The cytohesin Steppke is essential for insulin signalling in Drosophila
| Autor: | Thomas Becker, Bernhard Fuss, Ingo Zinke, Michael Hoch |
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| Rok vydání: | 2006 |
| Předmět: | |
| Zdroj: | Nature. 444:945-948 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Insulin resistance syndrome, a condition in which various organs respond insufficiently to insulin, is a major risk factor for the development of type 2 diabetes. For the majority of affected individuals, the underlying molecular defects are unknown. Hafner et al. now show that chemical inhibition of cytohesins, regulatory proteins not previously implicated in insulin-regulated metabolism, induces hepatic insulin resistance in mice. This points to impaired cytohesin function as a possible cause for insulin resistance and to cytohesin activators as a treatment for this disease. In a separate study the Drosophila cytohesin equivalent Steppke is shown to be an essential component of insulin signalling. Taken together, the two papers provide independent evidence for the involvement of cytohesins in the insulin pathway and demonstrate that the cytohesin-mediated control of this pathway is at least 800 million years old. A complementary study to that of Famulock et al. shows that feeding SecinH3 to flies inhibits steppke, a cytohesin, leading to growth defects and a block in insulin signalling. In metazoans, the insulin signalling pathway has a key function in regulating energy metabolism and organismal growth1. 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) GTPases2,3,4. 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. |
| Databáze: | OpenAIRE |
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