Merlin/NF2 Functions Upstream of the Nuclear E3 Ubiquitin Ligase CRL4(DCAF1) to Suppress Oncogenic Gene Expression

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Science Signaling (Impact Factor: 6.28). 08/2011; 4(188):pt6. DOI: 10.1126/scisignal.2002314
Source: PubMed


Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain-containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL4(DCAF1) to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL4(DCAF1) and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).

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Available from: Hediye Erdjument-Bromage, May 05, 2015
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    • "It has been demonstrated that Merlin-deficient tumors are frequent and can be multiple in certain patients [1] [7]. The tumor suppressor Merlin is a regulatory mediator of the cell cycle [8] [9] [10]. Its deficiency has initially been associated with neurofibromatosis-2 (NF-2) [9] [10] [11]. "
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    • "A number of FERM containing proteins such as kindlins (-1, -2, and -3) localize to the nucleus (Frame et al., 2010). Although not all of them have specific roles identified in the nucleus, Merlin encoded by the neurofibromatosis type 2 (NF2) gene suppresses ubiquitin E3 ligase CRL4 DCAF1 in the nucleus inhibits cell proliferation (Cooper et al., 2011). Prototype FERM proteins such as ezrin, radixin, and moesin (ERMs) are also found in the nucleus, however, the role of these proteins in the nucleus remains unclear. "
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