title: PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42.
abstract: Formation of the apical surface and lumen is a fundamental, yet poorly understood, step in epithelial organ development. We show that PTEN localizes to the apical plasma membrane during epithelial morphogenesis to mediate the enrichment of PtdIns(4,5)P2 at this domain during cyst development in three-dimensional culture. Ectopic PtdIns(4,5)P2 at the basolateral surface causes apical proteins to relocalize to the basolateral surface. Annexin 2 (Anx2) binds PtdIns(4,5)P2 and is recruited to the apical surface. Anx2 binds Cdc42, recruiting it to the apical surface. Cdc42 recruits aPKC to the apical surface. Loss of function of PTEN, Anx2, Cdc42, or aPKC prevents normal development of the apical surface and lumen. We conclude that the mechanism of PTEN, PtdIns(4,5)P2, Anx2, Cdc42, and aPKC controls apical plasma membrane and lumen formation.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA. fernando.martin-belmonte@ucsf.edu
authors.forename: Fernando
authors.initials: F
authors.lastname: Martin-Belmonte
authors.forename: Ama
authors.initials: A
authors.lastname: Gassama
authors.forename: Anirban
authors.initials: A
authors.lastname: Datta
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Ursula
authors.initials: U
authors.lastname: Rescher
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.forename: Keith
authors.initials: K
authors.lastname: Mostov
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D002451:Cell Compartmentation / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D016764:Cell Polarity / Q000235:genetics*; D004285:Dogs; D004848:Epithelium / Q000378:metabolism*; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; C115015:PKC-3 protein; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase; D020764:cdc42 GTP-Binding Protein