Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen

Ogris, Egon; Gibson, Daryl; Pallas, David C.

doi:10.1038/sj.onc.1201259

Cited by 126 publications

(208 citation statements)

References 23 publications

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“…PP2A C Tyr307 phosphorylation might selectively inhibit holoenzyme assembly As stated, the PP2A C Tyr307!Asp [55] or Tyr307!Glu [44] phospho-mimetic mutants cannot be methylated and, therefore, fail to interact with PR55/B [44,51,54,55] or Cdc55p [22,23]; hence, Tyr307 phosphorylation might indirectly affect PP2A T55 assembly. Moreover, these mutations also inhibit interaction of PP2A C with PR61/ B 0 abge [54,55] or Rts1p [23] (which can occur in the absence of methylation), indicating that, in this case, stabilizing contacts with Tyr307 are needed.…”

Section: Reviewmentioning

confidence: 93%

“…Although the PP2A C Thr304!Asp or Thr304!Ala mutants do not affect methylation patterns [44,55], the Thr304!Asp mutant fails to recruit PR55/B subunits [22,23,51,54,55] (binding to A [51,55], PR61/B 0 [23,54,55] and PR72/B 00 [54,55] is not affected). By contrast, the Thr301!Asp mutant can still recruit PR55/B subunits [51]. This suggests that phosphorylation of Thr304 (and not Thr301) might be a mechanism for selective inhibition of PR55/B recruitment or even dissociation of PR55/B from a pre-existing trimer.…”

Section: Reviewmentioning

confidence: 97%

“…However, a variety of experimental approaches both in yeast and mammalian cells demonstrate that PP2A C methylation has a crucial role in B-type-subunit binding, specifically in the recruitment of PR55/B subunits [20][21][22][23]44,[51][52][53][54][55]. By contrast, the recruitment of A [44,[51][52][53]55], PR61/B 0 [21][22][23]55], PR72/B 00 [54,55] and striatin [44] does not strictly require PP2A C methylation in vivo, and binding of polyoma middle T [44,51] and a4 [20,56] is increased in the absence of methylation. In yeast, the deletion of PPM1 (protein phosphatase methyltransferase 1, which encodes the yeast LCMT1 ortholog) or the expression of PP2A C harboring a Leu309!Ala substitution, inhibits Cdc55p binding [20][21][22][23], whereas Tpd3p (tRNA-processing-deficient mutant 3; the yeast A subunit homolog) and Rts1p binding is only slightly diminished [20][21][22][23].…”

Section: Trends In Biochemical Sciencesmentioning

confidence: 99%

See 2 more Smart Citations

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

Janssens

Longin

Goris

2008

Trends in Biochemical Sciences

366

424

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Section: Reviewmentioning

confidence: 93%

Section: Reviewmentioning

confidence: 97%

Section: Trends In Biochemical Sciencesmentioning

confidence: 99%

See 1 more Smart Citation

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

Janssens

Longin

Goris

2008

Trends in Biochemical Sciences

366

424

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mentioning

confidence: 99%

“…Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).PP2A methylation is catalyzed in vivo by the methyl transferase, leucine carboxyl methyltransferase 1 (LCMT-1) (20)(21)(22), and its demethylation is catalyzed by the methylesterase, protein phosphatase methylesterase 1 (PME-1) (23-25). To explore the role of PP2A in AD further, we generated lines of transgenic mice that overexpress these enzymes and tested their effect on the sensitivity of animals to electrophysiogical and behavioral impairments caused by β-amyloid (Aβ).…”

mentioning

confidence: 99%

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Nicholls

Sontag

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Aβ-induced impairments. Neither transgene affected Aβ production or the electrophysiological response to low concentrations of Aβ, suggesting that these manipulations selectively affect the pathological response to elevated Aβ levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Aβ levels in AD patients.M ultiple observations suggest a role for the serine/threonine protein phosphatase 2A (PP2A) in the molecular pathways that underlie Alzheimer's disease (AD). Analyses conducted on postmortem AD brains have found reduced PP2A expression and activity, and studies conducted in animal models have found that inhibiting PP2A produces AD-like tau pathology and cognitive impairment (1-3). One of the ways in which PP2A may affect AD is through its role as the principal tau phosphatase (4-7). PP2A also interacts with a number of kinases implicated in AD including glycogen synthase kinase 3β (GSK3β), cyclindependent kinase 5 (CDK5), and ERK and JNK as well as amyloid precursor protein and the NMDA and metabotropic glutamate receptors (reviewed in ref.2).PP2A is a heterotrimeric protein composed of a catalytic, scaffolding, and regulatory subunit. Each subunit is encoded by multiple genes and splice isoforms, and the subunit composition of a particular PP2A molecule determines its subcellular distribution and substrate specificity (reviewed in ref.2). One of the ways in which PP2A activity is regulated is through C-terminal methylation of the catalytic subunit (reviewed in refs. 8 and 9). Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).PP2A m...

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Identification of a type 6 protein Ser/Thr phosphatase regulated by interleukin-2 stimulation

Filali

Kim

et al. 1999

J. Cell. Biochem.

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We have identified a 36 kD phosphoprotein that forms a complex with spliceosomal small nuclear ribonucleoproteins in lymphocyte extracts. This 36 kD protein is differentially phosphorylated in transformed human lymphoid cell lines and is regulated by IL-2 in peripheral blood T cells. We purified the 36 kD protein from human lymphocytes by employing a combination of immuno-affinity chromatography and preparative two-dimensional gel electrophoresis. Internal amino acid sequence analysis of the purified protein yielded two peptides that had perfect matches with sequences in the human protein serine/threonine phosphatase 6 (PP6). Using degenerate primers corresponding to the peptides, we obtained from a human T lymphocyte cDNA library a DNA fragment whose sequence is homologous to an EST cDNA clone (R05547). The predicted amino acid sequence of this clone showed over 98% sequence identity to human PP6. The identification of an IL-2 regulated type 6 protein serine/threonine phosphatase in lymphocytes was further substantiated by immunoblotting with anti-peptide antibodies. These findings suggest that PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL-2 receptor stimulation.

show abstract

Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen

Cited by 126 publications

References 23 publications

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Identification of a type 6 protein Ser/Thr phosphatase regulated by interleukin-2 stimulation

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