CTDNEP1 is a serine/threonine protein phosphatase that functions as a component of the CTDNEP1-NEP1R1 membrane phosphatase complex, localized to the nuclear envelope and endoplasmic reticulum 1. The NEP1R1 regulatory subunit allosterically activates CTDNEP1 through direct binding at a site distant from the active site, stabilizing substrate recognition 1. CTDNEP1 dephosphorylates R-SMAD transcription factors at the inner nuclear membrane in complex with the scaffold protein MAN1, suppressing TGF-β/SMAD signaling 2. The complex maintains ER membrane morphology and restricts ER expansion, essential for proper nuclear and ER membrane dynamics 1. CTDNEP1 is also required for nuclear membrane stability, preventing rupture-associated genome instability 3. Clinically, CTDNEP1 inactivating mutations are significantly enriched in MYC-driven medulloblastomas, correlating with high-risk disease 4. Loss of CTDNEP1 promotes medulloblastoma transformation by stabilizing MYC activity through elevated MYC serine-62 phosphorylation and triggering chr17 instability, p53 loss, and MYC amplification 4. Co-targeting MYC and CHEK1 synergistically inhibits CTDNEP1-deficient tumor growth 4. Additionally, CTDNEP1 expression is regulated by placental DNA methylation and influences birthweight-associated cardiometabolic pathways 5.