Cytohesins Crucial for Hepatic Response to Insulin

Science's STKE  19 Dec 2006:
Vol. 2006, Issue 366, pp. tw424
DOI: 10.1126/stke.3662006tw424

Hafner et al. used an RNA aptamer displacement assay to identify new small molecule inhibitors of the guanine nucleotide exchange factor (GEF) family called cytohesins, which stimulate the activity of the ADP ribosylation factors (ARFs). The most potent and selective of these molecules was named SecinH3. Fuss et al. found that mutations in the Drosophila homolog of cytohesin, a protein called Steppke, caused a phenotype very similar to that seen with insulin signaling defects--small overall fly size at each stage of development but no impairment in eating. Feeding of SecinH3 to flies caused the same phenotype. Both the steppke-mutant flies and the SecinH3-treated flies exhibited biochemical and transcriptional evidence of loss of insulin signaling. Cytohesin appeared to act upstream of activation of phosphoinositide 3-kinase (PI3K), because the steppke-mutant phenotype was alleviated by expression of a constitutively active form of PI3K. Hafner et al. showed that SecinH3 inhibited insulin-dependent signaling in cultured HepG2 cells, a human liver cell line. Insulin also stimulated GTP loading of ARF6, which was blocked by SecinH3. Insulin signaling was blocked at the step of phosphorylation of insulin receptor substrate 1 (IRS1), but insulin receptor phosphorylation was not affected. Coimmunoprecipitation experiments showed that SecinH3 decreased the formation of an insulin-induced complex of cytohesin 2, cytohesin 3, ARF6, the insulin receptor, and IRS1. Mice fed SecinH3 exhibited signs of hepatic insulin resistance and increased circulating insulin, phenomena that are thought to cause type 2 diabetes in humans. Thus, alterations in cytohesin function may contribute to metabolic disorders (see Jackson for discussion).

M. Hafner, A. Schmitz, I. Grüne, S. G. Srivatsan, B. Paul, W. Kolanus, T. Quast, E. Kremmer, I. Bauer, M. Famulok, Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444, 941-944 (2006). [PubMed]

B. Fuss, T. Becker, I. Zinke, M. Hoch, The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 444, 945-948 (2006). [PubMed]

C. Jackson, Kicking off the insulin cascade. Nature 444, 833-834 (2006). [PubMed]