{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:17:27Z","timestamp":1768504647843,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,27]]},"group-title":"Cell Biology","reference-count":69,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Variants in the phosphoprotein phosphatase-2 regulatory protein-5D gene (\n                  <jats:italic>PPP2R5D<\/jats:italic>\n                  ) cause the clinical phenotype of Jordan\u2019s Syndrome (PPP2R5D-related disorder), which includes intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder and delayed motor skill development. The disorder originates from\n                  <jats:italic>de novo<\/jats:italic>\n                  single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for \u223c40% of reported cases. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G&gt;A) in the\n                  <jats:italic>PPP2R5D<\/jats:italic>\n                  allele in a heterozygous manner in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of wild-type, E198K, and E420K cell lines and find unique and shared changes between variants and wild-type cells in kinase- and phosphatase-controlled signaling cascades. As shared signaling alterations, we observed ribosomal protein S6 (RPS6) hyperphosphorylation, indicative of increased ribosomal protein S6-kinase activity. Rapamycin treatment suppressed RPS6 phosphorylation in both, suggesting activation of mTORC1. Intriguingly, our data suggest AKT-dependent (E420K) and -independent (E198K) activation of mTORC1. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, treatment with rapamycin or a p70S6K inhibitor warrants further investigation as potential therapeutic strategies for patients.\n                <\/jats:p>","DOI":"10.1101\/2023.03.27.534397","type":"posted-content","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T19:05:15Z","timestamp":1679943915000},"source":"Crossref","is-referenced-by-count":2,"title":["Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades"],"prefix":"10.64898","author":[{"given":"KA","family":"Smolen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CM","family":"Papke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MR","family":"Swingle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Musiyenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AD","family":"Camp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"RE","family":"Honkanen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AN","family":"Kettenbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023033004050532000_2023.03.27.534397v1.1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79860"},{"key":"2023033004050532000_2023.03.27.534397v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-015-0466-9"},{"key":"2023033004050532000_2023.03.27.534397v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv182"},{"key":"2023033004050532000_2023.03.27.534397v1.4","unstructured":"Mirzaa, G. , Foss, K. , Nattakom, M. , and Chung, W. 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