Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors.
Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.
Hartmann
A M
AM
Max Planck Institute of Neurobiology, Am Klopferspitz 18a, Martinsried, D-82152, Germany.
Rujescu
D
D
Giannakouros
T
T
Nikolakaki
E
E
Goedert
M
M
Mandelkow
E M
EM
Gao
Q S
QS
Andreadis
A
A
Stamm
S
S
D017398:Alternative Splicing / Q000502:physiology*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005091:Exons; D006801:Humans; D007668:Kidney / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics; D014162:Transfection; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D012322:RNA Precursors; D016875:tau Proteins; C066780:Clk dual-specificity kinases; C087728:SRPK1 protein, human; D011505:Protein-Tyrosine Kinases; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases