β-Cateninrelated protein WRM-1 is a multifunctional regulatory subunit of the LIT-1 MAPK complex

Xiao Dong Yang, Tejas R. Karhadkar, Jessica Medina, Scott M. Robertson, Rueyling Lin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Vertebrate β-catenin has two functions, as a structural component of the adherens junction in cell adhesion and as the T-cell factor (TCF) transcriptional coactivator in canonical Wnt (wingless-related integration site) signaling. These two functions are split between three of the four β-catenin-related proteins present in the round worm Caenorhabditis elegans. The fourth β-catenin-related protein, WRM-1, exhibits neither of these functions. Instead, WRM-1 binds the MAPK loss of intestine 1 (LIT-1), and these two proteins have been shown to be essential for the transcription ofWnt target genes by phosphorylating and regulating the nuclear level of the sole worm TCF protein.We showed previously thatWRM-1 binds to worm TCF and functions as the substrate-binding subunit for LIT-1. In this study, we show that phosphorylation of T220 in the activation loop is essential for LIT-1 kinase activity in vivo and in vitro. T220 can be phosphorylated either through LIT-1 autophosphorylation or directly by the upstream MAP3K MOM-4. Our data support a model in which WRM-1, which can undergo homotypic interaction, binds LIT-1 and thereby generates a kinase complex in which LIT-1 molecules are situated in a conformation enabling autophosphorylation as well as promoting phosphorylation of the T220 residue by MOM-4. In addition, we show that WRM-1 is essential for the translocation of the LIT-1 kinase complex to the nucleus, the site of its TCF substrate. To our knowledge, this is the first report of a MAP3K directly activating a MAPK by phosphorylation within the activation loop. This study should help uncover novel and as yet underappreciated functions of vertebrate β-catenin.

Original languageEnglish (US)
Pages (from-to)E137-E146
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number2
DOIs
StatePublished - Jan 13 2015

Keywords

  • C. elegans
  • LIT-1
  • MAP3K
  • MAPK activation
  • MOM-4

ASJC Scopus subject areas

  • General

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