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Cancer Research 67, 520, January 15, 2007. doi: 10.1158/0008-5472.CAN-06-1608
© 2007 American Association for Cancer Research

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Cell, Tumor, and Stem Cell Biology

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

Helen Morrison1,2, Tobias Sperka1,2, Jan Manent3, Marco Giovannini3, Helmut Ponta2 and Peter Herrlich1,2

1 Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; 2 Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Karlsruhe, Germany; and 3 Institut National de la Sante et de la Recherche Medicale U674 "Génomique Fonctionnelle des Tumeurs Solides," Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France

Requests for reprints: Helen Morrison, Institute of Age Research, Fritz-Lipmann-Institute, Herrlich Group, Beutenbergstr. 11, 07745 Jena, Germany. Phone: 49-3641-656139; E-mail: Helen{at}fli-leibniz.de.

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 tumor-suppressor 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 Rac-dependent signal transfer represents part of the tumor-suppressive action of merlin. [Cancer Res 2007;67(2):520–7]




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Copyright © 2007 by the American Association for Cancer Research.