The tumor suppressor APC differentially regulates multiple beta-catenins through the function of Axin and casein kinase 1alpha during C. elegans asymmetric stem cell divisions

Abstract

The APC tumor suppressor regulates diverse stem cell processes from gene regulation through Wnt/β-catenin signaling to chromosome stability via microtubule interactions, but how disparate functions of APC are controlled is not well understood. As part of a Wnt/β-catenin pathway that controls asymmetric cell division, C. 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 POP-1/TCF to activate gene expression. Here we show APR-1 regulates SYS-1 levels in asymmetric stem cell division in addition to its known role lowering nuclear WRM-1. We demonstrate that SYS-1 is also negatively regulated by the C. elegans homolog of casein kinase 1α, KIN-19. We show that KIN-19 restricts APR-1 localization such that KIN-19 regulates nuclear WRM-1. Finally, the polarity of APR-1 cortical localization is controlled by PRY-1/Axin such that PRY-1 controls the polarity of both SYS-1 and WRM-1 asymmetries. We propose a model whereby Wnt signaling, via CKIα, regulates the function of two distinct pools of APC: one APC pool negatively regulates SYS-1 while the second stabilizes microtubules and promotes WRM-1 nuclear export.