Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

Francisco Bustos, Anna Segarra-Fas, Gino Nardocci, Andrew Cassidy, Odetta Antico, Lindsay Davidson, Lennart Brandenburg, Thomas J. Macartney, Rachel Toth, C. James Hastie, Jennifer Moran, Robert Gourlay, Joby Varghese, Renata F. Soares, Martin Montecino, Greg M. Findlay

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)629-647.e7
JournalDevelopmental Cell
Volume55
Issue number5
DOIs
StatePublished - 7 Dec 2020
Externally publishedYes

Bibliographical note

Funding Information:
We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship (211209/Z/18/Z) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC-PPU prize studentship. G.N. and M.M. are supported by research grants ANID/FONDAP/15090007 and FONDECYT/11190998. F.B. and G.M.F. conceived the study and designed the experiments. F.B. A.S.-F. A.C. O.A. L.B. L.D. J.M. R.G. J.V. and G.M.F. performed experiments. G.N. and M.M. analyzed data and prepared figures. T.M. and R.T. performed DNA cloning and CRISPR-Cas9 design. C.J.H. generated reagents. R.S. analyzed mass-spectrometry data. F.B. and G.M.F. wrote the paper. The authors declare no competing interests.

Funding Information:
We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust /Royal Society Sir Henry Dale fellowship ( 211209/Z/18/Z ) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC -PPU prize studentship. G.N. and M.M. are supported by research grants ANID /FONDAP/ 15090007 and FONDECYT / 11190998 .

Publisher Copyright:
© 2020 The Authors

Keywords

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

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