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

• Published in: Human molecular genetics 2016-10, Vol.25 (19), p.4201-4210
• Main Authors: Yang, Jin, Bassuk, Alexander G, Merl-Pham, Juliane, Hsu, Chun-Wei, Colgan, Diana F, Li, Xiaorong, Au, Kit Sing, Zhang, Lijuan, Smemo, Scott, Justus, Sally, Nagahama, Yasunori, Grossbach, Andrew J, Howard, 3rd, Matthew A, Kawasaki, Hiroto, Feldstein, Neil A, Dobyns, William B, Northrup, Hope, Hauck, Stefanie M, Ueffing, Marius, Mahajan, Vinit B, Tsang, Stephen H
• Format: Article
• Language: English
• Subjects: Astrocytes - drug effects; Astrocytes - pathology; Catenins - genetics; Cell Adhesion - drug effects; Cell Line, Tumor; Contact Inhibition - drug effects; Epithelial-Mesenchymal Transition - genetics; Hamartoma - genetics; Hamartoma - pathology; Humans; Naphthyridines - administration & dosage; Neoplasm Metastasis; Phosphorylation - drug effects; Protein Kinase C-epsilon - genetics; TOR Serine-Threonine Kinases - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw253

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.