Journal article
Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors
Human molecular genetics, Vol.25(19), pp.4201-4210
10/01/2016
DOI: 10.1093/hmg/ddw253
PMCID: PMC5291196
PMID: 27516388
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.
Details
- Title: Subtitle
- Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors
- Creators
- Jin Yang - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USAAlexander G Bassuk - Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USAJuliane Merl-Pham - Research Unit Protein Science, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Munich, GermanyChun-Wei Hsu - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USADiana F Colgan - Omics Laboratory, University of Iowa, Iowa, IA, USAXiaorong Li - Tianjin Medical University Eye Hospital, Tianjin, People's Republic of ChinaKit Sing Au - Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USALijuan Zhang - Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, ChinaScott Smemo - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USASally Justus - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USAYasunori Nagahama - Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USAAndrew J Grossbach - Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USAMatthew A Howard III - Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USAHiroto Kawasaki - Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USANeil A Feldstein - Departments of Neurosurgery, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY, USAWilliam B Dobyns - 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, USAHope Northrup - Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USAStefanie M Hauck - Research Unit Protein Science, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Munich, GermanyMarius Ueffing - Institute for Ophthalmic Research, Center of Ophthalmology, University Medical Center, University of Tübingen, GermanyVinit B Mahajan - Omics Laboratory, University of Iowa, Iowa, IA, USAStephen H Tsang - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.25(19), pp.4201-4210
- Publisher
- England
- DOI
- 10.1093/hmg/ddw253
- PMID
- 27516388
- PMCID
- PMC5291196
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Grant note
- R01 EY025225 / NEI NIH HHS R01 EY018213 / NEI NIH HHS R01 NS098590 / NINDS NIH HHS P30 CA013696 / NCI NIH HHS R01 EY024698 / NEI NIH HHS R01 EY026682 / NEI NIH HHS K08 EY020530 / NEI NIH HHS R01 EY024665 / NEI NIH HHS R21 AG050437 / NIA NIH HHS P30 EY019007 / NEI NIH HHS
- Language
- English
- Date published
- 10/01/2016
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics); Neurosurgery; Otolaryngology; Internal Medicine
- Record Identifier
- 9984020646302771
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