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

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

Abstract

Conserved 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.

Más información

Título según WOS: Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling
Título de la Revista: DEVELOPMENTAL CELL
Volumen: 55
Número: 5
Editorial: Cell Press
Fecha de publicación: 2020
Página de inicio: 629
Página final: +
DOI:

10.1016/J.DEVCEL.2020.09.025

Notas: ISI