title: β-Catenin-related protein WRM-1 is a multifunctional regulatory subunit of the LIT-1 MAPK complex.
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 of Wnt target genes by phosphorylating and regulating the nuclear level of the sole worm TCF protein. We showed previously that WRM-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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas TX 75390.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas TX 75390.
authors.forename: Tejas R
authors.initials: TR
authors.lastname: Karhadkar
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas TX 75390.
authors.forename: Jessica
authors.initials: J
authors.lastname: Medina
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas TX 75390.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Robertson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas TX 75390 rueyling.lin@utsouthwestern.edu.
authors.forename: Rueyling
authors.initials: R
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; C120104:WRM-1 protein, C elegans; D051176:beta Catenin; C120084:mom-4 protein, C elegans; D017346:Protein Serine-Threonine Kinases; C120085:lit-1 protein, C elegans
keywords: C. elegans; LIT-1; MAP3K; MAPK activation; MOM-4