Mobilization of a splicing factor through a nuclear kinase-kinase complex

Biochem J. 2018 Feb 14;475(3):677-690. doi: 10.1042/BCJ20170672.

Abstract

The splicing of mRNA is dependent on serine-arginine (SR) proteins that are mobilized from membrane-free, nuclear speckles to the nucleoplasm by the Cdc2-like kinases (CLKs). This movement is critical for SR protein-dependent assembly of the macromolecular spliceosome. Although CLK1 facilitates such trafficking through the phosphorylation of serine-proline dipeptides in the prototype SR protein SRSF1, an unrelated enzyme known as SR protein kinase 1 (SRPK1) performs the same function but does not efficiently modify these dipeptides in SRSF1. We now show that the ability of SRPK1 to mobilize SRSF1 from speckles to the nucleoplasm is dependent on active CLK1. Diffusion from speckles is promoted by the formation of an SRPK1-CLK1 complex that facilitates dissociation of SRSF1 from CLK1 and enhances the phosphorylation of several serine-proline dipeptides in this SR protein. Down-regulation of either kinase blocks EGF-stimulated mobilization of nuclear SRSF1. These findings establish a signaling pathway that connects SRPKs to SR protein activation through the associated CLK family of kinases.

Keywords: SR proteins; phosphorylation/dephosphorylation; protein-serine-threonine kinases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CDC2-CDC28 Kinases / chemistry
  • CDC2-CDC28 Kinases / genetics
  • Epidermal Growth Factor / metabolism
  • HeLa Cells
  • Humans
  • Protein Serine-Threonine Kinases / genetics*
  • Protein-Tyrosine Kinases / genetics*
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • Serine-Arginine Splicing Factors / genetics*
  • Signal Transduction / genetics
  • Spliceosomes / genetics

Substances

  • RNA, Messenger
  • SRSF1 protein, human
  • Serine-Arginine Splicing Factors
  • Epidermal Growth Factor
  • Clk dual-specificity kinases
  • SRPK1 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases