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Nature Communications 8: Article number: 14338 (2017); Published: 6 February 2017; Updated: 13 June 2017 This Article contains errors in Figs 2 and 3, for which we apologize. In Fig. 2c, the four images were inadvertently duplicated from the images in Fig. 2b. In Fig. 3g, the image at the upper right corner, corresponding to the condition UT_ Cln3Δex7-8 was inadvertently duplicated from the image in the lower right corner of Fig.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell survival and autophagy, and its activity is regulated by amino acid availability. Rag GTPase-GATOR1 interactions inhibit mTORC1 in the absence of amino acids, and GATOR1 release and activation of RagA/B promotes mTORC1 activity in the presence of amino acids. However, the factors that play a role in Rag-GATOR1 interaction are still poorly characterized. Here, we show that the tyrosine kinase Src is crucial for amino acid-mediated activation of mTORC1. Src acts upstream of the Rag GTPases by promoting dissociation of GATOR1 from the Rags, thereby determining mTORC1 recruitment and activation at the lysosomal surface. Accordingly, amino acid-mediated regulation of Src/mTORC1 modulates autophagy and cell size expansion. Finally, Src hyperactivation overrides amino acid signaling in the activation of mTORC1. These results shed light on the mechanisms underlying pathway dysregulation in many cancer types., The growth-promoting activity of mTORC1 is regulated by amino acid availability via the Rag GTPases. Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPase–GATOR1 complex and mTORC1 activation at the lysosomal surface.

The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3′-untranslated region (3′-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3′-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression., Epithelial-to-mesenchymal transition is a key process in tumorigenesis but little is known about the molecular mechanism regulating such process at the translational level. Here, the authors identify a subset of mRNAs important for this process that are specifically modulated by the RNA-binding protein CELF1.

Alternative polyadenylation (APA) is a pervasive mechanism in the regulation of most human genes, and its implication in diseases including cancer is only beginning to be appreciated. Since conventional APA profiling has not been widely adopted, global cancer APA studies are very limited. Here we develop a novel bioinformatics algorithm (DaPars) for the de novo identification of dynamic APAs from standard RNA-seq. When applied to 358 TCGA Pan-Cancer tumour/normal pairs across seven tumour types, DaPars reveals 1,346 genes with recurrent and tumour-specific APAs. Most APA genes (91%) have shorter 3'-untranslated regions (3' UTRs) in tumours that can avoid microRNA-mediated repression, including glutaminase (GLS), a key metabolic enzyme for tumour proliferation. Interestingly, selected APA events add strong prognostic power beyond common clinical and molecular variables, suggesting their potential as novel prognostic biomarkers. Finally, our results implicate CstF64, an essential polyadenylation factor, as a master regulator of 3'-UTR shortening across multiple tumour types.