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.