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Hum Mol Genet. 2016 Oct 1;25(19):4201-4210. doi: 10.1093/hmg/ddw253. Epub 2016 Aug 11.

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors.

Author information

1
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.
2
Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China.
3
Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
4
Department of Pediatrics and Neurology, Departments of Neurosurgery, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa, IA, USA.
5
Research Unit Protein Science, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Munich, Germany.
6
Omics Laboratory, University of Iowa, Iowa, IA, USA.
7
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
8
Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China.
9
Departments of Neurosurgery, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA.
10
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.
11
Institute for Ophthalmic Research, Center of Ophthalmology, University Medical Center, University of Tübingen, Germany.
12
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.

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.

PMID:
27516388
PMCID:
PMC5291196
DOI:
10.1093/hmg/ddw253
[Indexed for MEDLINE]
Free PMC Article

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