Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4(DCAF1) in the Nucleus

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Feb 25

PMID 20178741

Citations 197

Authors

Wei Li

Liru You

Jonathan Cooper

Gaia Schiavon

Angela Pepe-Caprio

Lu Zhou

Ryohei Ishii

Marco Giovannini

C Oliver Hanemann

Stephen B Long

Hediye Erdjument-Bromage

Pengbo Zhou

Paul Tempst

Filippo G Giancotti

Affiliations

Soon will be listed here.

Abstract

Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4(DCAF1), and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).

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References

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine K . Delineation of a Fat tumor suppressor pathway. Nat Genet. 2006; 38(10):1142-50. DOI: 10.1038/ng1887. View

Pan D . Hippo signaling in organ size control. Genes Dev. 2007; 21(8):886-97. DOI: 10.1101/gad.1536007. View

Lee J, Zhou P . DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Mol Cell. 2007; 26(6):775-80. DOI: 10.1016/j.molcel.2007.06.001. View

McClatchey A, Giovannini M . Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin. Genes Dev. 2005; 19(19):2265-77. DOI: 10.1101/gad.1335605. View

lAllemand D, Manent J, Couvelard A, Watilliaux A, Siena M, Chareyre F . Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas. Oncogene. 2008; 28(6):854-65. DOI: 10.1038/onc.2008.427. View

OConnell B, Harper J . Ubiquitin proteasome system (UPS): what can chromatin do for you?. Curr Opin Cell Biol. 2007; 19(2):206-14. DOI: 10.1016/j.ceb.2007.02.014. View

Shimizu T, Seto A, Maita N, Hamada K, Tsukita S, Tsukita S . Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain. J Biol Chem. 2002; 277(12):10332-6. DOI: 10.1074/jbc.M109979200. View

McClatchey A, Fehon R . Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009; 19(5):198-206. PMC: 2796113. DOI: 10.1016/j.tcb.2009.02.006. View

10.

Okada T, You L, Giancotti F . Shedding light on Merlin's wizardry. Trends Cell Biol. 2007; 17(5):222-9. DOI: 10.1016/j.tcb.2007.03.006. View

11.

Lim S, Chen X, Lim Y, Hanson D, Vo T, Howerton K . Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008; 29(1):9-22. PMC: 2234035. DOI: 10.1016/j.molcel.2007.11.031. View

12.

Kissil J, Wilker E, Johnson K, Eckman M, Yaffe M, Jacks T . Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell. 2003; 12(4):841-9. DOI: 10.1016/s1097-2765(03)00382-4. View

13.

Schrecengost R, Riggins R, Thomas K, Guerrero M, Bouton A . Breast cancer antiestrogen resistance-3 expression regulates breast cancer cell migration through promotion of p130Cas membrane localization and membrane ruffling. Cancer Res. 2007; 67(13):6174-82. PMC: 4109708. DOI: 10.1158/0008-5472.CAN-06-3455. View

14.

Jin J, Arias E, Chen J, Harper J, Walter J . A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006; 23(5):709-21. DOI: 10.1016/j.molcel.2006.08.010. View

15.

Kaempchen K, Mielke K, Utermark T, Langmesser S, Hanemann C . Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Hum Mol Genet. 2003; 12(11):1211-21. DOI: 10.1093/hmg/ddg146. View

16.

Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C . The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2005; 8(1):27-36. DOI: 10.1038/ncb1339. View

17.

McCall C, Miliani de Marval P, Chastain 2nd P, Jackson S, He Y, Kotake Y . Human immunodeficiency virus type 1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development. Mol Cell Biol. 2008; 28(18):5621-33. PMC: 2546929. DOI: 10.1128/MCB.00232-08. View

18.

Bretscher A, Edwards K, Fehon R . ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002; 3(8):586-99. DOI: 10.1038/nrm882. View

19.

Shaw R, Paez J, Curto M, Yaktine A, Pruitt W, Saotome I . The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell. 2001; 1(1):63-72. DOI: 10.1016/s1534-5807(01)00009-0. View

20.

Liu L, Lee S, Zhang J, Peters S, Hannah J, Zhang Y . CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis. Mol Cell. 2009; 34(4):451-60. PMC: 2722740. DOI: 10.1016/j.molcel.2009.04.020. View