The Phosphotyrosyl Phosphatase Activator of Protein Phosphatase 2A

Hoof, Christine Van; Cayla, Xavier; Bosch, Mariette; Merlevede, Wilfried; Goris, Jozef

doi:10.1111/j.1432-1033.1994.00899.x

Cited by 38 publications

(3 citation statements)

References 51 publications

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“…These results suggest that PTPA possesses an activation chaperone function and might preferentially stabilize the binding of one metal ion. This notion is consistent with the high expression level of PTPA in all mammalian cells in the micromolar range 21 , similar to PP2Ac itself.…”

Section: Resultssupporting

confidence: 85%

Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone

et al. 2013

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Proper activation of protein phosphatase 2A (PP2A) catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function. The crystal structure of PP2A bound to PP2A phosphatase activator (PTPA) and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP. PTPA-binding stabilizes the protein fold of apo-PP2A required for activation, and orients ATP phosphoryl groups to bind directly to the PP2A active site. This allows ATP to modulate the metal-binding preferences of the PP2A active site and utilize the PP2A active site for ATP hydrolysis. In vitro, ATP selectively and drastically enhances binding of endogenous catalytic metal ions, which requires ATP hydrolysis and is crucial for acquisition of pSer/Thr-specific phosphatase activity. Furthermore, both PP2A- and ATP-binding are required for PTPA function in cell proliferation and survival. Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP-binding pocket that could potentially serve as a specific therapeutic target.

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Section: Resultssupporting

confidence: 85%

Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone

et al. 2013

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“…The greatest changes were seen in phosphotyrosyl phosphatase activator (PTPA), 14-3-3-epsilon and DnaJB6. PTPA, which is decreased in the basal ganglia of exercised BDNF+/− mice compared to WT littermates, functions to regulate the expression of several proteins, including protein phosphatase 2A (PP2A) [105]. PP2A has been shown to be modulated by changes in tau and alpha-synuclein aggregation; both critical to the neuropathology of Parkinson’s disease [106]–[109].…”

Section: Discussionmentioning

confidence: 99%

Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

et al. 2012

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Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/−) with strain-matched wild-type (WT) mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/− mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/− mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

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“…This was surprising because in human cells these proteins associate with PP2c, the catalytic subunit of the PP2 complex, and not the PP4 complex. Specifically, PR65α/PR65β are scaffolding units of the PP2 complex, and PTPA has been shown to modify the catalytic site of the PP2c enzyme [48][49][50]. This raises the intriguing possibility that certain subunits may associate with both a PP4c-containing complex and with PP2A complexes in C. elegans, a scenario that is supported by biochemical evidence in mammalian systems [37,46].…”

Section: Plos Onementioning

confidence: 97%

The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 and confers resistance to environmental stress in postreproductive adult C. elegans

2020

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Insulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 transcriptional activity during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, and SMK-1 also appear to regulate DAF-16 in an age-dependent manner, and together with PPFR-2 they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.

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The Phosphotyrosyl Phosphatase Activator of Protein Phosphatase 2A

Cited by 38 publications

References 51 publications

Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone

Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone

Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 and confers resistance to environmental stress in postreproductive adult C. elegans

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