title: Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors.
abstract: Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Jin
authors: J
authors: Yang
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
authors: Alexander G
authors: AG
authors: Bassuk
authors: Research Unit Protein Science, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Munich, Germany.
authors: Juliane
authors: J
authors: Merl-Pham
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Chun-Wei
authors: CW
authors: Hsu
authors: Omics Laboratory, University of Iowa, Iowa, IA, USA.
authors: Diana F
authors: DF
authors: Colgan
authors: Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China.
authors: Xiaorong
authors: X
authors: Li
authors: Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
authors: Kit Sing
authors: KS
authors: Au
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.|Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China.
authors: Lijuan
authors: L
authors: Zhang
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Scott
authors: S
authors: Smemo
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Sally
authors: S
authors: Justus
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
authors: Yasunori
authors: Y
authors: Nagahama
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
authors: Andrew J
authors: AJ
authors: Grossbach
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
authors: Matthew A
authors: MA
authors: Howard
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
authors: Hiroto
authors: H
authors: Kawasaki
authors: Departments of Neurosurgery, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA.
authors: Neil A
authors: NA
authors: Feldstein
authors: Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA Departments of Pediatrics and Neurology, University of Washington, Seattle, Washington, WA, USA.
authors: William B
authors: WB
authors: Dobyns
authors: Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
authors: Hope
authors: H
authors: Northrup
authors: Research Unit Protein Science, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Munich, Germany.
authors: Stefanie M
authors: SM
authors: Hauck
authors: Institute for Ophthalmic Research, Center of Ophthalmology, University Medical Center, University of Tübingen, Germany.
authors: Marius
authors: M
authors: Ueffing
authors: Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.|Omics Laboratory, University of Iowa, Iowa, IA, USA.
authors: Vinit B
authors: VB
authors: Mahajan
authors: Barbara & Donald Jonas Stem Cell Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA sht2@cumc.columbia.edu.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Stephen H
authors: SH
authors: Tsang
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D051177:Catenins / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003260:Contact Inhibition / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006222:Hamartoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009287:Naphthyridines / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000095002:Delta Catenin
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D051177:Catenins; D009287:Naphthyridines; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051744:Protein Kinase C-epsilon; D000095002:Delta Catenin; C000722347:CTNND1 protein, human