Distinct molecular regulation of glycogen synthase kinase-3α isozyme controlled by its N-terminal region functional role in CALCIUM/CALPAIN signaling

Inbar Azoulay-Alfaguter, Yakey Yaffe, Avital Licht-Murava, Malgorzata Urbanska, Jacek Jaworsk, Shmuel Pietrokovski, Koret Hirschberg, Hagit Eldar-Finkelman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glycogen synthase kinase-3 (GSK-3) is expressed as two isozymes α and β. They share high similarity in their catalytic domains but differ in their N- and C-terminal regions, with GSK-3α having an extended glycine-rich N terminus. Here, we undertook live cell imaging combined with molecular and bioinformatic s udies to understand the distinct functions of the GSK-3 isozymes focusing on GSK-3α N-terminal region. We found that unlike GSK-3β, which shuttles between the nucleus and cytoplasm, GSK-3α was excluded from the nucleus. Deletion of the N-terminal region of GSK-3α resulted in nuclear localization, and treatment with leptomycin B resulted in GSK-3α accumulation in the nucleus. GSK-3α rapidly accumulated in the nucleus in response to calcium or serum deprivation, and accumulation was strongly inhibited by the calpain inhibitor calpeptin. This nuclear ccumulation was not mediated by cleavage of the N-terminal region or phosphorylation of GSK-3α. Rather, we show that calcium-induced GSK-3α nuclear accumulation was governed by GSK-3α binding with as yet unknown calpain-sensitive protein or proteins; this binding was mediated by the N-terminal region. Bioinformatic and experimental analyses indicated that nuclear exclusion of GSK-3α was likely an exclusive characteristic ofmammalian GSK-3α. Finally, we show that nuclear localization of GSK-3α reduced the nuclear pool ofβ-catenin and its target cyclin D1. Taken together, these data suggest that the N-terminal region of GSK-3α is responsible for its nuclear exclusion and that binding with a calcium/calpain-sensitive product enables GSK-3α nuclear retention.Wefurther uncovered a novel link between calcium and nuclear GSK-3α-mediated inhibition of the canonical Wnt/β-catenin pathway.

Original languageEnglish
Pages (from-to)13470-13480
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number15
DOIs
StatePublished - 15 Apr 2011

Funding

FundersFunder number
Seventh Framework Programme223276

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