Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

• Deregulated CRL4DCAF1 induces activation of YAP in NF2-mutant tumor cells
• CRL4DCAF1 promotes ubiquitin-mediated proteasomal degradation of Lats1
• CRL4DCAF1-mediated oligoubiquitylation inhibits the kinase activity of Lats2
• CRL4DCAF1 activates YAP-dependent oncogenic gene expression

SummaryIt is currently unclear whether Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4DCAF1 in the nucleus. We found that derepressed CRL4DCAF1 promotes YAP- and TEAD-dependent transcription by ubiquitylating and, thereby, inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2-mutant tumors. We conclude that derepressed CRL4DCAF1 promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

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