title: CDK5 activator protein p25 preferentially binds and activates GSK3β.
abstract: Glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5) are tau kinases and have been proposed to contribute to the pathogenesis of Alzheimer's disease. The 3D structures of these kinases are remarkably similar, which led us to hypothesize that both might be capable of binding cyclin proteins--the activating cofactors of all CDKs. CDK5 is normally activated by the cyclin-like proteins p35 and p39. By contrast, we show that GSK3β does not bind to p35 but unexpectedly binds to p25, the calpain cleavage product of p35. Indeed, overexpressed GSK3β outcompetes CDK5 for p25, whereas CDK5 is the preferred p35 partner. FRET analysis reveals nanometer apposition of GSK3β:p25 in cell soma as well as in synaptic regions. Interaction with p25 also alters GSK3β substrate specificity. The GSK3β:p25 interaction leads to enhanced phosphorylation of tau, but decreased phosphorylation of β-catenin. A partial explanation for this situation comes from in silico modeling, which predicts that the docking site for p25 on GSK3β is the AXIN-binding domain; because of this, p25 inhibits the formation of the GSK3β/AXIN/APC destruction complex, thus preventing GSK3β from binding to and phosphorylating β-catenin. Coexpression of GSK3β and p25 in cultured neurons results in a neurodegeneration phenotype that exceeds that observed with CDK5 and p25. When p25 is transfected alone, the resulting neuronal damage is blocked more effectively with a specific siRNA against Gsk3β than with one against Cdk5. We propose that the effects of p25, although normally attributed to activate CDK5, may be mediated in part by elevated GSK3β activity.
authors.affiliation: Division of Life Science and the State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, Hong Kong;
authors.forename: Hei-Man
authors.initials: HM
authors.lastname: Chow
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; and.
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; and.
authors.forename: Jie-Chao
authors.initials: JC
authors.lastname: Zhou
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; and.
authors.forename: Guan-Yun
authors.initials: GY
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; and.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Li
authors.affiliation: Division of Life Science and the State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, Hong Kong; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854 jiezhang@xmu.edu.cn herrup@ust.hk.
authors.forename: Karl
authors.identifier: http://orcid.org/0000-0001-7786-5844
authors.initials: K
authors.lastname: Herrup
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; and jiezhang@xmu.edu.cn herrup@ust.hk.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C492236:Cdk5r1 protein, mouse; D046912:Multiprotein Complexes; D051176:beta Catenin; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: GSK3β; neurodegeneration; p25; tau; β-catenin