Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

Sandal, P. C.; Jong, Chian Ju; Merrill, Ronald A.; Song, Jianing; Strack, Stefan

doi:10.1242/jcs.248187

Cited by 41 publications

(35 citation statements)

References 247 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of PP2A in neurodevelopmental disorders has been well described, and abnormal phosphorylation of tau is observed in AD. 136 PP2A has been identified as a tau phosphatase 137 and is responsible for approximately 71% of the total tau phosphatase activity in the human brain. 138 However, patients with AD show lower PP2A activity in both gray and white matter.…”

Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 99%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

show abstract

Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 99%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The A and C subunits are each encoded by two different genes that generate two isoforms of high-sequence identity. On the other hand, the regulatory B subunits are very diverse and are subdivided into four families, each of which contains several different genetically encoded isoforms ( Sents et al, 2013 ; Sandal et al, 2021 ). The multiplicity of these subunits allows for many combinatorial possibilities with diverse function in different cells and makes it challenging to identify which specific isoform is responsible for a particular functional task.…”

Section: Discussionmentioning

confidence: 99%

Arrestin Facilitates Rhodopsin Dephosphorylationin Vivo

et al. 2022

View full text Add to dashboard Cite

Deactivation of G-protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G-protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process.In vitroevidence suggests that visual arrestin (ARR1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether ARR1 binding also affects rhodopsin dephosphorylationin vivois not known. We investigated this using both male and female mice lacking ARR1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For WT mice, rhodopsin dephosphorylation was nearly complete by 1 h in darkness. Surprisingly, we observed that, in theArr1KO rods, rhodopsin remained phosphorylated even after 3 h. Delayed dephosphorylation inArr1KO rods cannot be explained by cell stress induced by persistent signaling, since it is not prevented by the removal of transducin, the visual G-protein, nor can it be explained by downregulation of protein phosphatase 2A, the putative rhodopsin phosphatase. We further show that cone arrestin (ARR4), which binds light-activated, phosphorylated rhodopsin poorly, had little effect in enhancing rhodopsin dephosphorylation, whereas mice expressing binding-competent mutant ARR1-3A showed a similar time course of rhodopsin dephosphorylation as WT. Together, these results reveal a novel role of ARR1 in facilitating rhodopsin dephosphorylationin vivo.SIGNIFICANCE STATEMENTG-protein-coupled receptors (GPCRs) are transmembrane proteins used by cells to receive and respond to a broad range of extracellular signals that include neurotransmitters, hormones, odorants, and light (photons). GPCR signaling is terminated by two sequential steps: phosphorylation and arrestin binding. Both steps must be reversed when GPCRs are recycled and reused. Dephosphorylation, which is required for recycling, is an understudied process. Using rhodopsin as a prototypical GPCR, we discovered that arrestin facilitated rhodopsin dephosphorylation in living mice.

show abstract

“…Thus far, most PP2A research has been performed in a cancer-context, where the large majority of PP2A trimers act as tumour suppressors ( Meeusen and Janssens, 2018 ; Remmerie and Janssens, 2019 ). Since 2015, however, de novo mutations in several PP2A genes have been implicated as causative for neurodevelopmental or other inborn brain disorders ( Houge et al, 2015 ; Loveday et al, 2015 ; Sandal et al, 2021 ; Verbinnen et al, 2021 ), while some inherited mutations in other PP2A genes mainly affected development of other organs ( Guran et al, 2019 ). Specifically, PP2A-related neurodevelopmental disorders are characterized by mutations in PPP2R1A (Aα), PPP2CA (Cα), PPP2R2C (B55γ), PPP2R5B (B56β) , PPP2R5C (B56γ) , and PPP2R5D (B56δ), with most patients and mutations, so far, found in PPP2R5D ( Figures 3A–C ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Vaneynde

Verbinnen²,

Janssens³

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues.

show abstract

Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

Cited by 41 publications

References 247 publications

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Arrestin Facilitates Rhodopsin Dephosphorylationin Vivo

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Contact Info

Product

Resources

About