Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing

Phosphorylation has been generally thought to activate the SR family of splicing factors for efficient splice-site recognition, but this idea is incompatible with an early observation that overexpression of an SR protein kinase, such as the CDC2-like kinase 1 (CLK1), weakens splice-site selection. Here, we report that CLK1 binds SR proteins but lacks the mechanism to release phosphorylated SR proteins, thus functionally inactivating the splicing factors. Interestingly, CLK1 overcomes this dilemma through a symbiotic relationship with the serine-arginine protein kinase 1 (SRPK1). We show that SRPK1 interacts with an RS-like domain in the N terminus of CLK1 to facilitate the release of phosphorylated SR proteins, which then promotes efficient splice-site recognition and subsequent spliceosome assembly. These findings reveal an unprecedented signaling mechanism by which two protein kinases fulfill separate catalytic features that are normally encoded in single kinases to institute phosphorylation control of pre-mRNA splicing in the nucleus. [Display omitted] •SRPK1 and CLK1 form a stable complex in the nucleus of cells•The kinase domain of SRPK1 interacts with the disordered N terminus of CLK1•SRPK1 acts as a release factor that strips CLK1 from tightly bound SR proteins•SRPK1-induced release promotes U1 binding and mRNA splicing Although CLK1 is required for splicing, this protein kinase does not efficiently dissociate its product, phosphorylated splicing factor SRSF1. Aubol et al. show that nuclear SRPK1 strips CLK1 from the tightly bound SRSF1, freeing the splicing factor for engagement with the U1 component of the spliceosome and splicing activation.