{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330231/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330231"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Divergent signaling profiles in mTOR gain-of-function Smith-Kingsmore syndrome and TSC2 deficiency","description":"Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder caused by gain-of-function mutations in MTOR, yet whether these mutations phenocopy TSC2 loss or establish a distinct signaling state remains unclear. Using quantitative proteomics, phosphoproteomics, and transcriptomics in isogenic cell models of SKS (MTORΔ4aa), TSC2 loss (TSC2–/–), and wild-type controls under glucose depletion and refeeding, we find that MTORΔ4aa and TSC2–/– cells occupy fundamentally distinct regulatory states. TSC2–/– cells exhibit broad anabolic remodeling and a transcriptional program dominated by NF-κB- and STAT-driven inflammatory responses. MTORΔ4aa cells instead display enrichment of nuclear and RNA processing programs, E2F/MYC-driven transcription, and a constrained proteomic dynamic range across nutrient states. Phosphoproteomic analysis of MTORΔ4aa reveals rerouting of nutrient-responsive signaling toward MAPK/ERK- and Ca2+/CaMK-dependent pathways with limited canonical mTORC1/S6K1 engagement. These findings establish SKS as a signaling rewiring disorder distinct from classical mTORC1 hyperactivation, with implications for therapeutic targeting.","dates":{"publication":"2026/05/11"},"accession":"GSE330231","cross_references":{"GSM":["GSM9721989","GSM9721979","GSM9721987","GSM9721988","GSM9721985","GSM9721986","GSM9721983","GSM9721984","GSM9721981","GSM9721982","GSM9721990","GSM9721980"],"GPL":["34281"],"GSE":["330231"],"taxon":["Homo sapiens"]}}