Home LiteratureArticle Details
PMID: 17078951 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.

FEBS letters ·Vol. 580 ·No. 26 ·2006-11-13 ·Pages 6269-74

Liu F, Liang Z, Shi J, Yin D, El-Akkad E, Grundke-Iqbal I, Iqbal K, Gong CX

Abstract

Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.

MeSH Terms
Amino Acids Catalysis Cyclic AMP-Dependent Protein Kinases/physiology Cyclin-Dependent Kinase 5/metabolism Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Phosphorylation tau Proteins/metabolism
Chemicals
Amino Acids tau Proteins Cyclin-Dependent Kinase 5 GSK3B protein, human Glycogen Synthase Kinase 3 beta Cyclic AMP-Dependent Protein Kinases Glycogen Synthase Kinase 3
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Liu Fei
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. feiliu63@hotmail.com
Liang Zhihou
Shi Jianhua
Yin Dongmei
El-Akkad Ezzat
Grundke-Iqbal Inge
Iqbal Khalid
Gong Cheng-Xin
References (30)
30 references, click to expand
  1. Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5.
    Mol Cell Biochem. 1997 Feb;167(1-2):99-105 PMID: 9059986
  2. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study.
    Ann Neurol. 2002 May;51(5):567-77 PMID: 12112102
  3. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.
    Nature. 2006 Jun 1;441(7093):646-50 PMID: 16511445
  4. Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356.
    Biochem J. 1996 Jun 1;316 ( Pt 2):655-60 PMID: 8687413
  5. Regulation of GSK-3: a cellular multiprocessor.
    Cell. 2001 Jun 29;105(7):821-4 PMID: 11439177
  6. Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells.
    J Biol Chem. 2002 Jun 28;277(26):23330-5 PMID: 11967263
  7. Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease.
    Biochem Biophys Res Commun. 1986 Dec 15;141(2):790-6 PMID: 3099793
  8. Post-translational modifications of tau protein in Alzheimer's disease.
    J Neural Transm (Vienna). 2005 Jun;112(6):813-38 PMID: 15517432
  9. Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases.
    FEBS Lett. 1995 Jan 16;358(1):4-8 PMID: 7821426
  10. Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain.
    FEBS Lett. 1994 Apr 4;342(2):203-8 PMID: 8143878
  11. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.
    Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7 PMID: 3088567
  12. Dynamic regulation of expression and phosphorylation of tau by fibroblast growth factor-2 in neural progenitor cells from adult rat hippocampus.
    J Neurosci. 1999 Jul 1;19(13):5245-54 PMID: 10377336
  13. Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5.
    Neuroscience. 2002;115(3):829-37 PMID: 12435421
  14. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404.
    J Neurosci Res. 1994 Dec 15;39(6):669-73 PMID: 7534834
  15. Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding.
    J Biol Chem. 2003 Jan 3;278(1):187-93 PMID: 12409305
  16. Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis.
    Acta Neuropathol. 1987;74(3):209-25 PMID: 3673513
  17. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.
    Neurology. 1992 Mar;42(3 Pt 1):631-9 PMID: 1549228
  18. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.
    Mol Cell. 2001 Jun;7(6):1321-7 PMID: 11430833
  19. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase.
    FEBS Lett. 1998 Sep 25;436(1):28-34 PMID: 9771888
  20. Phosphorylation of recombinant tau by cAMP-dependent protein kinase. Identification of phosphorylation sites and effect on microtubule assembly.
    J Biol Chem. 1993 Jan 15;268(2):1166-73 PMID: 8419321
  21. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain.
    J Biol Chem. 2004 Nov 26;279(48):50078-88 PMID: 15375165
  22. Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta.
    FEBS Lett. 2002 Oct 23;530(1-3):209-14 PMID: 12387894
  23. Tau pathology in Alzheimer disease and other tauopathies.
    Biochim Biophys Acta. 2005 Jan 3;1739(2-3):198-210 PMID: 15615638
  24. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9 PMID: 15249677
  25. GSK3: a SHAGGY frog story.
    Trends Cell Biol. 1996 Jul;6(7):274-9 PMID: 15157454
  26. Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated tau by neuroleptics.
    Brain Res. 1996 Nov 25;741(1-2):95-102 PMID: 9001710
  27. Reconstitution of neuronal Cdc2-like kinase from bacteria-expressed Cdk5 and an active fragment of the brain-specific activator. Kinase activation in the absence of Cdk5 phosphorylation.
    J Biol Chem. 1995 May 5;270(18):10847-54 PMID: 7738023
  28. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
    J Biol Chem. 1986 May 5;261(13):6084-9 PMID: 3084478
  29. Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments.
    FEBS Lett. 1993 Jul 5;325(3):167-72 PMID: 7686508
  30. Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein.
    J Biol Chem. 2001 Oct 12;276(41):37967-73 PMID: 11495914
Article Info
Journal
FEBS letters
Abbr.
FEBS Lett
ISSN
0014-5793
DOI
10.1016/j.febslet.2006.10.033
Email
feiliu63@hotmail.com
Published
2006-11-13
Epub
2006-00-24
Pages
6269-74
Language
English
Region
England
NLM ID
0155157
PMCID
PMC1828604
Subset
IM
Grants
NIA NIH HHS · R01 AG027429 · United States
NIA NIH HHS · R01 AG016760 · United States
NIA NIH HHS · R01 AG019158 · United States
NIA NIH HHS · AG019158 · United States
NIA NIH HHS · AG016760 · United States
NIA NIH HHS · AG027429 · United States
External Links
PubMed source DOI: 10.1016/j.febslet.2006.10.033 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2