Identification of the Axin and Frat binding region of glycogen synthase kinase-3. |
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Authors: | Elizabeth Fraser Neville Young Rana Dajani Jonathan Franca-Koh Jonathan Ryves Robin S B Williams Margaret Yeo Marie-Therese Webster Chris Richardson Matthew J Smalley Laurence H Pearl Adrian Harwood Trevor C Dale |
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Affiliation: | Cancer Research Campaign Centre for Cell and Molecular Biology and Section of Structural Biology, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, United Kingdom. |
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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. |
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