title: Cyclic AMP-dependent protein kinase enhances SC35-promoted Tau exon 10 inclusion.
abstract: Alternative splicing of tau exon 10 generates tau with three or four microtubule-binding repeats (3R-tau or 4R-tau). The ratio of 3R-tau to 4R-tau is approximately 1:1 in the adult normal human brain. Disturbances in the ratio result in neurodegenerative tauopathies. Splicing factor SC35 acts on a SC35-like element located at the 5' end of tau exon 10 and promotes tau exon 10 inclusion. Here, we report that protein kinase (PKA) was able to interact and phosphorylate SC35. Activation or overexpression of PKA catalytic subunits promoted SC35-mediated tau exon 10 inclusion. Four PKA catalytic subunits, α1, α2, β1, and β2, all enhanced SC35-promoted tau exon 10 inclusion. SC35 has four putative PKA phosphorylation sites, Ser121, Ser128, Ser130, and Ser171. Pseudophosphorylation (SC354E) and blockage (SC354A) of phosphorylation of SC35 at these four sites increased and decreased, respectively, SC35's ability to promote tau exon 10 inclusion. Moreover, PKA catalytic subunits no longer further enhanced tau exon 10 inclusion when these four were mutated to either alanine or glutamate. These results suggest that PKA interacts with and phosphorylates SC35 and enhances SC35-promoted tau exon 10 inclusion. In Alzheimer's brain, down-regulation of the PKA pathway could lead to dysregulation of tau exon 10, contributing to tau pathogenesis.
authors.affiliation: Department of Cellular and Genetic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Caoyi
authors.initials: C
authors.lastname: Chen
authors.forename: Nana
authors.initials: N
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Xiangling
authors.initials: X
authors.lastname: Tan
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Ji
authors.initials: J
authors.lastname: Zuo
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D005091:Exons / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000068103:Serine-Arginine Splicing Factors; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D009687:Nuclear Proteins; D021122:Protein Subunits; D012261:Ribonucleoproteins; D016875:tau Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D017868:Cyclic AMP-Dependent Protein Kinases
references.citation: Nature. 1996 May 2;381(6577):80-2
references.pmid: 8609994
references.citation: Neuron. 1989 Apr;2(4):1389-97
references.pmid: 2560640
references.citation: J Biol Chem. 2008 Oct 17;283(42):28660-9
references.pmid: 18658135
references.citation: Science. 1998 Nov 6;282(5391):1075-9
references.pmid: 9804538
references.citation: Biochim Biophys Acta. 2005 Jan 3;1739(2-3):179-97
references.pmid: 15615637
references.citation: J Biol Chem. 2004 Jan 30;279(5):3801-6
references.pmid: 14602710
references.citation: FEBS Lett. 2006 Nov 13;580(26):6269-74
references.pmid: 17078951
references.citation: Biochem Biophys Res Commun. 1986 Dec 15;141(2):790-6
references.pmid: 3099793
references.citation: Biochemistry. 1992 Nov 3;31(43):10626-33
references.pmid: 1420178
references.citation: Nucleic Acids Res. 1993 Dec 25;21(25):5803-16
references.pmid: 8290338
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8
references.pmid: 11381127
references.citation: J Neurochem. 2007 Dec;103(6):2462-70
references.pmid: 17908236
references.citation: Neurodegener Dis. 2007;4(2-3):236-53
references.pmid: 17596718
references.citation: J Cell Biol. 1998 Feb 23;140(4):737-50
references.pmid: 9472028
references.citation: Anat Rec (Hoboken). 2009 Aug;292(8):1135-42
references.pmid: 19645017
references.citation: J Biol Chem. 2011 Apr 22;286(16):14639-48
references.pmid: 21367856
references.citation: EMBO J. 1989 Feb;8(2):393-9
references.pmid: 2498079
references.citation: Nature. 1994 Jun 23;369(6482):678-82
references.pmid: 8208298
references.citation: Bioorg Med Chem Lett. 2007 Jul 1;17(13):3642-6
references.pmid: 17485207
references.citation: EMBO J. 1996 Jan 15;15(2):265-75
references.pmid: 8617202
references.citation: Acta Neuropathol. 2013 Apr;125(4):565-79
references.pmid: 23407988
references.citation: Cytogenet Cell Genet. 1992;60(1):22-5
references.pmid: 1339328
references.citation: Mol Cell Biol. 1989 Apr;9(4):1389-96
references.pmid: 2498650
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references.pmid: 3088567
references.citation: Mol Cell Biol. 1989 Apr;9(4):1381-8
references.pmid: 2498649
references.citation: Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15
references.pmid: 15615630
references.citation: Biochim Biophys Acta. 2008 Jan;1784(1):16-26
references.pmid: 17996741
references.citation: Eur J Neurosci. 2007 Dec;26(12):3429-36
references.pmid: 18052981
references.citation: Neuron. 1989 Oct;3(4):519-26
references.pmid: 2484340
references.citation: FEBS Lett. 2011 Mar 23;585(6):875-80
references.pmid: 21333649
references.citation: Biochim Biophys Acta. 1993 Sep 13;1178(3):249-58
references.pmid: 8395890
references.citation: J Biol Chem. 2004 Nov 26;279(48):50078-88
references.pmid: 15375165
references.citation: J Alzheimers Dis. 2008 May;14(1):1-16
references.pmid: 18525123
references.citation: Nucleic Acids Res. 2011 Aug;39(14):6161-71
references.pmid: 21470964
references.citation: J Biol Chem. 1986 May 5;261(13):6084-9
references.pmid: 3084478
references.citation: Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50
references.pmid: 15615642
references.citation: J Biol Chem. 1992 Aug 25;267(24):17047-54
references.pmid: 1512244
references.citation: Protein Sci. 1996 Sep;5(9):1865-73
references.pmid: 8880910
references.citation: J Biol Chem. 2009 Sep 4;284(36):24512-25
references.pmid: 19592491