title: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion.
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.
authors: Jiangsu Key Laboratory of Neuroregeneration, Medical School, Nantong University, Nantong, Jiangsu, 226001, China.
authors: Xiaomin
authors: X
authors: Yin
authors: Nana
authors: N
authors: Jin
authors: Jianlan
authors: J
authors: Gu
authors: Jianhua
authors: J
authors: Shi
authors: Jianhua
authors: J
authors: Zhou
authors: Cheng-Xin
authors: CX
authors: Gong
authors: Khalid
authors: K
authors: Iqbal
authors: Inge
authors: I
authors: Grundke-Iqbal
authors: Fei
authors: F
authors: Liu
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007438:Introns; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000068103:Serine-Arginine Splicing Factors; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D016875:tau Proteins; D000097603:Dyrk Kinases; C054369:MAPT protein, human; C489131:Mapt protein, rat; C489470:SRSF6 protein, human