A Critical Role for beta-Catenin in Modulating Levels of Insulin Secretion from beta-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization
The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic beta-cells are only partly understood. Here we investigate the involvement of beta-catenin in these processes. Reducing beta-catenin levels using siRNA knockdown attenuated GSIS in a range of beta-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both beta-cell models and isolated islets by short-term exposure to the beta-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases beta-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that beta-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of beta-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating beta-catenin from the plasma membrane pool to the nucleus. We show that beta-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that beta-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that beta-catenin levels modulate Ca2+-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion.
|ISBN||1083-351X (Electronic) 0021-9258 (Linking)|
|Authors||Sorrenson, B.; Cognard, E.; Lee, K. L.; Dissanayake, W. C.; Fu, Y.; Han, W.; Hughes, W. E.; Shepherd, P. R.;|
|Publisher Name||JOURNAL OF BIOLOGICAL CHEMISTRY|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/27777306 http://www.jbc.org/content/291/50/25888.full.pdf|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14005|