Fuss Bernhard, Becker Thomas, Zinke Ingo, Hoch Michael
LIMES-Institute, Program Unit Development and Genetics, Laboratory for Molecular Developmental Biology, University of Bonn, Meckenheimer Allee 169, D-53115 Bonn, Germany.
Nature. 2006 Dec 14;444(7121):945-8. doi: 10.1038/nature05412.
In metazoans, the insulin signalling pathway has a key function in regulating energy metabolism and organismal growth. Its activation stimulates a highly conserved downstream kinase cascade that includes phosphatidylinositol-3-OH kinase (PI(3)K) and the serine-threonine protein kinase Akt. This study identifies a new component of insulin signalling in Drosophila, the steppke gene (step). step encodes a member of the cytohesin family of guanine nucleotide exchange factors (GEFs), which have been characterized as activators for ADP-ribosylation factor (ARF) GTPases. In step mutant animals both cell size and cell number are reduced, resulting in decreased body size and body weight in larvae, pupae and adults. step acts upstream of PI(3)K and is required for the proper regulation of Akt and the transcription factor FOXO. Temporally controlled interference with the GEF activity of the Step protein by feeding the chemical inhibitor SecinH3 causes a block of insulin signalling and a phenocopy of the step mutant growth defect. Step represses its own expression and the synthesis of growth inhibitors such as the translational repressor 4E-BP. Our findings indicate a crucial role of an ARF-GEF in insulin signalling that has implications for understanding insulin-related disorders, such as diabetes and obesity.
在多细胞动物中，胰岛素信号通路在调节能量代谢和机体生长方面具有关键作用。其激活会刺激一个高度保守的下游激酶级联反应，该反应包括磷脂酰肌醇-3-羟基激酶（PI(3)K）和丝氨酸-苏氨酸蛋白激酶Akt。本研究在果蝇中鉴定出胰岛素信号的一个新组分——steppke基因（step）。step编码鸟嘌呤核苷酸交换因子（GEF）细胞粘附分子家族的一个成员，该家族已被表征为ADP-核糖基化因子（ARF）GTP酶的激活剂。在step突变动物中，细胞大小和细胞数量均减少，导致幼虫、蛹和成虫的体型和体重下降。step在PI(3)K的上游起作用，是正确调节Akt和转录因子FOXO所必需的。通过喂食化学抑制剂SecinH3对Step蛋白的GEF活性进行时间控制的干扰会导致胰岛素信号传导受阻，并产生step突变体生长缺陷的表型模拟。Step抑制其自身的表达以及生长抑制剂的合成，如翻译抑制因子4E-BP。我们的研究结果表明ARF-GEF在胰岛素信号传导中起关键作用，这对于理解胰岛素相关疾病，如糖尿病和肥胖症具有重要意义。
