A comprehensive overview of PPM1A: From structure to disease

Li, Mao; Xu, Xingfeng; Su, Yan; Shao, Xia; Zhou, Yali; Yan, Jieyu

doi:10.1177/15353702211061883

Cited by 7 publications

(6 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BCI is known to inhibit DUSP1 and DUSP6 [51]. Sanguinarine is known to inhibit PP2C family of Mg2 + /Mn2 + -dependent phosphatases which includes PPM1A, PPM1B, PPM1C, PPM1D, PPM1E and PPM1G [52–54]. We found that injection of FK506 significantly reduced numbers of proliferating Sox2 + MGPCs om damaged retinas (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…In addition, PPM1B dephosphorylates IKKβ to terminate TNFα-induced NFkB activation [78], and inhibition of NFkB is known to stimulate the proliferation of MGPCs [35]. Sanguinarine is also known to inhibit PPM1A which is known to deactivate pSMAD2/3 [52, 79]; SMAD3-signaling is known to suppress the formation of MGPCs in the chick retina [29]. Thus, inhibition of PPM1A by sanguinarine might be expected to increase MGPC proliferation by suppressing SMAD3- and NFkB-signaling.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

Kelly,

El-Hodiri,

Crider

et al. 2023

Preprint

View full text Add to dashboard Cite

Different kinase-dependent cell signaling pathways are known to play important roles in glia-mediated neuroprotection and reprogramming of Müller glia (MG) into Müller glia-derived progenitor cells (MGPCs) in the retina. However, very little is known about the phosphatases that regulate kinase-dependent signaling in MG. Using single-cell RNA-sequencing (scRNA-seq) databases, we investigated patterns of expression of Dual Specificity Phosphatases (DUSP1/6) and other protein phosphatases in normal and damaged chick retinas. We found thatDUSP1, DUSP6, PPP3CB, PPP3R1andPPPM1A/B/D/E/Gare dynamically expressed by MG and MGPCs in retinas during the process of reprogramming. We find that inhibition of DUSP1/6 and PP2C phosphatases enhances the formation of proliferating MGPCs in damaged retinas and in retinas treated with insulin in FGF2 in the absence of damage. By contrast, inhibition of PP2B phosphatases suppressed the formation of proliferating MGPCs, but increased numbers of proliferating MGPCs in undamaged retinas treated with insulin and FGF2. In damaged retinas, inhibition of DUSP1/6 increased levels of pERK1/2 and cFos in MG whereas inhibition of PP2B’s decreased levels of pStat3 and pS6 in MG. Analyses of scRNA-seq libraries identified numerous differentially activated gene modules in MG in damaged retinas versus MG in retinas treated with insulin+FGF2 suggesting significant differences in kinase-dependent signaling pathways that converge on the formation of MGPCs. Inhibition of phosphatases had no significant effects upon numbers of dying cells in damaged retinas. We conclude that the activity of different protein phosphatases “fine-tune” the cell signaling responses of MG in damaged retinas and during the reprogramming of MG into MGPCs.

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

Kelly,

El-Hodiri,

Crider

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…2022a), which may induce global non-specific dephosphorylation effects or compensatory effects in the cell line due to the broad number of pathways influenced by PPM1A activity (Li et al . 2015, 2022; Berton et al . 2022b).…”

Section: Discussionmentioning

confidence: 99%

“…As PPM1A is a phosphatase, this suggests that histone-modifying enzymes may be activated or repressed by dephosphorylation to mediate opening of chromatin upon Mtb infection. The unusually large number of DAR in the PPM1A + cells may be partially a result of artificially high overexpression of PPM1A (Berton et al 2022a), which may induce global non-specific dephosphorylation effects or compensatory effects in the cell line due to the broad number of pathways influenced by PPM1A activity (Li et al 2015(Li et al , 2022Berton et al 2022b). We also observe this phenotype through differences in baseline CA and gene expression, compared to WT cells, (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

View full text Add to dashboard Cite

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (ΔPPM1A) and PPM1A overexpressing (PPM1A+) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, CEBPD and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

show abstract

“…PPM1A, a metal-dependent protein phosphatase, can modulate cell proliferation, apoptosis, and immune response via dephosphorylation, which is related to the occurrence and development of cancers, autoimmune diseases, and neurodegenerative diseases. 30 We recently identified PPM1A as a promising target for HDT against Mtb 31 and developed a small molecule, SMIP-30, to inhibit PPM1A (IC 50 = 1.19 μM). 32 Encouraged by these promising results, herein, we systematically investigate the structure−activity relationship (SAR) and discover SMIP-031, a more potent inhibitor for PPM1A (IC 50 = 180 nM).…”

Section: ■ Introductionmentioning

confidence: 99%

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy

Yu,

Liang,

Berton

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC 50 = 1.19 μM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC 50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

show abstract

A comprehensive overview of PPM1A: From structure to disease

Cited by 7 publications

References 77 publications

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy

Contact Info

Product

Resources

About