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The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic β cells.

Authors :
Torii S
Kubota C
Saito N
Kawano A
Hou N
Kobayashi M
Torii R
Hosaka M
Kitamura T
Takeuchi T
Gomi H
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.)

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