Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation

Fraenzer, Juergen-Theodor; Pan, Huiqi; Minimo, Lauro; Smith, George M.; Knauer, Dan; Hung, Gene

doi:10.3892/ijo.23.6.1493

Cited by 63 publications

(83 citation statements)

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“…Interestingly, in a schwannoma cell line, merlin regulates membrane levels of PDGFR-b by inducing its degradation (Fraenzer et al, 2003), revealing an additional degree of complexity in merlin regulation of growth factor steady state levels. ERM proteins also are implicated in vesicular trafficking (Pujuguet et al, 2003;Deretic et al, 2004;Stanasila et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Merlin inhibits the proliferation of many different cell types, although the proposed mechanisms vary considerably. Merlin was shown to downregulate a wide range of mitogenic signaling pathways, such as Ras, Rac or PI3K (Fraenzer et al, 2003;Kissil et al, 2003;Lim et al, 2003;Hirokawa et al, 2004;McClatchey and Giovannini, 2005;Morrison et al, 2007). Moreover, Nf2 inactivation results in destabilization of adherens junctions (AJs) that are essential for contact inhibition of proliferation in mouse embryonic fibroblasts (MEFs) (Lallemand et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, merlin can block ligandinduced epidermal growth factor receptor internalization and signaling in various cell types (Curto et al, 2007). In a rat schwannoma cells, merlin also inhibits growth by promoting platelet-derived growth factor receptor (PDGFR) degradation (Fraenzer et al, 2003). Finally, in Drosophila, D-Merlin and Expanded cooperate to stimulate endocytosis of membrane proteins, such as Notch and epidermal growth factor receptor, thereby reducing their levels at the cell surface and inhibiting downstream signaling (Maitra et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

et al. 2008

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The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cellto-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and plateletderived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

et al. 2008

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“…To study schwannoma pathobiology and define therapeutic targets, we used our human in vitro model for schwannoma. We showed that plateletderived growth factor receptor b (PDGFRb) and ErbB2/3 are overexpressed/activated in schwannoma in vitro and in vivo leading to strong/long-lasting activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT (Fraenzer et al, 2003;Ammoun et al, 2008Ammoun et al, , 2010aHilton et al, 2009). ERK1/2 activation increases schwannoma proliferation (Ammoun et al, 2008(Ammoun et al, , 2010b.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via b1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin b1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of antiapoptotic AKT. Thus, IGFBP-1/integrin b1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.

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“…Two signal transduction pathways that are commonly implicated in mediating cell cycle progression through G 1 are the MAPK and PI3K/Akt pathways. The 4.1 family members ezrin and merlin have been shown to regulate these signaling cascades (Gautreau et al, 1999;Fraenzer et al, 2003). In addition, DAL-1 can induce JNK phosphorylation in IOMM-Lee meningioma cells (Robb et al, 2005).…”

Section: Protein 41b Does Not Mediate Its Growth Inhibitory Effect Tmentioning

confidence: 99%

Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation

et al. 2005

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4.1B is a member of the protein 4.1 superfamily of proteins that link transmembrane proteins to the actin cytoskeleton. The 4.1B gene localizes to chromosome 18p11.3, which undergoes loss of heterozygosity in mammary tumors. Here, we examine the expression of 4.1B in murine mammary epithelium and find that 4.1B is dramatically upregulated in mammary epithelial cells during pregnancy when there is extensive cell proliferation. In contrast, 4.1B is not expressed in virgin, lactating, or involuting mammary epithelium. To examine the consequence of 4.1B loss on mammary epithelial cell proliferation, we analysed mammary glands in 4.1B-null mice. 4.1B loss results in a significant increase in mammary epithelial cell proliferation during pregnancy, but has no effect on mammary epithelial cell proliferation, in virgin or involuting mice. Furthermore, we show that 4.1B inhibits the proliferation of mammary epithelial cell lines by inducing a G 1 cell cycle arrest, characterized by decreased cyclin A expression and reduced Rb phosphorylation, and accompanied by reduced erbB2 phosphorylation. This cell cycle arrest does not involve alterations in the activities of MAPK, JNK, or Akt. Collectively, our findings demonstrate that 4.1B regulates mammary epithelial cell proliferation during pregnancy and suggest that its loss may influence mammary carcinoma pathogenesis in multiparous women.

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Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation

Cited by 63 publications

References 0 publications

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation

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