The tumor suppressor APC differentially regulates multiple β-catenins through the function of axin and CKIα during C. elegans asymmetric stem cell divisions.
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.
Department of Biology, University of Iowa, 143 Biology Building, Iowa City, IA 52242-1324, USA.
Austin T
AT
Baldwin
Department of Biology, University of Iowa, 143 Biology Building, Iowa City, IA 52242-1324, USA bryan-phillips@uiowa.edu.
Bryan T
BT
Phillips
D021581:Active Transport, Cell Nucleus; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D060049:Asymmetric Cell Division; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology; D016764:Cell Polarity; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D021381:Protein Transport; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D025601:Adenomatous Polyposis Coli Protein; D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; C117260:Pry-1 protein, C elegans; C502083:Sys-1 protein, C elegans; D014157:Transcription Factors; C120104:WRM-1 protein, C elegans; D011494:Protein Kinases; C508382:KIN-19 protein, C elegans
APC; C. elegans; SYS-1; WRM-1; Wnt; β-catenin