Examinando por Autor "Davidson L."

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    Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling
    (Cell Press, 2020-12) Bustos F.; Segarra-Fas A.; Nardocci G.; Cassidy A.; Antico O.; Davidson L.; Brandenburg L.; Macartney T.J.; Toth R.; Hastie C.J.; Moran J.; Gourlay R.; Varghese J.; Soares R.F.; Montecino M.; Findlay G.M.
    Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders. © 2020 The AuthorsConserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. The Ser/Arg (SR)-rich splicing factor (SRSF) protein kinase (SRPK), which is implicated in splicing regulation, is one such conserved eukaryotic kinase. Surprisingly, we show that SRPK has acquired the capacity to control a neurodevelopmental ubiquitin signaling pathway. In mammalian embryonic stem cells and cultured neurons, SRPK phosphorylates Ser-Arg motifs in RNF12/RLIM, a key developmental E3 ubiquitin ligase that is mutated in an intellectual disability syndrome. Processive phosphorylation by SRPK stimulates RNF12-dependent ubiquitylation of nuclear transcription factor substrates, thereby acting to restrain a neural gene expression program that is aberrantly expressed in intellectual disability. SRPK family genes are also mutated in intellectual disability disorders, and patient-derived SRPK point mutations impair RNF12 phosphorylation. Our data reveal unappreciated functional diversification of SRPK to regulate ubiquitin signaling that ensures correct regulation of neurodevelopmental gene expression. © 2020 The Authors