A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis. EMBO Reports

Department of Cancer and Cell Biology, The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
EMBO Reports (Impact Factor: 9.06). 02/2010; 11(3):226-32. DOI: 10.1038/embor.2010.7
Source: PubMed


In vivo genetic inactivation of the signalling adapter p62 leads to mature-onset obesity and insulin resistance, which correlate with reduced energy expenditure (EE) and increased adipogenesis, without alterations in feeding or locomotor functions. Enhanced extracellular signal-regulated kinase (ERK) activity in adipose tissue from p62-knockout (p62(-/-)) mice, and differentiating fibroblasts, suggested an important role for this kinase in the metabolic alterations of p62(-/-) mice. Here, we show that genetic inactivation of ERK1 in p62(-/-) mice reverses their increased adiposity and adipogenesis, lower EE and insulin resistance. These results establish genetically that p62 is a crucial regulator of ERK1 in metabolism.

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Available from: Rubén Nogueiras
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    • "For example, ERK1-mediated phosphorylation of Bcl-2 promotes autophagy by dissociating Bcl-2 and Beclin 127,33. Because p62 can regulate the activity of various kinases such as PKC and ERK34,35,36, it is possible that p62 may affect the phosphorylation of Bcl-2 through its interaction with Bcl-2 and then modulate Bcl-2- and Beclin 1-mediated autophagy. The precise molecular mechanism underlying the modification of the interaction between Bcl-2 and Beclin 1 driven by p62 needs to be further explored in the future. "
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    ABSTRACT: Aim: To investigate whether sequestosome 1/p62 (p62), a key cargo adaptor protein involved in both the ubiquitin-proteasome system and the autophagy-lysosome system, could directly regulate autophagy in vitro. Methods: HEK 293 cells or HeLa cells were transfected with p62-expressing plasmids or siRNA targeting p62. The cells or the cell lysates were subsequently subjected to immunofluorescence assay, immunoprecipitation assay, or immunoblot analysis. In vitro pulldown assay was used to study the interaction of p62 with Bcl-2. Results: Overexpression of p62 significantly increased the basal level of autophagy in both HEK 293 cells and HeLa cells, whereas knockdown of p62 significantly decreased the basal level of autophagy. In vitro pulldown assay showed that p62 directly interacted with Bcl-2. It was observed in HeLa cells that p62 co-localized with Bcl-2. Furthermore, knockdown of p62 in HEK 293 cells significantly increased the amount of Beclin 1 that co-immunoprecipitated with Bcl-2. Conclusion: p62 induces autophagy by disrupting the association between Bcl-2 and Beclin 1.
    Full-text · Article · Apr 2013 · Acta Pharmacologica Sinica
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    • "Thus, ERK1-deficient mice were investigated, and they were shown to be protected from diet-induced obesity and insulin resistance [104]. Nonetheless, mice lacking the ERK1 negative regulator p62 presented altered metabolism with increased adipogenesis, reduced energy expenditure, and reduced insulin sensitivity [105]. However, these animals were not investigated on concomitant cardiac remodeling and might be considered a good model to assess metabolic syndrome adverse heart remodeling. "
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    Full-text · Article · Jan 2013 · Mediators of Inflammation
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    • "This modulation of the NFκB pathway by p62 is essential for proper osteoclastogenesis. Finally, it has been reported that the PB1 domain of p62 can also interact with ERK1 to promote adipogenesis [10]. "
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    ABSTRACT: Although p62/SQSTM1 was initially identified as an essential mediator of NFκB signaling, several recent studies have also highlighted its important role at the crossroad between the mTOR or MAPK signaling pathways and selective autophagy. The p62 structure containing important interaction domains attests to the ability of this protein to regulate and modulate the activation of these signaling pathways during tumor formation and propagation. The second very important function of this protein is to act as a molecular adaptor between the autophagic machinery and its substrates. Consequently, p62 is degraded following an increase in autophagic flux for which this protein currently serves as an indicator. However, the measurement of p62 expression strictly as a marker of autophagic flux is still controversial and can be misinterpreted mainly because this protein is subject to complex regulation at both the transcriptional and post-translational levels. Finally, because p62 is an autophagic substrate, it acts as a molecular link between cancer and autophagy by conferring a high level of selectivity through the degradation of important signaling molecules.
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