ABSTRACT
The APC tumor suppressor regulates diverse stem cell processes including gene regulation through Wnt–β-catenin signaling and chromosome stability through microtubule interactions, but how the disparate functions of APC are controlled is not well understood. Acting as part of a Wnt–β-catenin pathway that controls asymmetric cell division, Caenorhabditis elegans APC, APR-1, promotes asymmetric nuclear export of the β-catenin WRM-1 by asymmetrically stabilizing microtubules. Wnt function also depends on a second β-catenin, SYS-1, which binds to the C. elegans TCF POP-1 to activate gene expression. Here, we show that APR-1 regulates SYS-1 levels in asymmetric stem cell division, in addition to its known role in lowering nuclear levels of WRM-1. We demonstrate that SYS-1 is also negatively regulated by the C. elegans homolog of casein kinase 1α (CKIα), KIN-19. We show that KIN-19 restricts APR-1 localization, thereby regulating nuclear WRM-1. Finally, the polarity of APR-1 cortical localization is controlled by PRY-1 (C. elegans Axin), such that PRY-1 controls the polarity of both SYS-1 and WRM-1 asymmetries. We propose a model whereby Wnt signaling, through CKIα, regulates the function of two distinct pools of APC – one APC pool negatively regulates SYS-1, whereas the second pool stabilizes microtubules and promotes WRM-1 nuclear export.
Author contributions
A.T.B. designed experiments, performed experiments and prepared the manuscript. B.T.P. designed experiments and prepared the manuscript.
Funding
This work was supported by research grants from the March of Dimes Foundation [grant number 5-FY11-109]; and from the American Cancer Society [grant number RSG-11-140-01-DDC].
