Journal article
Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations
Cells & development, Vol.182, 204013
06/2025
DOI: 10.1016/j.cdev.2025.204013
PMCID: PMC12158637
PMID: 40010690
Abstract
β-catenin is a highly conserved multifunctional protein capable of mediating cell adhesion via E-cadherin and transactivation of target genes of the canonical Wnt signaling pathway. The nematode, C. elegans contains four paralogs of β-catenin which are highly specific in their functions. Though similar in overall structure, the four beta-catenins are functionally distinct, each regulating different aspects of development. Of the four, SYS-1 is a key player in Wnt dependent asymmetric cell division (ACD). In ACD, a polarized mother will give rise to a daughter with high nuclear SYS-1 and another with low nuclear SYS-1. Despite sequence dissimilarity, SYS-1 shares a close structural resemblance with human β-catenin where it retains an unstructured amino-terminus (NTD) and 12 armadillo repeats. Using existing genome sequence data from several nematode species, we find that the four β-catenin paralogs result from 3 sequential gene duplications and neofunctionalizations during nematode evolution. SYS-1, however, lacks an unstructured carboxyl-terminus (CTD) that is essential for human β-catenin transactivation processes. This work supports the hypothesis that SYS-1 compensated for the lack of CTD by acquiring novel transactivation domains with cryptic nuclear localization signals in the NTD and the first four armadillo repeats, as shown by transactivation assays in worms and yeast. Furthermore, SYS-1 regulatory domains are not localized to the NTD as in canonical β-catenin and instead spans the entire length of the protein. Truncating SYS-1 abolishes the classical SYS-1 nuclear asymmetry, resulting in daughter cells with symmetrical SYS-1 truncation localization. A screen for SYS-1 physical interactors followed by in vivo SYS-1 localization analyses and effects on cell fate suggest that proper SYS-1 nuclear export is facilitated by XPO-1, while an interaction with IMB-3, an importin β-like protein, suggests import mechanisms. Interestingly, XPO-1 is especially required for lowering SYS-1 in the Wnt-unsignaled nucleus, suggesting a distinct mechanism for regulating asymmetric nuclear SYS-1. In summary, we provide insights on the mechanism of β-catenin evolution within nematodes and inform SYS-1 transactivation and nuclear transport mechanisms.
Details
- Title: Subtitle
- Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations
- Creators
- Arielle K Wolf - University of IowaLori C Adams-Phillips - University of IowaAmanda N D Adams - University of IowaAlbert J Erives - University of IowaBryan T Phillips - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cells & development, Vol.182, 204013
- DOI
- 10.1016/j.cdev.2025.204013
- PMID
- 40010690
- PMCID
- PMC12158637
- NLM abbreviation
- Cells Dev
- ISSN
- 2667-2901
- eISSN
- 2667-2901
- Publisher
- ELSEVIER
- Grant note
- National Institute of Health (NIH) Office of Research Infrastructure Programs: P40 OD01440 NIH: GM114007 Ballard-Seashore Dissertation Fellowship (AKW)
We thank members of the Phillips lab for helpful comments on the manuscript. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institute of Health (NIH) Office of Research Infrastructure Programs [P40 OD01440] . This work was supported by NIH GM114007 (BTP) and the Ballard-Seashore Dissertation Fellowship (AKW) . We thank the laboratory of Thomas Rutkowski (UI) for the anti-RFP antibody used in immunoprecipitations and the Wickens lab (UW-Madison) for the pBTMKnDB vector.
- Language
- English
- Electronic publication date
- 02/24/2025
- Date published
- 06/2025
- Academic Unit
- Office Of The Provost; Biology
- Record Identifier
- 9984795375102771
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