Identification of the Axin and Frat binding region of glycogen synthase kinase-3

Fraser, Elizabeth, Young, N., Dajani, R., Franca-Koh, J., Ryves, William Jonathan, Williams, R. S. B., Yeo, M., Webster, M.-T., Richardson, C., Smalley, Matthew John ORCID: https://orcid.org/0000-0001-9540-1146, Pearl, L. H., Harwood, Adrian John ORCID: https://orcid.org/0000-0003-3124-5169 and Dale, Trevor Clive ORCID: https://orcid.org/0000-0002-4880-9963 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277 (3) , pp. 2176-2185. 10.1074/jbc.M109462200

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Neuroscience and Mental Health Research Institute (NMHRI) European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Last Modified:	22 Jun 2023 10:01
URI:	https://orca.cardiff.ac.uk/id/eprint/46400

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