title: Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/β-catenin signaling.
abstract: Receptor-like tyrosine kinase (RYK) functions as a transmembrane receptor for the Wnt family of secreted protein ligands. Although RYK undergoes endocytosis in response to Wnt, the mechanisms that regulate its internalization and concomitant activation of Wnt signaling are unknown. We discovered that RYK both physically and functionally interacts with the E3 ubiquitin ligase Mindbomb 1 (MIB1). Overexpression of MIB1 promotes the ubiquitination of RYK and reduces its steady-state levels at the plasma membrane. Moreover, we show that MIB1 is sufficient to activate Wnt/β-catenin (CTNNB1) signaling and that this activity depends on endogenous RYK. Conversely, in loss-of-function studies, both RYK and MIB1 are required for Wnt-3A-mediated activation of CTNNB1. Finally, we identify the Caenorhabditis elegans orthologue of MIB1 and demonstrate a genetic interaction between ceMIB and lin-18/RYK in vulva development. These findings provide insights into the mechanisms of Wnt/RYK signaling and point to novel targets for the modulation of Wnt signaling.
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Berndt
authors.forename: Atsushi
authors.initials: A
authors.lastname: Aoyagi
authors.forename: Peitzu
authors.initials: P
authors.lastname: Yang
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Anastas
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000825:Animal Structures / Q000002:abnormalities; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D051153:Wnt Proteins / Q000494:pharmacology*; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000099177:Tsg101 Protein
chemical_list: D053829:Amyloid Precursor Protein Secretases; D029742:Caenorhabditis elegans Proteins; D002738:Chloroquine; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D007976:Leupeptins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins; D060509:Wnt3A Protein; D051176:beta Catenin; D020696:rab5 GTP-Binding Proteins; D000099177:Tsg101 Protein; C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; C513496:MIB1 ligase, human; C492691:LIN-18 protein, C elegans; C080836:RYK protein, human; C118148:Ryk protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde