MTH1) and the genes encoding the glucose sensors that affect gene expression in response to changes in extracellular glucose levels. Moreover, interactions between Std1/Mth1 and glucose sensors regulate the activity of the Snf1 kinase. Since Std1 can interact with both the glucose sensors and the Snf1 kinase, the data support a model whereby the Std1 protein acts as a signaling intermediate between the membrane receptors and the intracellular protein kinase. The long term goal of these studies is to identify all of the proteins required for glucose signal transduction and to determine the sequence of their interactions and their mechanism of regulation. Three specific aims are proposed for this grant period: 1) Assess the biological significance of the interaction between the Std1 and Mth1 proteins with the glucose sensors; 2) Identify additional components of the Snf1 kinase signaling pathway; 3) Identify additional proteins that act in concert with Std1 and Mth1 to regulate gene expression.