Distinct and mutually inhibitory binding by two divergent β-catenins coordinates TCF levels and activity in C. elegans

Xiao Dong Yang, Shuyi Huang, Miao Chia Lo, Kota Mizumoto, Hitoshi Sawa, Wenqing Xu, Scott Robertson, Rueyling Lin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Wnt target gene activation in C. elegans requires simultaneous elevation of β-catenin/SYS-1 and reduction of TCF/POP-1 nuclear levels within the same signal-responsive cell. SYS-1 binds to the conserved N-terminal β-catenin-binding domain (CBD) of POP-1 and functions as a transcriptional co-activator. Phosphorylation of POP-1 by LIT-1, the C. elegans Nemo-like kinase homolog, promotes POP-1 nuclear export and is the main mechanism by which POP-1 nuclear levels are lowered. We present a mechanism whereby SYS-1 and POP-1 nuclear levels are regulated in opposite directions, despite the fact that the two proteins physically interact. We show that the C terminus of POP-1 is essential for LIT-1 phosphorylation and is specifically bound by the diverged β-catenin WRM-1. WRM-1 does not bind to the CBD of POP-1, nor does SYS-1 bind to the C-terminal domain. Furthermore, binding of WRM-1 to the POP-1 C terminus is mutually inhibitory with SYS-1 binding at the CBD. Computer modeling provides a structural explanation for the specificity in WRM-1 and SYS-1 binding to POP-1. Finally, WRM-1 exhibits two independent and distinct molecular functions that are novel for β-catenins: WRM-1 serves both as the substrate-binding subunit and an obligate regulatory subunit for the LIT-1 kinase. Mutual inhibitory binding would result in two populations of POP-1: one bound by WRM-1 that is LIT-1 phosphorylated and exported from the nucleus, and another, bound by SYS-1, that remains in the nucleus and transcriptionally activates Wnt target genes. These studies could provide novel insights into cancers arising from aberrant Wnt activation.

Original languageEnglish (US)
Pages (from-to)4255-4265
Number of pages11
JournalDevelopment
Volume138
Issue number19
DOIs
StatePublished - Oct 1 2011

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Keywords

  • β-Catenin
  • A-P polarity
  • C. elegans
  • NLK/LIT-1
  • TCF protein
  • Wnt signaling

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

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