Custos controls β-catenin to regulate head development during vertebrate embryogenesis

Abstract

Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders. A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of β-catenin, a process that remains incompletely understood. Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelledinteracting protein. Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis. Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer. In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited β-catenin/TCF-dependent transcription. Custos binds to β-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of β-catenin. This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling. The function of Custos is conserved as loss-of-function and gainof-function studies in zebrafish also demonstrate a role for Custos in anterior head development. Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-β-catenin signal transduction cascade.

The regulation of β-catenin activity and function in cancer: therapeutic opportunities

“…Overexpression of NDRG1 in colon cancer cells inhibits the nuclear localization of PAK4, increasing the levels of membrane-associated β-catenin and downregulating β-catenin transcriptional activity [ 58 ]. Custos is another protein reported to be a component of canonical Wnt signaling [ 59 ]. Custos binds to β-catenin in a Wnt responsive manner without affecting its stability, and the interaction is required to promote β-catenin nuclear translocation during organizer formation.…”

Three-Dimensional Mapping of mRNA Export through the Nuclear Pore Complex

“…The study of the mRNA export process and the details of the export path through the NPC are critical to the understanding of a vital step in the expression of genes in eukaryotes [ 14 , 53 , 54 , 55 , 56 , 57 , 58 ], as well as its potential uses in cancer immunotherapy, prophylactic vaccines, therapeutic gene products, or protein replacement therapies in the treatment and prevention of human diseases [ 59 , 60 , 61 , 62 ]. More precisely, locating the major selective barrier to nucleocytoplasmic export and a refinement of the measure of transport kinetics are important contributions to the understanding of the details of NPC’s role in mRNA export and other vital cellular processes, such as mislocalization of cytoplasmic proteins to the nucleus and deregulation of signaling pathways can have disastrous consequences (such as developmental defects or cancer) and directly or indirectly involve the interaction of the NPC with various proteins [ 63 , 64 , 65 , 66 , 67 ]. Additionally, it is believed that precise localization of molecular interactions within the NPC’s central channel itself is directly relevant to cancer-drug targeting strategies [ 68 , 69 , 70 , 71 ].…”

Exploring the Uncharacterized Human Proteome Using neXtProt

“…Because of the lack of standards for gene names across species, we used some synonyms as inputs for the queries, in addition to the human official gene names. This is exemplified by the cases of C9orf116 and C12orf43, for which the papers describing the mouse and Xenopus knockout phenotypes use the synonyms Pierce1 and custos, respectively. We retrieved characterization papers for 113 proteins for all chromosomes except chromosomes 21 and Y (Table S1, column H), which were transmitted to Swiss-Prot curators for functional annotation update.…”