RRC ID 45894
Author Yang XD, Karhadkar TR, Medina J, Robertson SM, Lin R.
Title β-Catenin-related protein WRM-1 is a multifunctional regulatory subunit of the LIT-1 MAPK complex.
Journal Proc. Natl. Acad. Sci. U.S.A.
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.
Volume 112(2)
Pages E137-46
Published 2015-1-13
DOI 10.1073/pnas.1416339112
PII 1416339112
PMID 25548171
PMC PMC4299254
MeSH Amino Acid Sequence Animals Animals, Genetically Modified Caenorhabditis elegans / embryology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / chemistry* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cytoskeletal Proteins / chemistry* Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism MAP Kinase Signaling System Membrane Proteins / chemistry* Membrane Proteins / genetics Membrane Proteins / metabolism Molecular Sequence Data Phosphorylation Protein Binding Protein Interaction Domains and Motifs Protein Subunits Protein-Serine-Threonine Kinases / chemistry* Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism Recombinant Fusion Proteins / chemistry Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism Sequence Homology, Amino Acid beta Catenin / chemistry beta Catenin / metabolism
IF 9.504
Times Cited 0
C.elegans tm514