PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B

Luo, Yu; Nie, Yunjuan; Shi, Hang; Ni, Zhong-Fei; Wang, Qun; Wang, Jian‐Zhi; Liu, Gong‐Ping

doi:10.1016/j.bbamcr.2013.02.005

Cited by 29 publications

(19 citation statements)

References 42 publications

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“…Up-regulation of I 1 PP2A and I 2 PP2A , and mislocalization and cleavage of I 2 PP2A , could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al, 2005). Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al, 2013). Lastly, increased calpain-mediated cleavage of alpha4, which critically modulates PP2A stability, could be responsible for increased degradation of PP2A catalytic subunit in AD (Watkins et al, 2012).…”

Section: The Multifaceted Deregulation Of “Pp2a” In Admentioning

confidence: 99%

Protein phosphatase 2A dysfunction in Alzheimerâ€™s disease

Sontag

2014

Front. Mol. Neurosci.

250

202

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Protein phosphatase 2A (PP2A) is a large family of enzymes that account for the majority of brain Ser/Thr phosphatase activity. While PP2A enzymes collectively modulate most cellular processes, sophisticated regulatory mechanisms are ultimately responsible for ensuring isoform-specific substrate specificity. Of particular interest to the Alzheimer’s disease (AD) field, alterations in PP2A regulators and PP2A catalytic activity, subunit expression, methylation and/or phosphorylation, have been reported in AD-affected brain regions. “PP2A” dysfunction has been linked to tau hyperphosphorylation, amyloidogenesis and synaptic deficits that are pathological hallmarks of this neurodegenerative disorder. Deregulation of PP2A enzymes also affects the activity of many Ser/Thr protein kinases implicated in AD. This review will more specifically discuss the role of the PP2A/Bα holoenzyme and PP2A methylation in AD pathogenesis. The PP2A/Bα isoform binds to tau and is the primary tau phosphatase. Its deregulation correlates with increased tau phosphorylation in vivo and in AD. Disruption of PP2A/Bα-tau protein interactions likely contribute to tau deregulation in AD. Significantly, alterations in one-carbon metabolism that impair PP2A methylation are associated with increased risk for sporadic AD, and enhanced AD-like pathology in animal models. Experimental studies have linked deregulation of PP2A methylation with down-regulation of PP2A/Bα, enhanced phosphorylation of tau and amyloid precursor protein, tau mislocalization, microtubule destabilization and neuritic defects. While it remains unclear what are the primary events that underlie “PP2A” dysfunction in AD, deregulation of PP2A enzymes definitely affects key players in the pathogenic process. As such, there is growing interest in developing PP2A-centric therapies for AD, but this may be a daunting task without a better understanding of the regulation and function of specific PP2A enzymes.

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Section: The Multifaceted Deregulation Of “Pp2a” In Admentioning

confidence: 99%

Protein phosphatase 2A dysfunction in Alzheimerâ€™s disease

Sontag

2014

Front. Mol. Neurosci.

250

202

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“…Our recent finding indicated that PTPA activates PP2A through reducing the level of phosphorylated at tyrosine‐307 of PP2A C by activating protein tyrosine phosphotase 1B (Luo et al . ). PTPA was found to be a highly conserved protein during evolution, which has been found from yeast to human (Van Hoof et al .…”

mentioning

confidence: 97%

Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation

Luo

Feng

Wang

et al. 2014

Journal of Neurochemistry

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Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and the AD transgenic mouse models. Here, we investigated whether down-regulation of PTPA affects cell viability and the underlying mechanisms. We found that PTPA was located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines. PTPA knockdown decreased mitochondrial membrane potential and induced Bax translocation into the mitochondria with a simultaneous release of Cyt C, activation of caspase-3, cleavage of poly (DNA ribose) polymerase (PARP), and decrease in Bcl-xl and Bcl-2 protein levels. Over-expression of Protein phosphatase 2A (PP2A) catalytic subunit (PP2AC ) did not rescue the apoptosis induced by PTPA knockdown, and PTPA knockdown did not affect the level of and their phosphorylation of mitogen-activated protein kinases (MAPKs), indicating that PP2A and MAPKs were not involved in the apoptosis induced by PTPA knockdown. In the cells with over-expression of tau, PTPA knockdown induced PP2A inhibition and tau hyperphosphorylation but did not cause significant cell death. These data suggest that PTPA deficit causes apoptotic cell death through mitochondrial pathway and simultaneous tau hyperphosphorylation attenuates the PTPA-induced cell death. Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and AD transgenic mouse models. Here, we investigated whether down-regulation of PTPA affects cell viability. We found that PTPA located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines by decreasing mitochondrial membrane potential, which leads to translocation of Bax and a simultaneous release of Cyt C. In the cells with tau over-expression, PTPA knockdown inactivated PP2A to phosphorylate tau to avoid cell apoptosis which induced by PTPA knockdown.

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“…The primary hippocampal neurons isolated from embryonic 18-day-old (E18) rats were cultured according to the established procedure [9].…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Fluorocitrate induced the alterations of memory-related proteins and tau hyperphosphorylation in SD rats

Xiao-ling¹,

Wang²,

Liu³

et al. 2015

Neuroscience Letters

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PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B

Cited by 29 publications

References 42 publications

Protein phosphatase 2A dysfunction in Alzheimerâ€™s disease

Protein phosphatase 2A dysfunction in Alzheimerâ€™s disease

Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation

Fluorocitrate induced the alterations of memory-related proteins and tau hyperphosphorylation in SD rats

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