کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2041406 | 1073159 | 2016 | 12 صفحه PDF | دانلود رایگان |
• Lin28B, which inhibits let-7 microRNA, is a key downstream target of Merlin/NF2
• At low cell density, phosphorylated Merlin/NF2 does not bind to Lin28B
• Dephosphorylated Merlin/NF2 sequesters Lin28B, inhibiting growth
• Merlin/NF2 drives cell-density-dependent and Hippo-independent tumor suppression
SummaryContact 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.
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Journal: - Volume 14, Issue 12, 29 March 2016, Pages 2950–2961