Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex

Abstract

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

“…These biological functions associate with the protumour/prometastatic roles of inflammatory cells in cancer development and metastasis ( Table 3 ) ( 52 , 53 ). In terms of the cellular components, they mainly included the protein complex involved in cell adhesion and the integrin complex ( Table 3 ), functions associated with tumorigenesis ( 54 , 55 ). In addition, no results were obtained from the molecular function of the GO analysis and the KEGG pathways analysis, given that adjusted p > 0.05 in these functional analyses.…”