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

Jin Yang, Alexander G. Bassuk, Juliane Merl-Pham, Chun Wei Hsu, Diana F. Colgan, Xiaorong Li, Kit Sing Au, Lijuan Zhang, Scott Smemo, Sally Justus, Yasunori Nagahama, Andrew J. Grossbach, Matthew A. Howard, Hiroto Kawasaki, Neil A. Feldstein, William B. Dobyns, Hope Northrup, Stefanie M. Hauck, Marius Ueffing, Vinit B. MahajanStephen H. Tsang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4201-4210
Number of pages10
JournalHuman molecular genetics
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was conducted in the Barbara & Donald Jonas Laboratory of Regenerative Medicine and Bernard & Shirlee Brown Glaucoma Laboratory, which are supported by the Department of Defense CDMRP TSCRP:TS080017, National Institute of Health [5P30EY019007, R01EY018213, R01EY024698, 1R01EY026682, R21AG050437]; National Cancer Institute Core [5P30CA013696]; the Research to Prevent Blindness (RPB) Physician-Scientist Award; unrestricted funds from RPB, New York, NY, USA; the Tistou and Charlotte Kerstan Foundation; the Crowley Family Fund; the Schneeweiss Stem Cell Fund; New York State [C029572]; the Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]; and the Gebroe Family Foundation. JY is supported by National Natural Science Funds [81400412], the US Army Medical Research and Material Command [TS080017], China and the Key Program of Tianjin Natural Science Foundation [15JCZDJC34500] Tianjin, China. VBM is supported by NIH grants [K08EY020530, R01EY024665, R01EY025225, R01EY024698 and R21AG050437] and RPB. AGB is supported by 1R01NS098590-01.

Funding Information:
We would like to thank members of the Jonas Stem Cell Laboratory and the Brown Glaucoma Laboratory for sharing ideas and equipment and, especially Wei-Pu Wu for data analysis of cell motility, Yi-Ting Tsai and Wen-Hsuan Wu for genotyping instruction, and Rebecca Tuttle, Sally Justus for critical reviews of the manuscript. We also thank Jimmy Duong for comments on the statistical analyses. We would also like to thank the Columbia University Pathology Laboratory for their extensive assistance in exome sequencing for patient samples. This work was conducted in the Barbara & Donald Jonas Laboratory of Regenerative Medicine and Bernard & Shirlee Brown Glaucoma Laboratory, which are supported by the Department of Defense CDMRP TSCRP:TS080017, National Institute of Health [5P30EY019007, R01EY018213, R01EY024698, 1R01EY026682, R21AG050437]; National Cancer Institute Core [5P30CA013696]; the Research to Prevent Blindness (RPB) Physician-Scientist Award; unrestricted funds from RPB, New York, NY, USA; the Tistou and Charlotte Kerstan Foundation; the Crowley Family Fund; the Schneeweiss Stem Cell Fund; New York State [C029572]; the Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]; and the Gebroe Family Foundation. JY is supported by National Natural Science Funds [81400412], the US Army Medical Research and Material Command [TS080017], China and the Key Program of Tianjin Natural Science Foundation [15JCZDJC34500] Tianjin, China. VBM is supported by NIH grants [K08EY020530, R01EY024665, R01EY025225, R01EY024698 and R21AG050437] and RPB. AGB is supported by 1R01NS098590-01.

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