Identification of the Axin and Frat Binding Region of Glycogen Synthase Kinase-3

Glycogen synthase kinase-3 (GSK-3) is a key component of several signaling pathways including those regulated by Wnt and insulin ligands. Specificity in GSK-3 signaling is thought to involve interactions with scaffold proteins that localize GSK-3 regulators and substrates. This report shows that GSK...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-01, Vol.277 (3), p.2176-2185
Main Authors: Fraser, Elizabeth, Young, Neville, Dajani, Rana, Franca-Koh, Jonathan, Ryves, Jonathan, Williams, Robin S.B., Yeo, Margaret, Webster, Marie-Therese, Richardson, Chris, Smalley, Matthew J., Pearl, Laurence H., Harwood, Adrian, Dale, Trevor C.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Amino Acid Substitution
Animals
axin
Axin Protein
Binding Sites
Calcium-Calmodulin-Dependent Protein Kinases - chemistry
Calcium-Calmodulin-Dependent Protein Kinases - genetics
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Carrier Proteins
Cell Line
Crystallography, X-Ray
Dictyostelium
Frat protein
Glycogen Synthase Kinase 3
Glycogen Synthase Kinases
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins
Models, Molecular
Mutagenesis
Neoplasm Proteins
Protein Conformation
Proteins - metabolism
Proto-Oncogene Proteins - metabolism
Repressor Proteins
surface-scanning mutagenesis
T-cell factor
Xenopus
Xenopus Proteins
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Summary:Glycogen synthase kinase-3 (GSK-3) is a key component of several signaling pathways including those regulated by Wnt and insulin ligands. Specificity in GSK-3 signaling is thought to involve interactions with scaffold proteins that localize GSK-3 regulators and substrates. This report shows that GSK-3 forms a low affinity homodimer that is disrupted by binding to Axin and Frat. Based on the crystal structure of GSK-3, we have used surface-scanning mutagenesis to identify residues that differentially affect GSK-3 interactions. Mutations that disrupt Frat and Axin cluster at the dimer interface explaining their effect on homodimer formation. Loss of the Axin binding site blocks the ability of dominant negative GSK-3 to cause axis duplication in Xenopus embryos. The Axin binding site is conserved within all GSK-3 proteins, and its loss affects both cell motility and gene expression in the nonmetazoan,Dictyostelium. Surprisingly, we find no genetic interaction between a non-Axin-binding GSK-3 mutant and T-cell factor activity, arguing that Axin interactions alone cannot explain the regulation of T-cell factor-mediated gene expression.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109462200