title: The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation.
abstract: After cell fate specification, differentiating cells must amplify the specific subcellular features required for their specialized function. How cells regulate such subcellular scaling is a fundamental unanswered question. Here, we show that the E3 ubiquitin ligase Mindbomb 1 (MIB1) is required for the apical secretory apparatus established by gastric zymogenic cells as they differentiate from their progenitors. When Mib1 was deleted, death-associated protein kinase-1 (DAPK1) was rerouted to the cell base, microtubule-associated protein 1B (MAP1B) was dephosphorylated, and the apical vesicles that normally support mature secretory granules were dispersed. Consequently, secretory granules did not mature. The transcription factor MIST1 bound the first intron of Mib1 and regulated its expression. We further showed that loss of MIB1 and dismantling of the apical secretory apparatus was the earliest quantifiable aberration in zymogenic cells undergoing transition to a precancerous metaplastic state in mouse and human stomach. Our results reveal a mechanistic pathway by which cells can scale up a specific, specialized subcellular compartment to alter function during differentiation and scale it down during disease.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Capoccia
authors.forename: Ramon U
authors.initials: RU
authors.lastname: Jin
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D049108:Cell Enlargement; D016764:Cell Polarity; D019872:Chief Cells, Gastric / Q000201:enzymology / Q000502:physiology*; D017124:Conserved Sequence; D064550:Death-Associated Protein Kinases; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000473:pathology; D008679:Metaplasia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D013270:Stomach / Q000473:pathology; D013629:Tamoxifen; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D064550:Death-Associated Protein Kinases; D013629:Tamoxifen; D044767:Ubiquitin-Protein Ligases; C491312:Bhlha15 protein, mouse; C470629:MIB1 protein, mouse; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse