ArticleThe Journal of biological chemistry
A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.Cancer research · 2025Trial
- A functional map of phosphoprotein phosphatase regulation identifies an evolutionarily conserved reductase for the catalytic metal ions.Nature communications · 2026Article
- The clinical missense variant E282K in PPP3CA/calcineurin shifts substrate dephosphorylation by altering active site recruitment.Nature communications · 2026Article
- Jordan syndrome due toTranslational pediatrics · 2025Article
- Houge-Janssens syndrome.European journal of human genetics : EJHG · 2025Review
- Article
- Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.American journal of human genetics · 2025Article
- Targeting Long Noncoding RNA H19 in Subchondral Bone Osteocytes and the Alleviation of Cartilage Degradation in Osteoarthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- A de novo missense mutation in PPP2R5D alters dopamine pathways and morphology of iPSC-derived midbrain neurons.Stem cells (Dayton, Ohio) · 2025Article
- A protein phosphatase 1 specificProceedings of the National Academy of Sciences of the United States of America · 2024Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Unmasking Protein Phosphatase 2A Regulatory Subunit B as a Crucial Factor in the Progression of Dilated Cardiomyopathy.Biomedicines · 2024Article
- Thirteen New Patients ofChildren (Basel, Switzerland) · 2024Article
- A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss ofCancers · 2023Article
- Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme.bioRxiv : the preprint server for biology · 2023Article
- Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades.bioRxiv : the preprint server for biology · 2023Article
- Inducible protein degradation as a strategy to identify Phosphoprotein Phosphatase 6 substrates in RAS-mutant colorectal cancer cells.bioRxiv : the preprint server for biology · 2023Article
- Quantum-based modeling implies that bidentate ArgFrontiers in cell and developmental biology · 2023Article
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Authors and funding
12 authors.
Funding
Abstract
Functional genomic approaches have facilitated the discovery of rare genetic disorders and improved efforts to decipher their underlying etiology. PPP2R5D-related disorder is an early childhood onset condition characterized by intellectual disability, hypotonia, autism-spectrum disorder, macrocephaly, and dysmorphic features. The disorder is caused by de novo single nucleotide changes in PPP2R5D, which generate heterozygous dominant missense variants. PPP2R5D is known to encode a B'-type (B'56δ) regulatory subunit of a PP2A-serine/threonine phosphatase. To help elucidate the molecular mechanisms altered in PPP2R5D-related disorder, we used a CRISPR-single-base editor to generate HEK-293 cells in which a single transition (c.1258G>A) was introduced into one allele, precisely recapitulating a clinically relevant E420K variant. Unbiased quantitative proteomic and phosphoproteomic analyses of endogenously expressed proteins revealed heterozygous-dominant changes in kinase/phosphatase signaling. These data combined with orthogonal validation studies revealed a previously unrecognized interaction of PPP2R5D with AKT in human cells, leading to constitutively active AKT-mTOR signaling, increased cell size, and uncoordinated cellular growth in E420K-variant cells. Rapamycin reduced cell size and dose-dependently reduced RPS6 phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1 can suppress both the observed RPS6 hyperphosphorylation and increased cell size. Together, our findings provide a deeper understanding of PPP2R5D and insight into how the E420K-variant alters signaling networks influenced by PPP2R5D. Our comprehensive approach, which combines precise genome editing, isobaric tandem mass tag labeling of peptides generated from endogenously expressed proteins, and concurrent liquid chromatography-mass spectrometry (LC-MS
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.