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Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes.

ABSTRACT: Endoplasmic reticulum (ER) stress has been recognised as a common pathway in the development of obesity-associated insulin resistance. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signalling and is localised on the ER membrane. The aim of the study was to investigate the cross-talk between ER stress and PTP1B.Leptin-deficient obese (ob/ob), Ptp1b (also known as Ptpn1) knockout and C57BL/6J mice were subjected to a high-fat or normal-chow diet for 20 weeks. ER stress was induced in cultured myotubes by treatment with tunicamycin. Immunohistochemistry and western blotting were used to assess proteins involved in the ER stress response. Myotube glucose uptake was determined by measuring 2-deoxy[(3)H]glucose incorporation.A high-fat diet induced ER stress and PTP1B expression in the muscle tissue of mice and these responses were attenuated by treatment with the ER chaperone tauroursodeoxycholic acid (TUDCA). Cultured myotubes exhibited increased levels of PTP1B in response to tunicamycin treatment. Silencing of Ptp1b with small interfering RNA (siRNA) or overexpression of Ptp1b with adenovirus construct failed to alter the levels of ER stress. Ptp1b knockout mice did not differ from the wild-type mice in the extent of tunicamycin-induced upregulation of glucose-regulated protein-78. However, tunicamycin-induced phosphorylation of eukaryotic initiation factor 2? and c-Jun NH(2)-terminal kinase-2 were significantly attenuated in the Ptp1b knockout mice. Treatment with TUDCA or silencing of PTP1B reversed tunicamycin-induced blunted myotube glucose uptake.Our data suggest that PTP1B is activated by ER stress and is required for full-range activation of ER stress pathways in mediating insulin resistance in the skeletal muscle.

SUBMITTER: Panzhinskiy E

PROVIDER: S-EPMC3568946 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes.

Panzhinskiy E E Hua Y Y Culver B B Ren J J Nair S S

Diabetologia 20121124 3

<h4>Aims/hypothesis</h4>Endoplasmic reticulum (ER) stress has been recognised as a common pathway in the development of obesity-associated insulin resistance. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signalling and is localised on the ER membrane. The aim of the study was to investigate the cross-talk between ER stress and PTP1B.<h4>Methods</h4>Leptin-deficient obese (ob/ob), Ptp1b (also known as Ptpn1) knockout and C57BL/6J mice were subjected to a high-fat or ...[more]

PMID: 23178931

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Project description:A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn2+) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn2+) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing ("anti-diabetic") effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.

Dataset Information

Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes.

Publications

Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes.

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