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

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

doi:10.1016/j.devcel.2020.09.025

Abstract

SummaryConserved 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.

Highlights

Signal transduction by protein kinases controls all aspects of eukaryotic biology (Cohen, 2002), from metabolism to complex developmental programs
Data mining indicates that SRSF protein kinase (SRPK) family genes are mutated in intellectual disability disorders, and SRPK3 point mutations, identified in patients, impair RNF12 phosphorylation
This prompted us to examine the role of SRPK in mouse embryonic stem cells

Summary

Introduction

Signal transduction by protein kinases controls all aspects of eukaryotic biology (Cohen, 2002), from metabolism to complex developmental programs. Functional diversification of protein kinases can be achieved via several non-mutually exclusive mechanisms: (1) evolutionary wiring of protein kinase pathways to newly evolved cell-cell communication systems that control metazoan biology, such as receptor tyrosine kinases (Lim and Pawson, 2010), (2) evolution of new kinase-substrate relationships, and (3) evolution of specific kinase activity or expression profiles that differ according to developmental time and tissue context These mechanisms individually or in combination have the capacity to drive functional diversification, enabling highly conserved eukaryotic protein kinases to evolve novel functions in the control of key metazoan processes

Results

Discussion

Conclusion