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

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. , 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.

FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis

“…The product of relaxin receptor 2 (RXFP2) mediates G-protein dependent stimulation of adenylate cyclase and an increase of cAMP levels [65]. Receptor-type tyrosine-protein phosphatase N2 (PTPRN2) was shown to act as an autoantigen in type I diabetes and be required for the accumulation of insulin-containing vesicles, preventing their degradation in rat gastrointestinal endocrine cells [66]. Moreover, it has a role in the accumulation of norepinephrine, dopamine, and serotonin in autonomic nerve endings [67].…”

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

“…The product of relaxin receptor 2 (RXFP2) mediates G-protein dependent stimulation of adenylate cyclase and an increase of cAMP levels [61]. Receptor-type tyrosine-protein phosphatase N2 (PTPRN2) was shown to be required for the accumulation of insulin-containing vesicles preventing their degradation [62] and accumulation of norepinephrine, dopamine and serotonin [63]. Ephrin type-A receptor 5 (EPHA5) which has a role in regulation of insulin secretion [64] was also highly expressed in DN as compared to SC brown adipocytes.…”

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“…The expression of the insulin receptor (IR) in pancreatic β-cells plays an essential role in β-cell development and function during diabetes progression. Overexpression of the IR leads to increased β-cell proliferation and insulin production [7]. The IR can activate its main substrates, insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2), followed by the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which is important for regulating pancreatic β-cell function and survival [8].…”