Mutations in the PP2A regulatory subunit B family genesPPP2R5B,PPP2R5CandPPP2R5Dcause human overgrowth

Loveday, Chey; Tatton‐Brown, Katrina; Clarke, Matthew; Westwood, Isaac M.; Renwick, Anthony; Ramsay, Emma; Németh, Andrea H.; Campbell, Jennifer; Joss, Shelagh; Gardner, McKinlay; Zachariou, Anna; Elliott, Anna; Ruark, Elise; Montfort, Rob van; Rahman, Nazneen

doi:10.1093/hmg/ddv182

Cited by 74 publications

(65 citation statements)

References 14 publications

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“…Both these phosphatases have been implicated in a wide variety of psychiatric illness such as Alzheimer’s disease [118,119], intellectual disability [120–122] and drug addiction [123,124]. Recently PP2A was linked to psychiatric illness and depression-like phenotypes through both animal behavior and genetic screens [125,126].…”

Section: Physiological Consequences Of Camp Regulation Of Pp1 and Pp2mentioning

confidence: 99%

cAMP regulation of protein phosphatases PP1 and PP2A in brain

Leslie

Nairn

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Normal functioning of the brain is dependent upon a complex web of communication between numerous cell types. Within neuronal networks, the faithful transmission of information between neurons relies on an equally complex organization of inter- and intra-cellular signaling systems that act to modulate protein activity. In particular, post-translational modifications (PTMs) are responsible for regulating protein activity in response to neurochemical signaling. The key second messenger, cyclic adenosine 3’,5’- monophosphate (cAMP), regulates one of the most ubiquitous and influential PTMs, phosphorylation. While cAMP is canonically viewed as regulating the addition of phosphate groups through its activation of cAMP-dependent protein kinases, it plays an equally critical role in regulating removal of phosphate through indirect control of protein phosphatase activity. This dichotomy of regulation by cAMP places it as one of the key regulators of protein activity in response to neuronal signal transduction throughout the brain. In this review we focus on the role of cAMP in regulation of the serine/threonine phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) and the relevance of control of PP1 and PP2A to regulation of brain function and behavior.

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Section: Physiological Consequences Of Camp Regulation Of Pp1 and Pp2mentioning

confidence: 99%

cAMP regulation of protein phosphatases PP1 and PP2A in brain

Leslie

Nairn

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…While cancer remains the most researched disease context for PP2A disruption, PP2A inhibition also contributes to pathogenesis in cardiovascular disease [1-3], diabetes [4-7], neurodegenerative disease (e.g. Alzheimer’s and Parkinson’s disease) [8-12] and developmental conditions involving intellectual disability [13, 14]. Consequently, therapeutic targeting of PP2A has become an exciting area of research with promising potential for clinical impact across fields.…”

Section: Introductionmentioning

confidence: 99%

Targeting PP2A in cancer: Combination therapies

Mazhar¹,

Taylor²,

Sangodkar³

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

110

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The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted.

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“…Both proteins are present at the Drosophila NMJ (Cheng et al, 2011; Viquez et al, 2009, 2006) Single-cell Patch-Seq experiments confirmed the expression of these genes in Drosophila motoneurons at third-instar (Figure S1). Intriguingly, the PPP2R5D gene has recently been associated with intellectual disability and autism in human (Loveday et al, 2015; Shang et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Homeostatic Plasticity Commonly Fails at the Intersection of Autism-Gene Mutations and a Novel Class of Common Phenotypic Modifier

Genç

Fetter

et al. 2020

Preprint

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22We identify a set of common phenotypic modifiers that interact with five independent autism gene 23 orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic 24 homeostatic plasticity (PHP). Heterozygous null mutations in each autism gene are demonstrated to 25 have normal baseline neurotransmission and PHP. However, we find that PHP is sensitized and 26 rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first 27 known heterozygous mutations that commonly genetically interact with multiple ASD gene 28 orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and 29 PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological 30 analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of 31 CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, 32 we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to 33 commonly affect the robustness of synaptic transmission.34 35 36 observed in Drosophila, mice and humans (Davis, 2013). PHP has been documented at both central and 74 peripheral synapses in response to differences in target innervation (Liu and Tsien, 1995) altered 75 postsynaptic excitability (Davis, 2006; Marder and Goaillard, 2006; Mullins et al., 2016), following 76 chronic inhibition of neural activity (Kim and Ryan, 2010; Zhao et al., 2011) and following disruption of 77 postsynaptic neurotransmitter receptor function (Henry et al., 2012; Jakawich et al., 2010). The 78 mechanisms of PHP have a remarkable ability to modulate and stabilize synaptic transmission, with an 79 effect size that can exceed 200% (Müller and Davis, 2012; Ortega et al., 2018). 80Many of the rare de novo mutations that confer high risk for ASD are considered to be 81 heterozygous loss of function (LOF) mutations (Bourgeron, 2015; De Rubeis et al., 2014; Iossifov et al., 82 2014; Sanders et al., 2015). Therefore, we examine the phenotype of heterozygous LOF mutations in five 83 different ASD gene orthologs. We make several fundamental advances. First, we demonstrate that these 84 individual heterozygous LOF mutations have no overt effect on baseline transmission or PHP. However, 85we demonstrate that PHP is sensitized to failure. Next, we sought to define the molecular mechanisms 86 that connect ASD gene orthologs to the mechanisms of PHP. A genome-scale screen and subsequent 87 systems-genetic analyses yielded unexpected insight. We do not simply identify genes that, when mutated, 88 enhance the phenotype of individual ASD gene mutations. We discovered genes that, when their function 89 is diminished by heterozygous LOF mutations, commonly modify multiple ASD gene orthologs, causing a 90 selective failure of homeostatic plasticity. Thus, we define the first class of common phenotypic modifiers 91 of ASD genes in any system. Finally, we do not stop with the identification of a nove...

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Mutations in the PP2A regulatory subunit B family genesPPP2R5B,PPP2R5CandPPP2R5Dcause human overgrowth

Cited by 74 publications

References 14 publications

cAMP regulation of protein phosphatases PP1 and PP2A in brain

cAMP regulation of protein phosphatases PP1 and PP2A in brain

Targeting PP2A in cancer: Combination therapies

Homeostatic Plasticity Commonly Fails at the Intersection of Autism-Gene Mutations and a Novel Class of Common Phenotypic Modifier

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