TMT quantitative proteomics of a) protrusions and cells bodies of a panel of cell lines, b) protrusions and cells bodies of MDA-MB231 cells collected after 1 h, 2 h, 4 h, 8 h post- induction of protrusions, c) non-transfected (nt) or LARP6 siRNAs MDA-MB231 cells grown on either close or open collagen coated transwells and d) protrusions and cells bodies of a panel of breast cell lines.

ABSTRACT: Translation of Ribosomal Protein coding mRNAs (RP-mRNAs) constitutes a key step in regulation of ribosome biogenesis in human cells, but the exact mechanisms which modulate RP-mRNAs translation under various cellular and environmental conditions remain poorly understood. Here we show that the subcellular localisation of RP-mRNAs acts as a key regulator of their translation in mesenchymal-like migratory cells. As cells invade into their surroundings, RP-mRNAs localise to the actin-rich protrusions at the front of the cells. This localisation is mediated by La related protein-6 (LARP6), an RNA Binding Protein (RBP) that is enriched in protrusions. Importantly, translation initiation and elongation factors are also enriched in protrusions. LARP6 dependent localisation of RP-mRNAs enhances their translation, leading to up-regulation of ribosome biogenesis and increased overall protein synthesis. In breast carcinomas, enhanced expression of LARP6 is associated with Epithelial to Mesenchymal Transition (EMT), and can be therapeutically targeted by a small molecule inhibitor which interferes with LARP6 RNA binding. These findings reveal an RNA localisation based post-transcriptional mechanism that governs ribosome biogenesis in migratory cells, and implicate a role for this process in cancer progression downstream of EMT.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Disease Free,Breast Cancer

SUBMITTER: Maria Dermit Salazar  

LAB HEAD: Faraz K. Mardakheh

PROVIDER: PXD015808 | Pride | 2021-09-08

REPOSITORIES: Pride