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The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic β cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2018 Apr 20; Vol. 293 (16), pp. 5920-5933. Date of Electronic Publication: 2018 Feb 26. - Publication Year :
- 2018
-
Abstract
- Autocrine insulin signaling is critical for pancreatic β-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 β 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 β-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 β cells.<br /> (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Animals
Cell Line
Female
Gene Silencing
Male
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteolysis
Receptor-Like Protein Tyrosine Phosphatases, Class 8 genetics
Glucose metabolism
Insulin metabolism
Insulin Receptor Substrate Proteins metabolism
Insulin-Secreting Cells metabolism
Membrane Proteins metabolism
Receptor-Like Protein Tyrosine Phosphatases, Class 8 metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 293
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29483197
- Full Text :
- https://doi.org/10.1074/jbc.RA117.000301