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Functional Diversification of Ser-Arg Rich Protein Kinases to Control Ubiquitin-Dependent Neurodevelopmental Signalling

66 Pages Posted: 9 Apr 2020 Publication Status: Published

See all articles by Francisco Bustos

Francisco Bustos

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Anna Segarra-Fas

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Gino Nardocci

Universidad Andres Bello

Andrew Cassidy

University of Dundee

Odetta Antico

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Lennart Brandenburg

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Thomas Macartney

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Rachel Toth

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

C. James Hastie

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Robert Gourlay

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Joby Vargese

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Renata Soares

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

Martin Montecino

Universidad Andres Bello

Greg Findlay

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

More...

Abstract

Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. Ser-Arg Repeat Protein Kinase (SRPK) is one such conserved eukaryotic kinase, which controls mRNA splicing. Surprisingly, we show that SRPK has acquired a novel function in regulating a neurodevelopmental ubiquitin signalling pathway. In mammalian embryonic stem cells, 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 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.

Keywords: Metazoan Evolution, Development, signal transduction, protein kinase, protein phosphorylation, Ubiquitin Signalling, stem cells, Transcriptomics, neural development, neurodevelopmental disorders

Suggested Citation

Bustos, Francisco and Segarra-Fas, Anna and Nardocci, Gino and Cassidy, Andrew and Antico, Odetta and Brandenburg, Lennart and Macartney, Thomas and Toth, Rachel and Hastie, C. James and Gourlay, Robert and Vargese, Joby and Soares, Renata and Montecino, Martin and Findlay, Greg, Functional Diversification of Ser-Arg Rich Protein Kinases to Control Ubiquitin-Dependent Neurodevelopmental Signalling. Available at SSRN: https://ssrn.com/abstract=3565005 or http://dx.doi.org/10.2139/ssrn.3565005
This version of the paper has not been formally peer reviewed.

Francisco Bustos

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Anna Segarra-Fas

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Gino Nardocci

Universidad Andres Bello

Chile

Andrew Cassidy

University of Dundee

Dundee, Scotland DD1 4HN
United Kingdom

Odetta Antico

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Lennart Brandenburg

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Thomas Macartney

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Rachel Toth

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

C. James Hastie

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Robert Gourlay

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Joby Vargese

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Renata Soares

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit

United Kingdom

Martin Montecino

Universidad Andres Bello

Chile

Greg Findlay (Contact Author)

University of Dundee - MRC Protein Phosphorylation and Ubiquitylation Unit ( email )

United Kingdom

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