title: S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells.
abstract: MicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation. We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. We demonstrate the functional relevance of this interaction in primary human dermal lymphatic endothelial cells (HDLECs). Angiopoietin-1 (ANG1) can augment miRNA biogenesis in HDLECs through enhancing TRBP phosphorylation and expression in an S6K2-dependent manner. We propose that the S6K2/TRBP node controls miRNA biogenesis in HDLECs and provides a molecular link between the mTOR pathway and the miRNA biogenesis machinery.
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Warner
authors.affiliation: Centre of Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University London, London, EC1M 6BQ, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Bridge
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.affiliation: Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hodgkinson
authors.affiliation: Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Heyam
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Bailey C
authors.initials: BC
authors.lastname: Massa
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Haslam
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzifrangkeskou
authors.affiliation: Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Gareth J O
authors.initials: GJ
authors.lastname: Evans
authors.affiliation: Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Plevin
authors.affiliation: Centre of Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University London, London, EC1M 6BQ, UK.
authors.forename: Tyson V
authors.initials: TV
authors.lastname: Sharp
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, Wentworth Way, York, YO10 5DD, UK dimitris.lagos@york.ac.uk.
authors.forename: Dimitris
authors.identifier: http://orcid.org/0000-0003-0637-281X
authors.initials: D
authors.lastname: Lagos
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D042683:Angiopoietin-1; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D019893:Ribosomal Protein S6 Kinases; D000099253:Trans-Activation Responsive RNA-Binding Protein