RRC ID 45806
Author Hikasa H, Sekido Y, Suzuki A.
Title Merlin/NF2-Lin28B-let-7 Is a Tumor-Suppressive Pathway that Is Cell-Density Dependent and Hippo Independent.
Journal Cell Rep
Abstract Contact inhibition of proliferation is critical for tissue organization, and its dysregulation contributes to tumorigenesis. Merlin/NF2 is a tumor suppressor that governs contact inhibition. Although Merlin/NF2 inhibits YAP1 and TAZ, which are paralogous Hippo pathway transcriptional co-activators and oncoproteins, it is not fully understood how Merlin/NF2-mediated signal transduction triggered by cell-cell contact exerts tumor suppression. Here, we identify Lin28B, an inhibitor of let-7 microRNAs (miRNAs), as an important downstream target of Merlin/NF2. Functional studies revealed that, at low cell density, Merlin/NF2 is phosphorylated and does not bind to Lin28B, allowing Lin28B to enter the nucleus, bind to pri-let-7 miRNAs, and inhibit their maturation in a YAP1/TAZ-independent manner. This inhibition of pri-let-7 maturation then promotes cell growth. However, cell-cell contact triggers Merlin/NF2 dephosphorylation, which sequesters Lin28B in the cytoplasm and permits pri-let-7 maturation. Our results reveal that Merlin/NF2-mediated signaling drives a tumor-suppressive pathway that is cell-density dependent and Hippo independent.
Volume 14(12)
Pages 2950-61
Published 2016-3-29
DOI 10.1016/j.celrep.2016.02.075
PII S2211-1247(16)30210-8
PMID 26997273
MeSH Adaptor Proteins, Signal Transducing / metabolism Cell Line Cell Nucleus / metabolism Cell Proliferation HEK293 Cells Hippo Signaling Pathway Humans Immunoblotting Immunohistochemistry Immunoprecipitation MicroRNAs / antagonists & inhibitors MicroRNAs / metabolism* Neurofibromin 2 / antagonists & inhibitors Neurofibromin 2 / genetics Neurofibromin 2 / metabolism Phosphoproteins / metabolism Phosphorylation Protein Binding Protein Serine-Threonine Kinases / chemistry Protein Serine-Threonine Kinases / metabolism* RNA Interference RNA, Messenger / metabolism RNA, Small Interfering / metabolism RNA-Binding Proteins / antagonists & inhibitors RNA-Binding Proteins / genetics RNA-Binding Proteins / metabolism* Real-Time Polymerase Chain Reaction Transcription Factors YAP-Signaling Proteins
IF 8.109
Times Cited 16
DNA material pENTR4-H1 (RDB04395) CS-RfA-ETBsd (RDB07917).