Merlin/NF2 Functions Upstream of the Nuclear E3 Ubiquitin Ligase CRL4(DCAF1) to Suppress Oncogenic Gene Expression
ABSTRACT 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).
[Show abstract] [Hide abstract]
ABSTRACT: Background Intramedullary ependymomas are rare and benign tumors in the adult. Little is known about their physiopathology, but the implication of the NF2 gene is suspected because of their presence in a third of patients with type 2 neurofibromatosis (NF2), a disorder caused by mutation of the NF2 gene.Methods We conducted a clinical and genetic study of a family in which 5 of 9 members suffered from intramedullary ependymoma. Karyotyping and CGH array analysis were performed on DNA from peripheral blood lymphocytes from affected participants. The NF2 gene sequences were then determined in DNA from 3 nonaffected and all 5 affected members of the family.ResultsKaryotype and CGH array findings were normal. Sequencing of NF2 revealed a heterozygous deletion, c.811-39_841del69bp, at the intron 8/exon 9 junction, in all affected members that was absent from all nonaffected members. RT-PCR analysis and sequencing revealed a novel NF2 transcript characterized by a skipping of exon 9 (75 bp). This deletion is predicted to result in a 25-amino acid deletion in the N-terminal FERM domain of neurofibromin 2. Modeling of this mutant domain suggests possible disorganization of the subdomain C.Conclusion We report the first family with an NF2 mutation associated with intramedullary ependymomas without other features of NF2 syndrome. This mutation, which has not been described previously, may particularly affect the function of neurofibromin 2 in ependymocytes leading to the development of intramedullary WHO grade II ependymomas. We propose that sporadic intramedullary ependymomas should also be analyzed for this region of NF2 gene.Neuro-Oncology 12/2013; 16(2). DOI:10.1093/neuonc/not165 · 5.29 Impact Factor
Article: Schwannomas and Their Pathogenesis[Show abstract] [Hide abstract]
ABSTRACT: Schwannomas may occur spontaneously, or in the context of a familial tumor syndrome such as neurofibromatosis type 2, schwannomatosis and Carney's complex. Schwannomas have a variety of morphological appearances, but they behave as WHO grade I tumors, and only very rarely undergo malignant transformation. Central to the pathogenesis of these tumors is loss of function of merlin, either by direct genetic change involving the NF2 gene on chromosome 22, or secondarily to merlin inactivation. The genetic pathways and morphological features of schwannomas associated with the different genetic syndromes will be discussed. Merlin has multiple functions, including within the nucleus and at the cell membrane, and this review summarises our current understanding of the mechanisms by which merlin loss is involved in schwannoma pathogenesis, highlighting potential areas for therapeutic intervention.Brain Pathology 01/2014; 24(3). DOI:10.1111/bpa.12125 · 4.35 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The p-21-activated kinases (PAKs) are downstream effectors of Rho GTPases Rac and Cdc42. The PAK family consists of six members which are segregated into two subgroups (Group I and Group II) based on sequence homology. Group I PAKs (PAK1-3) are the most extensively studied but there is increasing interest in the functionality of Group II PAKs (PAK4-6). The PAK family proteins are thought to play an important role in many different cellular processes, some of which have particular significance in the context of cancer progression. This review explores established and more recent data, linking the PAK family kinases to cancer progression including expression profiles, evasion of apoptosis, promotion of cell survival, and regulation of cell invasion. Finally, we discuss attempts to therapeutically target the PAK family and outline the major obstacles that still need to be overcome.International review of cell and molecular biology 01/2014; 309C:347-387. DOI:10.1016/B978-0-12-800255-1.00007-7 · 4.52 Impact Factor