Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion

J Biol Chem. 2012 Aug 31;287(36):30497-506. doi: 10.1074/jbc.M112.355412. Epub 2012 Jul 5.

Abstract

Tau exon 10, which encodes the second microtubule-binding repeat, is regulated by alternative splicing. Its alternative splicing generates Tau isoforms with three- or four-microtubule-binding repeats, named 3R-tau and 4R-tau. Adult human brain expresses equal levels of 3R-tau and 4R-tau. Imbalance of 3R-tau and 4R-tau causes Tau aggregation and neurofibrillary degeneration. In the present study, we found that splicing factor SRp55 (serine/arginine-rich protein 55) promoted Tau exon 10 inclusion. Knockdown of SRp55 significantly promoted Tau exon 10 exclusion. The promotion of Tau exon 10 inclusion by SRp55 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization. Dyrk1A (dual specificity tyrosine-phosphorylated and regulated kinase 1A) interacted with SRp55 and mainly phosphorylated its proline-rich domain. Phosphorylation of SRp55 by Dyrk1A suppressed its ability to promote Tau exon 10 inclusion. Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • COS Cells
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Chlorocebus aethiops
  • Down Syndrome / genetics
  • Down Syndrome / metabolism
  • Down Syndrome / pathology
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Introns*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / genetics
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Protein Serine-Threonine Kinases / genetics
  • Protein-Tyrosine Kinases / biosynthesis*
  • Protein-Tyrosine Kinases / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Serine-Arginine Splicing Factors
  • Up-Regulation / genetics
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • Mapt protein, rat
  • Nuclear Proteins
  • Phosphoproteins
  • Protein Isoforms
  • RNA-Binding Proteins
  • SRSF6 protein, human
  • tau Proteins
  • Serine-Arginine Splicing Factors
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases