| Title | Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Li W, Cooper J, Zhou L, Yang C, Erdjument-Bromage H, Zagzag D, Snuderl M, Ladanyi M, C Hanemann O, Zhou P, Karajannis MA, Giancotti FG |
| Journal | Cancer Cell |
| Volume | 26 |
| Issue | 1 |
| Pagination | 48-60 |
| Date Published | 2014 Jul 14 |
| ISSN | 1878-3686 |
| Keywords | Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Carrier Proteins, Cell Nucleus, Cell Transformation, Neoplastic, Child, Epistasis, Genetic, Female, Gene Expression Regulation, Neoplastic, Hep G2 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Middle Aged, Mutation, Missense, Neurofibromatosis 2, Neurofibromin 2, Phosphoproteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, RNA Interference, Signal Transduction, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Young Adult |
| Abstract | It 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 CRL4(DCAF1) in the nucleus. We found that derepressed CRL4(DCAF1) 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 CRL4(DCAF1) promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus. |
| DOI | 10.1016/j.ccr.2014.05.001 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 25026211 |
| PubMed Central ID | PMC4126592 |
| Grant List | P30 CA08748 / CA / NCI NIH HHS / United States S10OD010591 / OD / NIH HHS / United States |
Related Lab:
Related Faculty:
Pengbo Zhou, Ph.D.