Projects per year
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 language | English |
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Pages (from-to) | 629-647.e7 |
Number of pages | 27 |
Journal | Developmental Cell |
Volume | 55 |
Early online date | 19 Oct 2020 |
DOIs | |
Publication status | Published - 7 Dec 2020 |
Keywords
- metazoan evolution
- development
- signal transduction
- protein kinase
- protein phosphorylation
- ubiquitin signaling
- stem cells
- transcriptomics
- neural development
- neurodevelopmental disorders
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Dive into the research topics of 'Functional diversification of SRSF protein kinase to control ubiquitin-dependent neurodevelopmental signalling'. Together they form a unique fingerprint.Projects
- 2 Finished
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Functions and Applications of a Novel Pluripotency Signalling Pathway (Sir Henry Dale Fellowship)
Findlay, G. (Investigator)
1/09/18 → 31/08/23
Project: Research
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Elucidating Novel Pluripotency Signalling Networks (New Investigator Award)
Findlay, G. (Investigator)
1/09/15 → 31/08/18
Project: Research
Student theses
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Analysis of PINK1-Parkin-dependent signalling in neurons
Antico, O. (Author), Muqit, M. (Supervisor) & Alessi, D. (Supervisor), 2022Student thesis: Doctoral Thesis › Doctor of Philosophy
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Datasets
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Bustos et al Dev Cell 2020 Source Data
Findlay, G. (Creator) & Bustos, F. (Creator), Mendeley Data, 23 Oct 2020
Dataset