Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

Revuelta-Cervantes, Jesús; Mayoral, Rafael; Miranda, Soledad; González-Rodrı́guez, Águeda; Fernández, Margarita; Martı́n-Sanz, Paloma; Valverde, Ángela M.

doi:10.1016/j.ajpath.2010.12.020

Cited by 34 publications

(30 citation statements)

References 55 publications

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“…Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors, including EGFR. In PTP1B null mice with partial hepatectomy, liver regeneration is enhanced due to activated EGFR signaling pathways (457).…”

Section: Role Of Egfr In the Livermentioning

confidence: 99%

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Chen

Zeng

Forrester

et al. 2016

Physiological Reviews

219

156

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The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

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Section: Role Of Egfr In the Livermentioning

confidence: 99%

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Chen

Zeng

Forrester

et al. 2016

Physiological Reviews

219

156

View full text Add to dashboard Cite

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“…Another potential mediator is the phosphatase PTP1B that binds Met and EGFR and decreases their activation. PTP1B deficiency results in enhanced EGF‐ and HGF‐mediated signalling in hepatocytes and livers submitted to partial hepatectomy resulting in accelerated regeneration, and also confers resistance on TGF‐β‐induced suppressor effects in hepatocytes . Whether the effects on tyrosine kinase receptors and TGF‐β signalling are mutually dependent has not been clarified.…”

Section: The Tgf‐β As a Guardian Of Liver Homeostasismentioning

confidence: 99%

TGF‐β signalling and liver disease

et al. 2016

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The transforming growth factor‐beta (TGF‐β) family signalling pathways play essential roles in the regulation of different cellular processes, including proliferation, differentiation, migration or cell death, which are essential for the homeostasis of tissues and organs. Because of the diverse and pleiotropic TGF‐β functions, deregulation of its pathways contributes to human disease. In the case of the liver, TGF‐β signalling participates in all stages of disease progression, from initial liver injury through inflammation and fibrosis, to cirrhosis and cancer. TGF‐β has cytostatic and apoptotic effects in hepatocytes, promoting liver differentiation during embryogenesis and physiological liver regeneration. However, high levels of TGF‐β, as a consequence of chronic liver damage, result in activation of stellate cells to myofibroblasts and massive hepatocyte cell death, which contributes to the promotion of liver fibrosis and later cirrhosis. During liver tumorigenesis, TGF‐β may behave as a suppressor factor at early stages; however, there is strong evidence that overactivation of TGF‐β signalling might contribute to later tumour progression, once cells escape from its cytostatic effects. For these reasons, targeting the TGF‐β signalling pathway is being explored to counteract liver disease progression. In this review, we aim to shed light on the state‐of‐the‐art in the signalling pathways induced by TGF‐β that are involved in different stages of liver physiology and pathology.

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“…There is a growing body of evidence to suggest that PTP1B inhibitors hold great promise for the treatment of type 2 diabetes as well as cancer [3,4,8,[16][17][18][22][23][24][25][26][27][28][29][30]. Numerous mouse and human studies have demonstrated that decreasing PTP1B in various tissues including muscle, liver and brain leads to a multitude of beneficial effects [17,18,22,31].…”

Section: Discussionmentioning

confidence: 99%

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice

et al. 2013

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Aims/hypothesis Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the Alb-Cre promoter to drive Ptp1b deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulinresistant adult mice. Methods Inducible Ptp1b liver-specific knockout mice were generated using SA-Cre-ER T2 mice crossed with Ptp1b floxed (Ptp1b fl/fl ) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liverspecific deletion of Ptp1b (SA-Ptp1b −/− mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined.Results Despite no significant change in body weight relative to HFD-fed Ptp1b fl/fl control mice, HFD-fed SAPtp1b −/− mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH 2 -terminal kinase 2 phosphorylation, and decreased expression of Pepck. Conclusions/interpretation Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects.

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Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

Cited by 34 publications

References 55 publications

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

TGF‐β signalling and liver disease

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice

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