Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets
2014 (English)In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 0022-0795, Vol. 223, no 3, 267-275 p.Article in journal (Refereed) Published
The Src homology-2 domain containing protein B (SHB) has previously been shown to function as a pleiotropic adapter protein, conveying signals from receptor tyrosine kinases to intracellular signaling intermediates. The overexpression of Shb in β-cells promotes β-cell proliferation by increased insulin receptor substrate (IRS) and focal adhesion kinase (FAK) activity, whereas Shb deficiency causes moderate glucose intolerance and impaired first-peak insulin secretion. Using an array of techniques, including live-cell imaging, patch-clamping, immunoblotting, and semi-quantitative PCR, we presently investigated the causes of the abnormal insulin secretory characteristics in Shb-knockout mice. Shb-knockout islets displayed an abnormal signaling signature with increased activities of FAK, IRS, and AKT. β-catenin protein expression was elevated and it showed increased nuclear localization. However, there were no major alterations in the gene expression of various proteins involved in the β-cell secretory machinery. Nor was Shb deficiency associated with changes in glucose-induced ATP generation or cytoplasmic Ca(2) (+) handling. In contrast, the glucose-induced rise in cAMP, known to be important for the insulin secretory response, was delayed in the Shb-knockout compared with WT control. Inhibition of FAK increased the submembrane cAMP concentration, implicating FAK activity in the regulation of insulin exocytosis. In conclusion, Shb deficiency causes a chronic increase in β-cell FAK activity that perturbs the normal insulin secretory characteristics of β-cells, suggesting multi-faceted effects of FAK on insulin secretion depending on the mechanism of FAK activation.
Place, publisher, year, edition, pages
2014. Vol. 223, no 3, 267-275 p.
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-236195DOI: 10.1530/JOE-14-0531ISI: 000345292500007PubMedID: 25274988OAI: oai:DiVA.org:uu-236195DiVA: diva2:763318