title: Distinct and mutually inhibitory binding by two divergent β-catenins coordinates TCF levels and activity in C. elegans.
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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Yang
authors.forename: Shuyi
authors.initials: S
authors.lastname: Huang
authors.forename: Miao-Chia
authors.initials: MC
authors.lastname: Lo
authors.forename: Kota
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sawa
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
authors.forename: Scott
authors.initials: S
authors.lastname: Robertson
authors.forename: Rueyling
authors.initials: R
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000096:biosynthesis* / Q000737:chemistry
chemical_list: D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008565:Membrane Proteins; C502083:Sys-1 protein, C elegans; D014157:Transcription Factors; C120104:WRM-1 protein, C elegans; D051176:beta Catenin; C096787:pop-1 protein, C elegans; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; C120085:lit-1 protein, C elegans