No abstract

mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the PH domain of Sin1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with Sin1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical Sin1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the Sin1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate Akt in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.

Background Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the β-catenin gene locus, circβ-catenin. Results Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. Conclusions Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma. Electronic supplementary material The online version of this article (10.1186/s13059-019-1685-4) contains supplementary material, which is available to authorized users.