The canonical Wnt Signal restricts the GSK3/Fbw7-dependent ubiquitination and degradation of Eya1 phosphatase.

Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is post-translational modified by ubiquitin and its ubiquitination ...
level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phospho-degron (CPD) signal, a target site of GSK3 kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decreases Eya1 ubiquitination. Conversely, activation of the PI3K/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1(+/-);Wnt9b(+/-) mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathway restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and further suggest that dysregulation of this novel axis contributes to tumorigenesis.
Mol. Cell. Biol.
Date: Apr. 21, 2014
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