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.

具有核心细胞功能的保守蛋白激酶在后生动物进化过程中经常被重新部署，以调节专门的发育过程。与剪接调节有关的富含丝氨酸/精氨酸 (SR) 的剪接因子 (SRSF) 蛋白激酶 (SRPK) 就是这样一种保守的真核激酶。令人惊讶的是，我们发现 SRPK 已经获得了控制神经发育泛素信号通路的能力。在哺乳动物胚胎干细胞和培养的神经元中，SRPK 磷酸化 RNF12/RLIM 中的 Ser-Arg 基序，这是一种在智力残疾综合征中发生突变的关键发育 E3 泛素连接酶。SRPK 进行性磷酸化刺激核转录因子底物的 RNF12 依赖性泛素化，从而起到抑制在智力残疾中异常表达的神经基因表达程序的作用。SRPK 家族基因在智力障碍疾病中也会发生突变，并且源自患者的 SRPK 点突变会损害 RNF12 磷酸化。我们的数据揭示了 SRPK 在调节泛素信号传导方面未被重视的功能多样化，从而确保了神经发育基因表达的正确调节。