Bustos F.Segarra-Fas A.Nardocci G.Cassidy A.Antico O.Davidson L.Brandenburg L.Macartney T.J.Toth R.Hastie C.J.Moran J.Gourlay R.Varghese J.Soares R.F.Montecino M.Findlay G.M.2021-08-052021-08-052020-12Developmental Cell, Volume 55, Issue 5, Pages 629 - 647.e77 December 202015345807http://repositorio.unab.cl/xmlui/handle/ria/19701Indexación ScopusBustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders. © 2020 The AuthorsConserved 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. © 2020 The AuthorsenRNA Splicing FactorRNA-binding ProteinAlternative SplicingNeurodevelopmentalUbiquitin signalingArtículo10.1016/j.devcel.2020.09.025