Functional diversification of SRSF protein kinase to control ubiquitin-dependent neurodevelopmental signalling

Francisco Bustos, Anna Segarra-Fas, Gino Nardocci, Andrew Cassidy, Odetta Antico, Lindsay Davidson, Lennart Brandenburg, Thomas Macartney, Rachel Toth, C. James Hastie, Jennifer Moran, Robert Gourlay, Joby Vargese, Renata Soares, Martín Montecino, Greg M. Findlay (Lead / Corresponding author)

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Abstract

Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. 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 signalling 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 programme 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 signalling that ensures correct regulation of neurodevelopmental gene expression.
Original languageEnglish
Pages (from-to)1-19
Number of pages19
JournalDevelopmental Cell
Volume55
Early online date19 Oct 2020
DOIs
Publication statusE-pub ahead of print - 19 Oct 2020

Keywords

  • metazoan evolution
  • development
  • signal transduction
  • protein kinase
  • protein phosphorylation
  • ubiquitin signaling
  • stem cells
  • transcriptomics
  • neural development
  • neurodevelopmental disorders

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