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Merlin/NF2 Tumor Suppressor and Ezrin–Radixin–Moesin (ERM) Proteins in Cancer Development and Progression

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Cancer Genome and Tumor Microenvironment

Part of the book series: Cancer Genetics ((CANGENETICS))

Abstract

The first evidence that mutations in the NF2 (a.k.a. merlin) gene cause neurofibromatosis II was obtained over 15 years ago (Rouleau et al. 1993; Trofatter et al. 1993). The hallmark of this disorder is the occurrence of schwannomas and other central nervous system tumors, such as multiple meningiomas. Both somatic and germline mutations were discovered in NF2 patients and in NF2-related tumors. Loss of the wild-type allele was demonstrated in 75% of all neoplasms, suggesting that NF2 is indeed a classical tumor suppressor. Curiously, no consistent or recurrent mutations have been identified in the genes encoding closely related ERM (ezrin–radixin–moesin) protein genes. There is a single known case of anaplastic large-cell lymphoma, where a fusion protein of truncated moesin and anaplastic lymphoma kinase was identified (Tort et al. 2001). However, ERM proteins are important regulators of the Rho GTPases (see Chapter Chapter 4), firmly implicating them in the control of cancer cell motility and invasion.

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References

  • Alfthan K, Heiska L, Gronholm M, Renkema GH, Carpen O (2004) Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin–ezrin heterodimerization. J Biol Chem 279:18559–18566.

    Article  PubMed  CAS  Google Scholar 

  • Allenspach EJ, Cullinan P, Tong J, Tang Q, Tesciuba AG, Cannon JL, Takahashi SM, Morgan R, Burkhardt JK, Sperling AI (2001) ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 15:739–750.

    Article  PubMed  CAS  Google Scholar 

  • Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157:1233–1245.

    Article  PubMed  CAS  Google Scholar 

  • Batchelor CL, Woodward AM, Crouch DH (2004) Nuclear ERM (ezrin, radixin, moesin) proteins: Regulation by cell density and nuclear import. Exp Cell Res 296:208–222.

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner M et al. (2006) The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors. Proc Natl Acad Sci U S A 103:13391–13396.

    Article  PubMed  CAS  Google Scholar 

  • Belbin TJ, Singh B, Smith RV, Socci ND, Wreesmann VB, Sanchez-Carbayo M, Masterson J, Patel S, Cordon-Cardo C, Prystowsky MB, Childs G (2005) Molecular profiling of tumor progression in head and neck cancer. Arch Otolaryngol Head Neck Surg 131:10–18.

    Article  PubMed  Google Scholar 

  • Berryman M, Franck Z, Bretscher A (1993) Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci 105 ( Pt 4):1025–1043.

    PubMed  CAS  Google Scholar 

  • Bonilha VL, Finnemann SC, Rodriguez-Boulan E (1999) Ezrin promotes morphogenesis of apical microvilli and basal infoldings in retinal pigment epithelium. J Cell Boil 147:1533–1548.

    Article  PubMed  CAS  Google Scholar 

  • Brault E, Gautreau A, Lamarine M, Callebaut I, Thomas G, Goutebroze L (2001) Normal membrane localization and actin association of the NF2 tumor suppressor protein are dependent on folding of its N-terminal domain. J Cell Sci 114:1901–1912.

    PubMed  CAS  Google Scholar 

  • Bretscher A (1983) Purification of an 80,000-dalton protein that is a component of the isolated microvillus cytoskeleton, and its localization in nonmuscle cells. J Cell Biol 97:425–432.

    Article  PubMed  CAS  Google Scholar 

  • Bretscher A (1989) Rapid phosphorylation and reorganization of ezrin and spectrin accompany morphological changes induced in A-431 cells by epidermal growth factor. J Cell Biol 108:921–930.

    Article  PubMed  CAS  Google Scholar 

  • Bruce B, Khanna G, Ren L, Landberg G, Jirström K, Powell C, Borczuk A, Keller ET, Wojno KJ, Meltzer P, Baird K, McClatchey A, Bretscher A, Hewitt SM, Khanna C (2007) Expression of the cytoskeleton linker protein ezrin in human cancers. Clin Exp Metastasis 24:69–78.

    Article  PubMed  CAS  Google Scholar 

  • Cant SH and Pitcher JA (2005) G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton. Mol Biol Cell 16:3088–3099.

    Article  PubMed  CAS  Google Scholar 

  • Castelo L, Jay DG (1999) Radixin is involved in lamellipodial stability during nerve growth cone motility. Mol Biol Cell 10:1511–1520.

    PubMed  CAS  Google Scholar 

  • Cha B, Tse M, Yun C, Kovbasnjuk O, Mohan S, Hubbard A, Arpin M, Donowitz M (2006) The NHE3 juxtamembrane cytoplasmic domain directly binds ezrin: Dual role in NHE3 trafficking and mobility in the brush border. Mol Biol Cell 17:2661–2673.

    Article  PubMed  CAS  Google Scholar 

  • Chen J and Mandel LJ (1997) Unopposed phosphatase action initiates ezrin dysfunction: A potential mechanism for anoxic injury. Am J Physiol 273:C710–716.

    PubMed  CAS  Google Scholar 

  • Chen J, Doctor RB, Mandel LJ (1994) Cytoskeletal dissociation of ezrin during renal anoxia: Role in microvillar injury. Am J Physiol 267:C784–795.

    PubMed  CAS  Google Scholar 

  • Claudio JO, Lutchman M, Rouleau GA (1995) Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene. Neuroreport 6:1942–1946.

    Article  PubMed  CAS  Google Scholar 

  • Crepaldi T, Gautreau A, Comoglio PM, Louvard D, Arpin M (1997) Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J Cell Biol 138:423–434.

    Article  PubMed  CAS  Google Scholar 

  • Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI (2007) Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J Cell Biol 177:893–903.

    Article  PubMed  CAS  Google Scholar 

  • Das V, Nal B, Roumier A, Meas-Yedid V, Zimmer C, Olivo-Marin JC, Roux P, Ferrier P, Dautry-Varsat A, Alcover A (2002) Membrane–cytoskeleton interactions during the formation of the immunological synapse and subsequent T-cell activation. Immunol Rev 189:123–135.

    Article  PubMed  CAS  Google Scholar 

  • Delon J, Kaibuchi K, Germain RN (2001) Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin. Immunity 15:691–701.

    Article  PubMed  CAS  Google Scholar 

  • DeSimone PA, East R, Powell RD, Jr. (1980) Phagocytic tumor cell activity in oat cell carcinoma of the lung. Hum Pathol 11:535–539.

    PubMed  CAS  Google Scholar 

  • Doi Y, Itoh M, Yonemura S, Ishihara S, Takano H, Noda T, Tsukita S (1999) Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout. J Biol Chem 274:2315–2321.

    Article  PubMed  CAS  Google Scholar 

  • Donowitz M, Cha B, Zachos NC, Brett CL, Sharma A, Tse CM, Li X (2005) NHERF family and NHE3 regulation. J Physiol 567:3–11.

    Article  PubMed  CAS  Google Scholar 

  • Dransfield DT, Bradford AJ, Smith J, Martin M, Roy C, Mangeat PH, Goldenring JR. (1997) Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. Embo J 16:35–43.

    Article  PubMed  CAS  Google Scholar 

  • Elliott BE, Qiao H, Louvard D, Arpin M (2004) Co-operative effect of c-Src and ezrin in deregulation of cell–cell contacts and scattering of mammary carcinoma cells. J Cell Biochem 92:16–28.

    Article  PubMed  CAS  Google Scholar 

  • Fais S (2007) Cannibalism: A way to feed on metastatic tumors. Cancer Lett 258:155–164.

    Article  PubMed  CAS  Google Scholar 

  • Fazioli F, Wong WT, Ullrich SJ, Sakaguchi K, Appella E, Di Fiore PP (1993) The ezrin-like family of tyrosine kinase substrates: Receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation. Oncogene 8:1335–1345.

    PubMed  CAS  Google Scholar 

  • Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M (2004) Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol 164:653–659.

    Article  PubMed  CAS  Google Scholar 

  • Fievet B, Louvard D, Arpin M (2007) ERM proteins in epithelial cell organization and functions. Biochim Biophys Acta 1773:653–660.

    Article  PubMed  CAS  Google Scholar 

  • Fukata Y, Kimura K, Oshiro N, Saya H, Matsuura Y, Kaibuchi K (1998) Association of the myosin-binding subunit of myosin phosphatase and moesin: Dual regulation of moesin phosphorylation by Rho-associated kinase and myosin phosphatase. J Cell Biol 141:409–418.

    Article  PubMed  CAS  Google Scholar 

  • Funayama N, Nagafuchi A, Sato N, Tsukita S (1991) Radixin is a novel member of the band 4.1 family. J Cell Biol 115:1039–1048.

    Article  PubMed  CAS  Google Scholar 

  • Gautreau A, Poullet P, Louvard D, Arpin M (1999) Ezrin, a plasma membrane–microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 96:7300–7305.

    Article  PubMed  CAS  Google Scholar 

  • Gautreau A, Louvard D, Arpin M (2002) ERM proteins and NF2 tumor suppressor: The Yin and Yang of cortical actin organization and cell growth signaling. Curr Opin Cell Biol 14:104–109.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Agosti C, Wiederhold T, Herndon ME, Gusella J, Ramesh V (1999) Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE-RF. J Biol Chem 274:34438–34442.

    Article  PubMed  CAS  Google Scholar 

  • Gould KL, Cooper JA, Bretscher A, Hunter T (1986) The protein-tyrosine kinase substrate, p81, is homologous to a chicken microvillar core protein. J Cell Biol 102:660–669.

    Article  PubMed  CAS  Google Scholar 

  • Gronholm M, Sainio M, Zhao F, Heiska L, Vaheri A, Carpen O (1999) Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. J Cell Sci 112 ( Pt 6):895–904.

    PubMed  CAS  Google Scholar 

  • Gronholm M, Vossebein L, Carlson CR, Kuja-Panula J, Teesalu T, Alfthan K, Vaheri A, Rauvala H, Herberg FW, Taskén K, Carpén O (2003) Merlin links to the cAMP neuronal signaling pathway by anchoring the RIbeta subunit of protein kinase A. J Biol Chem 278:41167–41172.

    Article  PubMed  CAS  Google Scholar 

  • Haase VH, Trofatter JA, MacCollin M, Tarttelin E, Gusella JF, Ramesh V (1994) The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms. Hum Mol Genet 3:407–411.

    Article  PubMed  CAS  Google Scholar 

  • Hamada K, Shimizu T, Matsui T, Tsukita S, Hakoshima T (2000) Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain. Embo J 19:4449–4462.

    Article  PubMed  CAS  Google Scholar 

  • Heiska L, Alfthan K, Gronholm M, Vilja P, Vaheri A, Carpen O (1998) Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. J Biol Chem 273:21893–21900.

    Article  PubMed  CAS  Google Scholar 

  • Hipfner DR, Keller N, Cohen SM (2004) Slik Sterile-20 kinase regulates Moesin activity to promote epithelial integrity during tissue growth. Genes Dev 18:2243–2248.

    Article  PubMed  CAS  Google Scholar 

  • Huynh DP, Tran TM, Nechiporuk T, Pulst SM (1996) Expression of neurofibromatosis 2 transcript and gene product during mouse fetal development. Cell Growth Differ 7:1551–1561.

    PubMed  CAS  Google Scholar 

  • Ilani T, Khanna C, Zhou M, Veenstra TD, Bretscher A (2007) Immune synapse formation requires ZAP-70 recruitment by ezrin and CD43 removal by moesin. J Cell Biol 179:733–746.

    Article  PubMed  CAS  Google Scholar 

  • Ilmonen S, Vaheri A, Asko-Seljavaara S, Carpen O (2005) Ezrin in primary cutaneous melanoma. Mod Pathol 18:503–510.

    Article  PubMed  CAS  Google Scholar 

  • James MF, Manchanda N, Gonzalez-Agosti C, Hartwig JH, Ramesh V (2001) The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association. Biochem J 356:377–386.

    Article  PubMed  CAS  Google Scholar 

  • Jankovics F, Sinka R, Lukacsovich T, Erdelyi M (2002) MOESIN crosslinks actin and cell membrane in Drosophila oocytes and is required for OSKAR anchoring. Curr Biol 12:2060–2065.

    Article  PubMed  CAS  Google Scholar 

  • Jensen PV and Larsson LI (2004) Actin microdomains on endothelial cells: Association with CD44, ERM proteins, and signaling molecules during quiescence and wound healing. Histochem Cell Biol 121:361–369.

    Article  PubMed  CAS  Google Scholar 

  • Jin H, Sperka T, Herrlich P, Morrison H (2006) Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature 442:576–579.

    Article  PubMed  CAS  Google Scholar 

  • Khanna C, Khan J, Nguyen P, Prehn J, Caylor J, Yeung C, Trepel J, Meltzer P, Helman L (2001) Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res 61:3750–3759.

    PubMed  CAS  Google Scholar 

  • Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ (2004) The membrane–cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10:182–186.

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi S, Hata M, Fukumoto K, Yamane Y, Matsui T, Tamura A, Yonemura S, Yamagishi H, Keppler D, Tsukita S, Tsukita S (2002) Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat Genet 31:320–325.

    Article  PubMed  CAS  Google Scholar 

  • Kishore R, Qin G, Luedemann C, Bord E, Hanley A, Silver M, Gavin M, Yoon YS, Goukassian D, Losordo DW (2005) The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A. J Clin Invest 115(7):1785–1796.

    Article  PubMed  CAS  Google Scholar 

  • Kissil JL, Johnson KC, Eckman MS, Jacks T (2002) Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem 277:10394–10399.

    Article  PubMed  CAS  Google Scholar 

  • Kitajiri S, Fukumoto K, Hata M, Sasaki H, Katsuno T, Nakagawa T, Ito J, Tsukita S, Tsukita S (2004) Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. J Cell Biol 166:559–570.

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Takeuchi K, Doi Y, Yonemura S, Nagata S, Tsukita S (1997) ERM (ezrin/radixin/ moesin)-based molecular mechanism of microvillar breakdown at an early stage of apoptosis. J Cell Biol 139:749–758.

    Article  PubMed  CAS  Google Scholar 

  • Kotani H, Takaishi K, Sasaki T, Takai Y (1997) Rho regulates association of both the ERM family and vinculin with the plasma membrane in MDCK cells. Oncogene 14:1705–1713.

    Article  PubMed  CAS  Google Scholar 

  • Kressel M and Schmucker B (2002) Nucleocytoplasmic transfer of the NF2 tumor suppressor protein merlin is regulated by exon 2 and a CRM1-dependent nuclear export signal in exon 15. Hum Mol Genet 11:2269–2278.

    Article  PubMed  CAS  Google Scholar 

  • Krieg J and Hunter T (1992) Identification of the two major epidermal growth factor-induced tyrosine phosphorylation sites in the microvillar core protein ezrin. J Biol Chem 267:19258–19265.

    PubMed  CAS  Google Scholar 

  • Krishnan K, Bruce B, Hewitt S, Thomas D, Khanna C, Helman LJ (2006) Ezrin mediates growth and survival in Ewing’s sarcoma through the AKT/mTOR, but not the MAPK, signaling pathway. Clin Exp Metastasis 23:227–236.

    Article  PubMed  CAS  Google Scholar 

  • LaJeunesse DR, McCartney BM, Fehon RG (1998) Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization. J Cell Biol 141:1589–1599.

    Article  PubMed  CAS  Google Scholar 

  • Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI (2003) NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev 17:1090–1100.

    Article  PubMed  CAS  Google Scholar 

  • Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, Hall A (2000) The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2:281–287.

    Article  PubMed  CAS  Google Scholar 

  • Lamprecht G, Weinman EJ, Yun CH (1998) The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3. J Biol Chem 273:29972–29978.

    Article  PubMed  CAS  Google Scholar 

  • Legg JW and Isacke CM (1998) Identification and functional analysis of the ezrin-binding site in the hyaluronan receptor, CD44. Curr Biol 8:705–708.

    Article  PubMed  CAS  Google Scholar 

  • Legg JW, Lewis CA, Parsons M, Ng T, Isacke CM (2002) A novel PKC-regulated mechanism controls CD44 ezrin association and directional cell motility. Nat Cell Biol 4:399–407.

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Wu M, Wang H, Xu G, Zhu T, Zhang Y, Liu P, Song A, Gang C, Han Z, Zhou J, Meng L, Lu Y, Wang S, Ma D (2008) Ezrin silencing by small hairpin RNA reverses metastatic behaviors of human breast cancer cells. Cancer Lett 261:55–63.

    Article  PubMed  CAS  Google Scholar 

  • Liu D, Ge L, Wang F, Takahashi H, Wang D, Guo Z, Yoshimura SH, Ward T, Ding X, Takeyasu K, Yao X (2007) Single-molecule detection of phosphorylation-induced plasticity changes during erzin activation. FEBS Lett 581:3563–3571.

    Article  PubMed  CAS  Google Scholar 

  • Lozupone F, Lugini L, Matarrese P, Luciani F, Federici C, Iessi E, Margutti P, Stassi G, Malorni W, Fais S (2004) Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J Biol Chem 279:9199–9207.

    Article  PubMed  CAS  Google Scholar 

  • Lugini L, Lozupone F, Matarrese P, Funaro C, Luciani F, Malorni W, Rivoltini L, Castelli C, Tinari A, Piris A, Parmiani G, Fais S (2003) Potent phagocytic activity discriminates metastatic and primary human malignant melanomas: A key role of ezrin. Lab Invest 83:1555–1567.

    Article  PubMed  CAS  Google Scholar 

  • Madan R, Brandwein-Gensler M, Schlecht NF, Elias K, Gorbovitsky E, Belbin TJ, Mahmood R, Breining D, Qian H, Childs G, Locker J, Smith R, Haigentz M Jr, Gunn-Moore F, Prystowsky MB (2006) Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues: Cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma. Head Neck 28:1018–1027.

    Article  PubMed  Google Scholar 

  • Maitra S, Kulikauskas RM, Gavilan H, Fehon RG (2006) The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol 16:702–709.

    Article  PubMed  CAS  Google Scholar 

  • Majander-Nordenswan P et al. (1998) Genomic structure of the human ezrin gene. Hum Genet 103:662–665.

    Article  PubMed  CAS  Google Scholar 

  • Makitie T, Carpen O, Vaheri A, Kivela T (2001) Ezrin as a prognostic indicator and its relationship to tumor characteristics in uveal malignant melanoma. Invest Ophthalmol Vis Sci 42:2442–2449.

    PubMed  CAS  Google Scholar 

  • Marin-Padilla M (1977) Erythrophagocytosis by epithelial cells of a breast carcinoma. Cancer 39:1085–1089.

    Article  PubMed  CAS  Google Scholar 

  • Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S, Tsukita S (1998) Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol 140:647–657.

    Article  PubMed  CAS  Google Scholar 

  • Matsui T, Yonemura S, Tsukita S (1999) Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinases. Curr Biol 9:1259–1262.

    Article  PubMed  CAS  Google Scholar 

  • McCartney BM and Fehon RG (1996) Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J Cell Biol 133:843–852.

    Article  PubMed  CAS  Google Scholar 

  • McClatchey AI and Giovannini M (2005) Membrane organization and tumorigenesis–the NF2 tumor suppressor, Merlin. Genes Dev 19:2265–2277.

    Article  PubMed  CAS  Google Scholar 

  • McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T (1997) The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev 11:1253–1265.

    Article  PubMed  CAS  Google Scholar 

  • McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, Jacks T (1998) Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev 12:1121–1133.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin ME, Kruger GM, Slocum KL, Crowley D, Michaud NA, Huang J, Magendantz M, Jacks T (2007) The Nf2 tumor suppressor regulates cell–cell adhesion during tissue fusion. Proc Natl Acad Sci U S A 104:3261–3266.

    Article  PubMed  CAS  Google Scholar 

  • Moilanen J, Lassus H, Leminen A, Vaheri A, Butzow R, Carpen O (2003) Ezrin immunoreactivity in relation to survival in serous ovarian carcinoma patients. Gynecol Oncol 90:273–281.

    Article  PubMed  CAS  Google Scholar 

  • Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H, Herrlich P (2001) The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 15:968–980.

    Article  PubMed  CAS  Google Scholar 

  • Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P (2007) Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res 67:520–527.

    Article  PubMed  CAS  Google Scholar 

  • Muranen T, Gronholm M, Renkema GH, Carpen O (2005) Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. Oncogene 24:1150–1158.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura N, Oshiro N, Fukata Y, Amano M, Fukata M, Kuroda S, Matsuura Y, Leung T, Lim L, Kaibuchi K (2000) Phosphorylation of ERM proteins at filopodia induced by Cdc42. Genes Cells 5:571–581.

    Article  PubMed  CAS  Google Scholar 

  • Ng T, Parsons M, Hughes WE, Monypenny J, Zicha D, Gautreau A, Arpin M, Gschmeissner S, Verveer PJ, Bastiaens PI, Parker PJ. (2001) Ezrin is a downstream effector of trafficking PKC–integrin complexes involved in the control of cell motility. Embo J 20:2723–2741.

    Article  PubMed  CAS  Google Scholar 

  • Nguyen R, Reczek D, Bretscher A (2001) Hierarchy of merlin and ezrin N- and C-terminal domain interactions in homo- and heterotypic associations and their relationship to binding of scaffolding proteins EBP50 and E3KARP. J Biol Chem 276:7621–7629.

    Article  PubMed  CAS  Google Scholar 

  • Nijhara R, van Hennik PB, Gignac ML, Kruhlak MJ, Hordijk PL, Delon J, Shaw S (2004) Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes. J Immunol 173:4985–4993.

    PubMed  CAS  Google Scholar 

  • Okada T, Lopez-Lago M, Giancotti FG (2005) Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol 171:361–371.

    Article  PubMed  CAS  Google Scholar 

  • Pakkanen R, Hedman K, Turunen O, Wahlstrom T, Vaheri A (1987) Microvillus-specific Mr 75,000 plasma membrane protein of human choriocarcinoma cells. J Histochem Cytochem 35:809–816.

    Article  PubMed  CAS  Google Scholar 

  • Parlato S, Giammarioli AM, Logozzi M, Lozupone F, Matarrese P, Luciani F, Falchi M, Malorni W, Fais S (2000) CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: A novel regulatory mechanism of the CD95 apoptotic pathway. Embo J 19:5123–5134.

    Article  PubMed  CAS  Google Scholar 

  • Pietromonaco SF, Simons PC, Altman A, Elias L (1998) Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence. J Biol Chem 273:7594–7603.

    Article  PubMed  CAS  Google Scholar 

  • Pilot F, Philippe JM, Lemmers C, Lecuit T (2006) Spatial control of actin organization at adherens junctions by a synaptotagmin-like protein Btsz. Nature 442:580–584.

    Article  PubMed  CAS  Google Scholar 

  • Polesello C and Payre F (2004) Small is beautiful: What flies tell us about ERM protein function in development. Trends Cell Biol 14:294–302.

    Article  PubMed  CAS  Google Scholar 

  • Polesello C, Delon I, Valenti P, Ferrer P, Payre F (2002) Dmoesin controls actin-based cell shape and polarity during Drosophila melanogaster oogenesis. Nat Cell Biol 4:782–789.

    Article  PubMed  CAS  Google Scholar 

  • Pykett MJ, Murphy M, Harnish PR, George DL (1994) The neurofibromatosis 2 (NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts. Hum Mol Genet 3:559–564.

    Article  PubMed  CAS  Google Scholar 

  • Reczek D and Bretscher A (1998) The carboxyl-terminal region of EBP50 binds to a site in the amino-terminal domain of ezrin that is masked in the dormant molecule. J Biol Chem 273:18452–18458.

    Article  PubMed  CAS  Google Scholar 

  • Ren L, Hong SH, Cassavaugh J, Osborne T, Chou A, Kim SY, Gorlick R, Hewitt SM, Khanna C (2009) The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC. Oncogene 28:792–802.

    Article  PubMed  CAS  Google Scholar 

  • Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, Kinzler KW, Vogelstein B (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521.

    Article  PubMed  CAS  Google Scholar 

  • Roumier A, Olivo-Marin JC, Arpin M, Michel F, Martin M, Mangeat P, Acuto O, Dautry-Varsat A, Alcover A (2001) The membrane–microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15:715–728.

    Article  PubMed  CAS  Google Scholar 

  • Saotome I, Curto M, McClatchey AI (2004) Ezrin is essential for epithelial organization and villus morphogenesis in the developing intestine. Dev Cell 6:855–864.

    Article  PubMed  CAS  Google Scholar 

  • Sato N, Yonemura S, Obinata T, Tsukita S, Tsukita S (1991) Radixin, a barbed end-capping actin-modulating protein, is concentrated at the cleavage furrow during cytokinesis. J Cell Biol 113:321–330.

    Article  PubMed  CAS  Google Scholar 

  • Sato N, Funayama N, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1992) A gene family consisting of ezrin, radixin and moesin. Its specific localization at actin filament/plasma membrane association sites. J Cell Sci 103 ( Pt 1):131–143.

    PubMed  CAS  Google Scholar 

  • Scoles DR, Huynh DP, Morcos PA, Coulsell ER, Robinson NG, Tamanoi F, Pulst SM (1998) Neurofibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin. Nat Genet 18:354–359.

    Article  PubMed  CAS  Google Scholar 

  • Serrador JM, Nieto M, Sanchez-Madrid F (1999) Cytoskeletal rearrangement during migration and activation of T lymphocytes. Trends Cell Biol 9:228–233.

    Article  PubMed  CAS  Google Scholar 

  • Serrador JM, Nieto M, Alonso-Lebrero JL, del Pozo MA, Calvo J, Furthmayr H, Schwartz-Albiez R, Lozano F, González-Amaro R, Sánchez-Mateos P, Sánchez-Madrid F (1998) CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell–cell contacts. Blood 91:4632–4644.

    PubMed  CAS  Google Scholar 

  • Serrador JM, Vicente-Manzanares M, Calvo J, Barreiro O, Montoya MC, Schwartz-Albiez R, Furthmayr H, Lozano F, Sánchez-Madrid F (2002) A novel serine-rich motif in the intercellular adhesion molecule 3 is critical for its ezrin/radixin/moesin-directed subcellular targeting. J Biol Chem 277:10400–10409.

    Article  PubMed  CAS  Google Scholar 

  • Shaw RJ, Henry M, Solomon F, Jacks T (1998a) RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane/actin protrusions in fibroblasts. Mol Biol Cell 9:403–419.

    PubMed  CAS  Google Scholar 

  • Shaw RJ, McClatchey AI, Jacks T (1998b) Regulation of the neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli. J Biol Chem 273:7757–7764.

    Article  PubMed  CAS  Google Scholar 

  • Shaw RJ, Paez JG, Curto M, Yaktine A, Pruitt WM, Saotome I, O’Bryan JP, Gupta V, Ratner N, Der CJ, Jacks T, McClatchey AI (2001) The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell 1:63–72.

    Article  PubMed  CAS  Google Scholar 

  • Sherman L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, Ponta H, Herrlich P, Gutmann DH (1997) Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 15:2505–2509.

    Article  PubMed  CAS  Google Scholar 

  • Stanasila L, Abuin L, Diviani D, Cotecchia S (2006) Ezrin directly interacts with the alpha1b-adrenergic receptor and plays a role in receptor recycling. J Biol Chem 281:4354–4363.

    Article  PubMed  CAS  Google Scholar 

  • Stickney JT, Bacon WC, Rojas M, Ratner N, Ip W (2004) Activation of the tumor suppressor merlin modulates its interaction with lipid rafts. Cancer Res 64:2717–2724.

    Article  PubMed  CAS  Google Scholar 

  • Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA (2000) E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells. J Biol Chem 275:29539–29546.

    Article  PubMed  CAS  Google Scholar 

  • Surace EI, Haipek CA, Gutmann DH (2004) Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function. Oncogene 23:580–587.

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K et al. (1997) Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem 272:23371–23375.

    Article  PubMed  CAS  Google Scholar 

  • Tang X, Jang SW, Wang X, Liu Z, Bahr SM, Sun SY, Brat D, Gutmann DH, Ye K (2007) Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol 9:1199–1207.

    Article  PubMed  CAS  Google Scholar 

  • Tokunou M, Niki T, Saitoh Y, Imamura H, Sakamoto M, Hirohashi S (2000) Altered expression of the ERM proteins in lung adenocarcinoma. Lab Invest 80:1643–1650.

    Article  PubMed  CAS  Google Scholar 

  • Tomas EM, Chau TA, Madrenas J (2002) Clustering of a lipid-raft associated pool of ERM proteins at the immunological synapse upon T cell receptor or CD28 ligation. Immunol Lett 83:143–147.

    Article  PubMed  CAS  Google Scholar 

  • Tort F, Pinyol M, Pulford K, Roncador G, Hernandez L, Nayach I, Kluin-Nelemans HC, Kluin P, Touriol C, Delsol G, Mason D, Campo E (2001) Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest 81:419–426.

    PubMed  CAS  Google Scholar 

  • Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, Haase VH, Ambrose CM, Munroe D, Bove C, Haines JL, Martuza RL, MacDonald ME, Seizinger BR, Short MP, Buckler AJ, Gusella JF (1993) A novel moesin-, erzin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 75:826.

    Article  PubMed  CAS  Google Scholar 

  • Tsukita S, Hieda Y, Tsukita S (1989) A new 82-kD barbed end-capping protein (radixin) localized in the cell-to-cell adherens junction: Purification and characterization. J Cell Biol 108:2369–2382.

    Article  PubMed  CAS  Google Scholar 

  • Tsukita S, Oishi K, Sato N, Sagara J, Kawai A (1994) ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol 126:391–401.

    Article  PubMed  CAS  Google Scholar 

  • Turunen O, Winqvist R, Pakkanen R, Grzeschik KH, Wahlstrom T, Vaheri A (1989) Cytovillin, a microvillar Mr 75,000 protein. cDNA sequence, prokaryotic expression, and chromosomal localization. J Biol Chem 264:16727–16732.

    PubMed  CAS  Google Scholar 

  • Wald FA, Oriolo AS, Mashukova A, Fregien NL, Langshaw AH, Salas PJ (2008) Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells. J Cell Sci 121:644–654.

    Article  PubMed  CAS  Google Scholar 

  • Weinman EJ, Steplock D, Donowitz M, Shenolikar S (2000) NHERF associations with sodium-hydrogen exchanger isoform 3 (NHE3) and ezrin are essential for cAMP-mediated phosphorylation and inhibition of NHE3. Biochemistry 39:6123–6129.

    Article  PubMed  CAS  Google Scholar 

  • Weng WH, Ahlen J, Astrom K, Lui WO, Larsson C (2005) Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas. Clin Cancer Res 11:6198–6204.

    Article  PubMed  CAS  Google Scholar 

  • Wilgenbus KK, Milatovich A, Francke U, Furthmayr H (1993) Molecular cloning, cDNA sequence, and chromosomal assignment of the human radixin gene and two dispersed pseudogenes. Genomics 16:199–206.

    Article  PubMed  CAS  Google Scholar 

  • Wu YX, Uezato T, Fujita M (2000) Tyrosine phosphorylation and cellular redistribution of ezrin in MDCK cells treated with pervanadate. J Cell Biochem 79:311–321.

    Article  PubMed  CAS  Google Scholar 

  • Xiao GH, Beeser A, Chernoff J, Testa JR (2002) p21-activated kinase links Rac/Cdc42 signaling to merlin. J Biol Chem 277:883–886.

    Article  PubMed  CAS  Google Scholar 

  • Xu HM and Gutmann DH (1998) Merlin differentially associates with the microtubule and actin cytoskeleton. J Neurosci Res 51:403–415.

    Article  PubMed  CAS  Google Scholar 

  • Yonemura S, Hirao M, Doi Y, Takahashi N, Kondo T, Tsukita S, Tsukita S (1998) Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J Cell Biol 140:885–895.

    Article  PubMed  CAS  Google Scholar 

  • Yonemura S, Tsukita S (1999) Direct involvement of erzin/radixin/moesin (ERM)-binding membrane proteins in the organization of microvilli in collaboration with activated ERM proteins. J Cell Biol 145:1497–1509.

    Article  PubMed  CAS  Google Scholar 

  • Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G (2004) Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10:175–181.

    Article  PubMed  CAS  Google Scholar 

  • Yu Y, Davicioni E, Triche TJ, Merlino G (2006) The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 66:1982–1989.

    Article  PubMed  CAS  Google Scholar 

  • Zhou R, Cao X, Watson C, Miao Y, Guo Z, Forte JG, Yao X (2003) Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation. J Biol Chem 278:35651–35659.

    Article  PubMed  CAS  Google Scholar 

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  1. Head, Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute, 37 Convent Drive, Suite 2144, Bethesda, MD, USA

    L. Ren & C. Khanna

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    Andrei Thomas-Tikhonenko

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Ren, L., Khanna, C. (2010). Merlin/NF2 Tumor Suppressor and Ezrin–Radixin–Moesin (ERM) Proteins in Cancer Development and Progression. In: Thomas-Tikhonenko, A. (eds) Cancer Genome and Tumor Microenvironment. Cancer Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0711-0_5

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