The 3D Structure of Protein Phosphatase 2A: New Insights into a Ubiquitous Regulator of Cell Signaling

Mumby, Marc C.

doi:10.1021/cb700021z

Cited by 62 publications

(63 citation statements)

References 23 publications

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“…It is becoming evident that the function of PP2A relies on the B subunit because the various B subunit proteins determine substrate specificity and PP2A complex subcellular localization (2, 3, 7, 10 -13). The recent crystal structure of PP2A supports this premise (4,(13)(14)(15). Thus the PP2A family of protein phosphatase isoforms can best be defined by its regulatory B subunit.…”

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confidence: 82%

“…Protein phosphatase 2A (PP2A) 2 is an important regulator of apoptosis and may be a tumor suppressor (1)(2)(3)(4). How PP2A might function as a tumor suppressor is not clear, as the enzyme on the one hand is required for cell survival but on the other is active in processes responsible for cell death (2-7).…”

mentioning

confidence: 99%

“…How PP2A might function as a tumor suppressor is not clear, as the enzyme on the one hand is required for cell survival but on the other is active in processes responsible for cell death (2-7). An explanation for this paradox is that PP2A is not a single enzyme but rather a family of protein phosphatase isoforms (3,4,8,9). PP2A is a heterotrimer composed of a catalytic (C) subunit, a scaffold (A) subunit, and a regulatory (B) subunit.…”

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confidence: 99%

“…It was found that PKR was indeed basally active in REH cells as well as in three other ALL-derived cell lines (i.e. CCRF-CEM, RS (4,11), and MOLT4). Loss of PKR rendered REH cells resistant to etoposide.…”

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confidence: 99%

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PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

Ruvolo

Kurinna

Karanjeet

et al. 2008

Journal of Biological Chemistry

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Protein phosphatase 2A (PP2A) is a heterotrimer comprising catalytic, scaffold, and regulatory (B) subunits. There are at least 21 B subunit family members. Thus PP2A is actually a family of enzymes defined by which B subunit is used. The B56 family member B56␣ is a phosphoprotein that regulates dephosphorylation of BCL2. The stress kinase PKR has been shown to phosphorylate B56␣ at serine 28 in vitro, but it has been unclear how PKR might regulate the BCL2 phosphatase. In the present study, PKR regulation of B56␣ in REH cells was examined, because these cells exhibit robust BCL2 phosphatase activity. PKR was found to be basally active in REH cells as would be predicted if the kinase supports B56␣-mediated dephosphorylation of BCL2. Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56␣ phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity. PKR supports stress signaling in REH cells, as suppression of PKR promoted chemoresistance to etoposide. Suppression of PKR promoted B56␣ proteolysis, which could be blocked by a proteasome inhibitor. However, the mechanism by which PKR supports B56␣ protein does not involve PKR-mediated phosphorylation of the B subunit at serine 28 but may involve eIF2␣ activation of AKT. Phosphorylation of serine 28 by PKR promotes mitochondrial localization of B56␣, because wild-type but not mutant S28A B56␣ promoted mitochondrial PP2A activity. Cells expressing wildtype B56␣ but not S28A B56␣ were sensitized to etoposide. These results suggest that PKR regulates B56␣-mediated PP2A signaling in REH cells.Protein phosphatase 2A (PP2A) 2 is an important regulator of apoptosis and may be a tumor suppressor (1-4). How PP2A might function as a tumor suppressor is not clear, as the enzyme on the one hand is required for cell survival but on the other is active in processes responsible for cell death (2-7). An explanation for this paradox is that PP2A is not a single enzyme but rather a family of protein phosphatase isoforms (3,4,8,9). PP2A is a heterotrimer composed of a catalytic (C) subunit, a scaffold (A) subunit, and a regulatory (B) subunit. The C and A subunits form a catalytic complex that interacts with one of at least 21 diverse B subunit members from three major families (i.e. B55, B56, and PR72/130; see Refs. 2, 3, and 9). It is becoming evident that the function of PP2A relies on the B subunit because the various B subunit proteins determine substrate specificity and PP2A complex subcellular localization (2, 3, 7, 10 -13). The recent crystal structure of PP2A supports this premise (4, 13-15). Thus the PP2A family of protein phosphatase isoforms can best be defined by its regulatory B subunit.PP2A function is regulated both negatively and positively by post-translational modification (4, 16 -18). Phosphorylation of B56␥ by ERK at serine 337 inhibits PP2A function (13, 18). Interestingly, this regulatory ERK site is conserved in all of the known B56 family members except B56␣. Although ERK may not regulate B56␣ function negatively, phosphory...

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confidence: 82%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

Ruvolo

Kurinna

Karanjeet

et al. 2008

Journal of Biological Chemistry

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“…The mechanism linking impaired methionine synthase activity to the primary pathological features of AD has been greatly illuminated by recent studies detailing the regulation of protein phosphatase 2A (PP2A) by methylation [180][181][182][183]. PP2A is responsible for de-phosphorylation of tau and a decrease in its activity leads to tau hyperphosphorylation and formation of NFTs.…”

Section: A Mechanistic Model Of Mercury Toxicitymentioning

confidence: 99%

Does Inorganic Mercury Play a Role in Alzheimer's Disease? A Systematic Review and an Integrated Molecular Mechanism

Mutter¹,

Curth

Naumann³

et al. 2010

JAD

147

113

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Abstract. Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible.

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Tautomycin’s Interactions with Protein Phosphatase 1

Sydnes

Isobe

2010

Chemistry An Asian Journal

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It has been a long journey since tautomycin (TTM) was isolated in 1987 and the discovery that it inhibited protein phosphatase 1 (PP1) more strongly than PP2A until finally the cocrystal structure of TTM and PP1 was presented early in 2009. The fact that TTM shows preference to inhibit PP1 over PP2A makes this compound unique among the known PP1 and PP2A inhibitors. A number of groups were involved in work aiming to unravel TTM's interactions with PP1 and by doing so hoping to disentangle the secrets as to why TTM is a better inhibitor of PP1 than PP2A. This Focus Review looks back at the work conducted with TTM in order to establish its point of interaction with PP1 prior to X-ray structure. Finally the conclusions before the X-ray structure are compared with the real situation.

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The 3D Structure of Protein Phosphatase 2A: New Insights into a Ubiquitous Regulator of Cell Signaling

Cited by 62 publications

References 23 publications

PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

Does Inorganic Mercury Play a Role in Alzheimer's Disease? A Systematic Review and an Integrated Molecular Mechanism

Tautomycin’s Interactions with Protein Phosphatase 1

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