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

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.