title: The RNF146 and tankyrase pathway maintains the junctional Crumbs complex through regulation of angiomotin.
abstract: The Crumbs complex is an important determinant of epithelial apical-basal polarity that functions in regulation of tight junctions, resistance to epithelial-to-mesenchymal transitions and as a tumour suppressor. Although the functional role of the Crumbs complex is being elucidated, its regulation is poorly understood. Here, we show that suppression of RNF146, an E3 ubiquitin ligase that recognizes ADP-ribosylated substrates, and tankyrase, a poly(ADP-ribose) polymerase, disrupts the junctional Crumbs complex and disturbs the function of tight junctions. We show that RNF146 binds a number of polarity-associated proteins, in particular members of the angiomotin (AMOT) family. Accordingly, AMOT proteins are ADP-ribosylated by TNKS2, which drives ubiquitylation by RNF146 and subsequent degradation. Ablation of RNF146 or tankyrase, as well as overexpression of AMOT, led to the relocation of PALS1 (a Crumbs complex component) from the apical membrane to internal puncta, a phenotype that is rescued by AMOTL2 knockdown. We thus reveal a new function of RNF146 and tankyrase in stabilizing the Crumbs complex through downregulation of AMOT proteins at the apical membrane.
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors: Craig I
authors: CI
authors: Campbell
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors: Payman
authors: P
authors: Samavarchi-Tehrani
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors: Miriam
authors: M
authors: Barrios-Rodiles
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors: Alessandro
authors: A
authors: Datti
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors: Anne-Claude
authors: AC
authors: Gingras
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 wrana@lunenfeld.ca.
authors: Jeffrey L
authors: 0000-0003-0932-0644
authors: JL
authors: Wrana
mesh_terms: D000091082:Angiomotins; D000818:Animals; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D038501:Tankyrases / Q000378:metabolism*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: C511047:Amot protein, mouse; D000091082:Angiomotins; C453730:Crb1 protein, mouse; D006575:Heterocyclic Compounds, 3-Ring; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C544261:XAV939; D062826:Zonula Occludens-1 Protein; C583436:Rnf146 protein, mouse; D044767:Ubiquitin-Protein Ligases; D038501:Tankyrases; D009703:Nucleoside-Phosphate Kinase; C499979:Mpp5 protein, mouse
keywords: Angiomotin; Crumbs; RNF146; Tankyrase