Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Abstract

Background: Tyrosine kinases and phosphatases modulate TGF-␤ signaling. Results: PTP1B deficiency attenuates TGF-␤-induced Smad phosphorylation correlating with suppression of growth inhibition and apoptosis, an effect that is reverted by genistein, and p65 or NOX1 knockdown. Conclusion: Lack of PTP1B impairs Smad activation in a NOX1 and NF-B-dependent manner. Significance: New insights are opened into the role of phosphatases in TGF-␤ signaling.

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…It has been reported that PTP1B participates in the development of fibrosis in liver (70) by activating hepatic stellate cells. PTP1B deficiency confers resistance to TGF-β through Smad inhibition in hepatocytes (57). Therefore, it would be worthwhile to further investigate the relationship among activation of α7 nAChR, PTP1B and TGF-β signaling in lung fibroblasts so that we can find novel therapeutic targets for combating lung fibrosis.…”

“…The A549 cell line is frequently used in research regarding alveolar type II epithelial cells (52)(53)(54)(55). Therefore, The Regulatory Effect of `7 nAChR on TGF-a Signaling Depends on PTP1B It has been reported that PTP1B deficiency confers resistance to TGF-β through Smad inhibition in hepatocytes (57). We silenced Ptpn1 by infecting the fibroblasts with pLKO.1 shRNA-Ptpn1 lentivirus and repeated the experiment (shown in Figures 8-9) to clarify whether α7 nAChR regulates TGF-β signaling via PTP1B.…”

Signalling pathways involved in paracetamol-induced hepatotoxicity: new insights on the role of protein tyrosine phosphatase 1B

“…Protection against Fasmediated apoptosis in the liver of PTP1B À/À mice correlated with an elevation and/or activation of numerous antiapoptotic signalling proteins including FLIPL, ERK1/2 and NF-kB. In addition, the resistance of PTPIB À/À hepatocytes to Fas-mediated apoptosis also required tyrosine kinase activity, because as occurred with TGF-b (Ortiz, 2012), PTP1B À/À hepatocytes were rendered susceptible to Fasmediated apoptosis by pre-treatment with genistein. Upon analysis of different PTP1B substrates, it was found that HGFR/Met showed sustained tyrosine phosphorylation and increased activation of its downstream mediator ERK1/2 in both livers and primary hepatocytes lacking PTP1B after Jo-2 treatment.…”

“…The suppressor effects of this cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. Using immortalized hepatocytes, Ortiz et al (2012) have found that PTP1B deficiency conferred resistance against TGF-b mediated apoptosis and growth inhibition. At the molecular level, this effect correlated with lower Smad2/Smad3 phosphorylation and nuclear translocation, the lack of up-regulation of the inhibitory Smad7 and sustained activation of Akt and ERK1/2.…”

Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma

“…Furthermore, VAS2870, a Nox inhibitor, decreased serum-dependent growth and phosphorylation of AKT and ERK and enhanced TGFβ-induced apoptosis in HCC cell lines (290). Nox1, which was co-elevated with Nox4 by HCV (71, 72), was also suggested to provide a partial resistance to hepatocyte apoptosis induced by TGFβ (290, 291), and excessive stimulation of the MAPK/ERK pathway produced similar effects (284). Furthermore, NS5A was recently found to interact with mixed lineage kinase 3 that activated p38 MAPK to combat apoptosis induced by sulfhydryl oxidizing agent, dithiodipyridine (292).…”