Merlin/Neurofibromatosis Type 2 Suppresses Growth by Inhibiting the Activation of Ras and Rac

Abstract

The small G-protein Ras is a tightly controlled regulator of cell fate. Prolonged or persistent arrest in the activated GTP-loaded state by mutation of Ras as in lung cancer or in a Ras-GTPase-activating protein as in neurofibromatosis type 1 promotes tumorigenesis. We now show that the tumorsuppressor protein merlin (mutated in neurofibromatosis type 2) also controls Ras activity. Systematic analysis of growth factor signaling located the step of merlin interference to the activation of Ras and Rac. Merlin independently uncouples both Ras and Rac from growth factor signals. In the case of Ras, merlin acts downstream of the receptor tyrosine kinase-growth factor receptor binding protein 2 (Grb2)-SOS complex. However, merlin does not bind either SOS or Ras, but it counteracts the ERM (ezrin, radixin, moesin)-dependent activation of Ras, which correlates with the formation of a complex comprising ERM proteins, Grb2, SOS, Ras, and filamentous actin. Because efficient signaling from Ras requires Rac-p21-activated kinase-dependent phosphorylations of Raf and mitogen-activated protein/extracellular signal-regulated kinase kinase, merlin can also inhibit signal transfer from dominantly active Ras mutants. We propose that the interference of merlin with Ras-and Racdependent signal transfer represents part of the tumorsuppressive action of merlin. [Cancer Res 2007;67(2):520-7]

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

“…Merlin has been suggested to restrain tumor growth through inhibiting Rac and ERK activities (Shaw et al, 2001;Kissil et al, 2003;Okada et al, 2005;Morrison et al, 2007). To further substantiate a role of VprBP in Merlin function regulation, we tested whether Rac and ERK activities might be altered in VprBP-depleted cells.…”

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

“…Schwannomas are the most frequent merlin-deficient tumours. Merlin belongs to the ERM (ezrin-radixin-moesin) family proteins (Rouleau et al, 1993;Bretscher et al, 2002) connecting actin cytoskeleton and membrane proteins and is crucial for the regulation of signalling pathways for maintaining normal cell function (Morrison et al, 2007;Okada et al, 2007;McClatchey and Fehon, 2009). Currently, there is no medical treatment for merlin-deficient tumours.…”

An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth

“…The volume calculation algorithm in OsiriX was used to obtain a threedimensional tumor volumetric measurement (mm 3 ) complex region, using the SC4-9 cell line. SC4-9 has become a standard model in NF2 research since it recapitulates signalling network signatures of human and mouse NF2 schwannomas [19,21,25,26], with high grafting efficiency when orthotopically injected into the sciatic nerves of immunodeficient NU/NU mice [34]. We found that the microsurgical approach successfully targeted the anatomic location where human VS predominantly arise and tumor development could be monitored by in vivo imaging.…”

“…The SC4 Schwann cell line was derived from adeno-Creinfected, spontaneously transformed Schwann cells isolated from adult Nf2 KO3/flox2 mouse sciatic nerve in the FVB/N background [18][19][20][21]. SC4 cells were transfected with a plasmid encoding a fusion EGFP-luciferase gene under the control of the CMV promoter, and stable cell clones were selected using cell sorting.…”

“…For the cell-derived allograft in this study we chose the SC4 cell line that has become a standard in NF2 basic and preclinical research [21,25,26]. SC4 cells were labeled with luciferase so that in vivo bioluminescence imaging could be applied to longitudinally monitor orthotopic tumor growth across the study.…”