biostudies-literatureUnknownYang ZIntramural NIH HHSWellcome TrustNeurological diseases are frequently characterised by dysregulation of the microtubule cytoskeleton, which is critical for neuronal integrity and functioning. However, the precise mechanisms by which microtubule dynamics are regulated during the development of the nervous system remain poorly understood. Here, we use global phosphoproteomic screening to identify cytoskeletal substrates of Ser-Arg Protein Kinase (SRPK), which is implicated in several neurodevelopmental and neurodegenerative conditions. We show that SRPK directly phosphorylates Microtubule Associated Protein (MAP)1S at multiple sites in a C-terminal region involved in proteolytic maturation and microtubule binding. SRPK-dependent MAP1S phosphorylation modulates the affinity of the MAP1S microtubule binding domain for microtubioRxiv : the preprint server for biology2025.09.19.677315https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458405biostudies-literaturePhosphorylation enables progressive microtubule-associated protein proteolysis and functionalisation during neural development.PMC12458405225930/Z/22/ZZIA AG000534211209/Z/18/ZBustos FWallace ISquires IToth RHao YBrown FFindlay GMHogg EKJGourlay RYang ZGierlinski MLi ZQi YALiczmanska MHastie CJZhou HMacartney TfalsePhosphorylation enables progressive microtubule-associated protein proteolysis and functionalisation during neural development.Neurological diseases are frequently characterised by dysregulation of the microtubule cytoskeleton, which is critical for neuronal integrity and functioning. However, the precise mechanisms by which microtubule dynamics are regulated during the development of the nervous system remain poorly understood. Here, we use global phosphoproteomic screening to identify cytoskeletal substrates of Ser-Arg Protein Kinase (SRPK), which is implicated in several neurodevelopmental and neurodegenerative conditions. We show that SRPK directly phosphorylates Microtubule Associated Protein (MAP)1S at multiple sites in a C-terminal region involved in proteolytic maturation and microtubule binding. SRPK-dependent MAP1S phosphorylation modulates the affinity of the MAP1S microtubule binding domain for microtu2025-01-01T00:00:00Z2025 Sep2026-06-30T03:30:52.66Z2026-06-30T03:23:22.761ZS-EPMC124584054100064310.1101/2025.09.19.677315