PP2A targeting by viral proteins: A widespread biological strategy from DNA/RNA tumor viruses to HIV-1

Guergnon, Julien; Godet, Angélique N.; Galioot, Amandine; Falanga, Pierre B.; Colle, Jean‐Hervé; Cayla, Xavier; García, Alphonse

doi:10.1016/j.bbadis.2011.07.001

Cited by 53 publications

(44 citation statements)

References 167 publications

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“…Polyomaviruses BK virus (BKV), JC virus (JCV), murine polyomavirus (Py) and simian virus 40 (SV40) sTs inhibit PP2A phosphatase activity via direct interactions (25). Interactions between either SV40 or Py sT and PP2A have been particularly well studied (26).…”

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confidence: 99%

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

Kwun

Shuda

Camacho

et al. 2015

J Virol

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Merkel cell polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purification followed by mass spectroscopy (MS) analysis, which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential cellular interacting proteins. PP2A targeting is critical for the transforming properties of nonhuman polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A A␣ and PP2A C, MCV sT coimmunopurified with PP2A A␣, PP2A A␤, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite molecular surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56␣ into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55␣, B56␣ and B56 into PP2A. We conclude that MCV sT is required for Merkel cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting. A pproximately 30 widely expressed serine/threonine (Ser/Thr) protein phosphatases (PPases) have been identified (1, 2). Protein phosphatase 2A (PP2A) is a combinatorial family of Ser/Thr phosphatases that are highly conserved in eukaryotes. The PP2A core enzyme structure is comprised of a 36-kDa catalytic C subunit (PP2A C) bound to a 65-kDa A regulatory subunit (PP2A A). This core heterodimer can be purified, but the PP2A holoenzyme generally contains a third, regulatory B subunit that provides substrate specificity and subcellular localization (3-7). Among the many combinatorial possibilities, there are two C catalytic subunits, at least two 〈 scaffolding subunits, and multiple B substrate recognition subunits (8), which allow for potentially hundreds of different phosphatase specificities and activities. Phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase, c-Myc, and other cancer signaling pathways that impact cellular processes, including cell cycle progression and cellular tumorigenesis are regulated by specific PP2A isoforms (9). Aberrant expression and mutations in PP2A subunits have been implicated in human cancers (8,(10)(11)(12)(13)(14)(15)(16). IMPORTANCE Merkel cell polyomavirus is a newly discovered human cancer virus that promotes cancer, in part, through expression of itsPP2A activity is regulated in part by posttranslational modifications of subunits (17-23). Methylation of PP2A C at Leu309 activates the holoenzyme to allow binding of the B subunit (17), while phosphorylation o...

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confidence: 99%

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

Kwun

Shuda

Camacho

et al. 2015

J Virol

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“…Protein phosphatase-2A (PP2A) is the major serine-threonine eukaryotic phosphatase (1), and accounts for up to 1% of total cellular protein (2). Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5).…”

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confidence: 99%

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Geraghty

Hardigan

Wallace

et al. 2013

Am J Respir Cell Mol Biol

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Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.Keywords: phosphorylation; inflammation; oxidation; kinase Protein phosphatase-2A (PP2A) is the major serine-threonine eukaryotic phosphatase (1), and accounts for up to 1% of total cellular protein (2). Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5). In the lung, PP2A is a key modulator of inflammatory responses in asthma (6) and chronic obstructive pulmonary disease (COPD) (5). Despite its importance in these and other biological processes, the mechanisms by which PP2A is regulated within the lung remains to be determined. Increasing evidence indicates that PP2A activity is sensitive to the redox status of the cell (7). Indeed, deficiencies in PP2A activity during Alzheimer disease (8) and chronic lymphocytic leukemia (9) are associated with enhanced oxidative stress and impaired antioxidant defenses (10,11). Despite the established links between oxidative stress and altered PP2A activity, the biological pathways by which redox factors modulate PP2A activity to influence disease development are not yet known.Increased oxidative injury has been detected in the lungs of patients with COPD, and animal studies demonstrate that inflammation in this disease can be regulated by the redox status of the lung (12, 13). COPD is the th...

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“…Both MCLR and okadaic acid have been shown to directly inhibit the methylation of PP2A preventing the formation of an active PP2A holoenzyme. Thus, MCs and okadaic acid are tumor-promoters through kinase driven malignancy [168,172,173]. In 2010, MCLR was classified as being "possibly carcinogenic to humans (Group 2B)" by the International Agency for Research on…”

Section: Effects On Other Tissues From Oral Exposure To Mcsmentioning

confidence: 99%

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

Miller

Beversdorf

Weirich

et al. 2017

Preprint

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Cyanobacteria are ubiquitous phototrophic bacteria that inhabit diverse environments across the planet. They dominate many eutrophic lakes impacted by excess nitrogen (N) and phosphorus (P) forming dense accumulations of biomass known as cyanobacterial harmful algal blooms or cyanoHABs. Their dominance in eutrophic lakes is attributed to a variety of unique adaptations including N and P concentrating mechanisms, N fixation, colony formation that inhibits predation, vertical movement via gas vesicles, and the production of toxic or otherwise bioactive molecules. While some of these molecules have been explored for their medicinal benefits, others are potent toxins harmful to humans, animals, and other wildlife known as cyanotoxins. In humans these cyanotoxins affect various tissues, including the liver, central and peripheral nervous system, kidneys, and reproductive organs among others. They induce acute effects at low doses in the parts-per-billion range and some are tumor promoters linked to chronic diseases such as liver and colorectal cancer. The occurrence of cyanoHABs and cyanotoxins in lakes presents challenges for maintaining safe recreational aquatic environments and the production of potable drinking water. CyanoHABs are a growing problem in the North American (Laurentian) Great Lakes basin. This review summarizes information on the occurrence of cyanoHABs in the Great Lakes, toxicological effects of cyanotoxins, and appropriate numerical limits on cyanotoxins in finished drinking water.

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PP2A targeting by viral proteins: A widespread biological strategy from DNA/RNA tumor viruses to HIV-1

Cited by 53 publications

References 167 publications

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

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