| First Author | Torii S | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 16 | Pages | 5920-5933 |
| PubMed ID | 29483197 | Mgi Jnum | J:263703 |
| Mgi Id | MGI:6162203 | Doi | 10.1074/jbc.RA117.000301 |
| Citation | Torii S, et al. (2018) The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic beta cells. J Biol Chem 293(16):5920-5933 |
| abstractText | Autocrine insulin signaling is critical for pancreatic beta-cell growth and activity and is at least partially controlled by protein-tyrosine phosphatases (PTPs) that act on insulin receptors (IRs). The receptor-type PTP phogrin primarily localizes on insulin secretory granules in pancreatic beta cells. We recently reported that phogrin knockdown decreases the protein levels of insulin receptor substrate 2 (IRS2), whereas high-glucose stimulation promotes formation of a phogrin-IR complex that stabilizes IRS2. However, the underlying molecular mechanisms by which phogrin affects IRS2 levels are unclear. Here, we found that relative to wildtype mice, IRS2 levels in phogrin-knockout mice islets decreased by 44%. When phogrin was silenced by shRNA in pancreatic beta-cell lines, glucose-induced insulin signaling led to proteasomal degradation of IRS2 via a negative feedback mechanism. Phogrin overexpression in a murine hepatocyte cell line consistently prevented chronic insulin treatment-induced IRS2 degradation. In vitro, phogrin directly bound the IR without the assistance of other proteins and protected recombinant PTP1B from oxidation to potentiate its activity toward the IR. Furthermore, phogrin expression suppressed insulin-induced local generation of hydrogen peroxide and subsequent PTP1B oxidation, which allowed progression of IR dephosphorylation. Together, these results suggest that a transient interaction of phogrin with the IR enables glucose-stimulated autocrine insulin signaling through the regulation of PTP1B activity, which is essential for suppressing feedback-mediated IRS2 degradation in pancreatic beta cells. |
