title: Merlin/NF2-Lin28B-let-7 Is a Tumor-Suppressive Pathway that Is Cell-Density Dependent and Hippo Independent.
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.
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hikasa
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: suzuki@bioreg.kyushu-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025581:Neurofibromin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516326:LIN28B protein, human; D035683:MicroRNAs; D025581:Neurofibromin 2; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C487931:mirnlet7 microRNA, human; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; Lin28B; Merlin/NF2; cell contact; let-7; microRNA