This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stickney, J. T. Articles by Ip, W. Search for Related Content PubMed PubMed Citation Articles by Stickney, J. T. Articles by Ip, W.

Activation of the Tumor Suppressor Merlin Modulates Its Interaction with Lipid Rafts

Department of Cell Biology, Neurobiology, and Anatomy, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio

Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by bilateral schwannomas of the eighth cranial nerve. The NF2 tumor suppressor protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane/F-actin linkers. Merlin resists solubilization by the detergent Triton X-100 (TX-100), a property commonly attributed to association with the cytoskeleton. Accordingly, NF2 patient mutations that encode merlins with enhanced TX-100 solubility have been explained previously in terms of loss of cytoskeletal attachment. However, here we present data to suggest that the detergent resistance of merlin is a result of its constitutive residence in lipid rafts. Furthermore, when cells are grown to high density, merlin shifts to a more buoyant lipid raft fraction in a density gradient. This shift is mimicked in subconfluent cells treated with cytochalasin D, suggesting that the shift results from merlin dissociation from the actin cytoskeleton, but not from lipid rafts. Intramolecular NH₂- and COOH-terminal binding, which occurs when merlin transitions to the growth-suppressive form, also brings about a similar change in buoyant density. Our results suggest that constitutive residence of merlin in lipid rafts is crucial for its function and that as merlin becomes growth suppressive in vivo, one significant molecular event may be the loss of interaction with the actin cytoskeleton. To our knowledge, merlin is the first tumor suppressor known to reside within lipid rafts, and the significance of this finding is underscored by known loss-of-function NF2 patient mutations that encode merlins with enhanced TX-100 solubility.

This article has been cited by other articles:

				N. Denisenko, C. Cifuentes-Diaz, T. Irinopoulou, M. Carnaud, E. Benoit, M. Niwa-Kawakita, F. Chareyre, M. Giovannini, J.-A. Girault, and L. Goutebroze Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves J. Neurosci., October 15, 2008; 28(42): 10472 - 10481. [Abstract] [Full Text] [PDF]

				M. Beneteau, M. Pizon, B. Chaigne-Delalande, S. Daburon, P. Moreau, F. De Giorgi, F. Ichas, A. Rebillard, M.-T. Dimanche-Boitrel, J.-L. Taupin, et al. Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway Mol. Cancer Res., April 1, 2008; 6(4): 604 - 613. [Abstract] [Full Text] [PDF]

				B. K. Cole, M. Curto, A. W. Chan, and A. I. McClatchey Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing Mol. Cell. Biol., February 15, 2008; 28(4): 1274 - 1284. [Abstract] [Full Text] [PDF]

				D. Delacour, A. Koch, W. Ackermann, I. E.-L. Parco, H.-P. Elsasser, F. Poirier, and R. Jacob Loss of galectin-3 impairs membrane polarisation of mouse enterocytes in vivo J. Cell Sci., February 15, 2008; 121(4): 458 - 465. [Abstract] [Full Text] [PDF]

				M. Curto, B. K. Cole, D. Lallemand, C.-H. Liu, and A. I. McClatchey Contact-dependent inhibition of EGFR signaling by Nf2/Merlin J. Cell Biol., June 21, 2007; 177(5): 893 - 903. [Abstract] [Full Text] [PDF]

				S. P. Thankamony and W. Knudson Acylation of CD44 and Its Association with Lipid Rafts Are Required for Receptor and Hyaluronan Endocytosis J. Biol. Chem., November 10, 2006; 281(45): 34601 - 34609. [Abstract] [Full Text] [PDF]

				K. A. Schachter, Y. Du, A. Lin, and K. A. Gallo Dynamic Positive Feedback Phosphorylation of Mixed Lineage Kinase 3 by JNK Reversibly Regulates Its Distribution to Triton-soluble Domains J. Biol. Chem., July 14, 2006; 281(28): 19134 - 19144. [Abstract] [Full Text] [PDF]

				T. Okada, M. Lopez-Lago, and F. G. Giancotti Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane J. Cell Biol., October 24, 2005; 171(2): 361 - 371. [Abstract] [Full Text] [PDF]

				A. I. McClatchey and M. Giovannini Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin Genes & Dev., October 1, 2005; 19(19): 2265 - 2277. [Abstract] [Full Text] [PDF]

				M. Schleicher, F. Brundin, S. Gross, W. Muller-Esterl, and S. Oess Cell Cycle-Regulated Inactivation of Endothelial NO Synthase through NOSIP-Dependent Targeting to the Cytoskeleton Mol. Cell. Biol., September 15, 2005; 25(18): 8251 - 8258. [Abstract] [Full Text] [PDF]