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Yang, J.* ; Bassuk, A.G.* ; Merl-Pham, J. ; Hsu, C.W.* ; Colgan, D.F.* ; Li, X.* ; Au, K.S.* ; Zhang, L.* ; Smemo, S.* ; Justus, S.* ; Nagahama, Y.* ; Grossbach, A.J.* ; Howard, M.A.* ; Kawasaki, H.* ; Feldstein, N.A.* ; Dobyns, W.B.* ; Northrup, H.* ; Hauck, S.M. ; Ueffing, M.* ; Mahajan, V.B.* ; Tsang, S.H.*

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

Hum. Mol. Genet. 25, 4201-4210 (2016)
Publ. Version/Full Text Postprint Research data DOI
Open Access Green
Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumors 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords E-cadherin; P120 Catenin; Cancer; Mtor; Adhesion; Activation; Expression; Motility; Reveals; Pathway
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 25, Issue: 19, Pages: 4201-4210 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed