Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation

Sun, Chunxiao; Robb, Victoria A.; Gutmann, David H.

doi:10.1242/jcs.00094

Cited by 166 publications

(142 citation statements)

References 97 publications

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“…2b), suggesting that when overexpressed this ezrin mutant competes with merlin for CD44 binding, shifting merlin interaction from this receptor to wild-type ezrin thus potentiating its tumor suppressor activity. 47,49 Moreover, these data suggest that the binding region of ezrin with merlin is included in the ezrin fragment downstream aminoacid 146.…”

Section: Ezrin-related Metastatic Functionsmentioning

confidence: 79%

Pleiotropic function of ezrin in human metastatic melanomas

Federici

Brambilla

Lozupone

et al. 2009

Intl Journal of Cancer

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The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. ' UICCKey words: CD44; merlin; Lamp-1; phagocytic vacuole; organelle acidity The molecular events governing progression from a primary tumor to an invasive, malignant tumor remain poorly defined despite intense scientific endeavor mostly due to molecular biology and biochemical data collected from non human models. 1 The metastatic phenomenon is characterized by a cascade of events that assumes the existence of very harmful cells within the primitive tumor mass. These cells must acquire the ability to breach underlying basement membrane, migrate through interstitial stroma, gain access to and migrate through blood or lymphatic vessels, attach, enter, survive and proliferate within metastatic organs.Mounting evidence suggesting that ezrin contributes to tumor metastasis promotion, arose mainly from experiments employing syngeneic implantation models correlated to gene expression profiling performed on pediatric tumors. 1,2 In human tumors, ezrin deregulation or impaired functionality is related to poor prognosis. [3][4][5][6][7][8][9] Ezrin belongs to the MERM family of cytoskeleton-associated proteins 10 and functions as a linker between the actin cortical cytoskeleton and various membrane-bound molecules 11,12 through its C-terminal and N-terminal domains, respectively.ERM proteins are implicated in a wide variety of important cellular processes. 10,13-18 Notably, ezrin is primarily involved in both cell-to-cell adhesion and cell adhesion to the ECM through association with ICAMs, CD44, E-cadherin and b-catenin. 12,19 To this family belongs also the tumor suppressor merlin (NF-2, schwannomin), whose loss is r...

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Section: Ezrin-related Metastatic Functionsmentioning

confidence: 79%

Pleiotropic function of ezrin in human metastatic melanomas

Federici

Brambilla

Lozupone

et al. 2009

Intl Journal of Cancer

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“…The Nf2 gene was isolated by positional cloning and encodes merlin, which was named for its striking structural similarity with the ERM family proteins (moesin, ezrin, and radixin) linking the actin cytoskeleton to various membraneassociated proteins (3)(4)(5)(6). Merlin also localizes at the membrane-cytoskeleton interface, which is unusual for tumor suppressors.…”

mentioning

confidence: 99%

“…Merlin interacts with a number of protein partners and inhibits many growth signal pathways when overexpressed (5,6). Studies using Nf2 mutant mice demonstrated that the Nf2 tumor suppressor regulates the proliferation of many cell types and that Nf2 loss plays a wide role in both tumor development and metastasis (7)(8)(9)(10).…”

mentioning

confidence: 99%

Merlin, a Tumor Suppressor, Interacts with Transactivation-responsive RNA-binding Protein and Inhibits Its Oncogenic Activity

Lee¹,

Kim²,

Ryu³

et al. 2004

Journal of Biological Chemistry

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The neurofibromatosis type 2 gene-encoded protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeleton-associated proteins. Recent studies suggest that the loss of neurofibromatosis type 2 function contributes to tumor development and metastasis. Although the cellular functions of merlin as a tumor suppressor are relatively well characterized, the cellular mechanism whereby merlin controls cell proliferation from membrane locations is still poorly understood. During our efforts to find potential merlin modulators through protein-protein interactions, we identified transactivation-responsive RNAbinding protein (TRBP) as a merlin-binding protein in a yeast two-hybrid screen. The interaction between TRBP and merlin was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization experiments. The carboxyl-terminal regions of each protein were responsible for their interaction. Cells overexpressing TRBP showed enhanced cell growth in cell proliferation assays and also exhibited transformed phenotypes, such as anchorage-independent cell growth and tumor development in mouse xenografts. Merlin efficiently inhibited these oncogenic activities of TRBP in our experiments. These results provide the first clue to the functional interaction between TRBP and merlin and suggest a novel mechanism for the tumor suppressor function of merlin both in vitro and in vivo.

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“…There have been several published reports in which models for the R-domain have been described on the basis of secondary structure analysis (1,13,15). The overwhelming consensus has predicted a heptad hydrophobicity pattern characteristic of coiled-coil proteins with a high propensity for helical dimers.…”

mentioning

confidence: 99%

Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

et al. 2003

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The members of the ezrin-radixin-moesin (ERM) family of proteins function as membranecytoskeletal cross-linkers in actin-rich cell surface structures. ERM proteins are thereby thought to be essential for cortical cytoskeleton organization, cell motility, adhesion, and proliferation. These modular polypeptides consist of a central helix-rich region, termed the R-domain, that connects an N-terminal FERM domain required for membrane binding and a C-terminal region which contains a major actinbinding motif. Conformational regulation of ERM protein function occurs by association of the FERM and C-terminal domains, whereby the membrane-and actin-binding activities are mutually suppressed and the protein is thought to take an inactive "closed" form. Here we report in Vitro and in ViVo studies of radixin to address the role of the R-domain in conformational activation of ERM proteins. Remarkably, an isolated R-domain comprised of radixin 311-469 forms a monomeric, stable helical rod that spans 240 Å in length from the N-terminus to the C-terminus, most likely stabilized by extensive salt bridge interactions. By fusing green fluorescent protein variants to the FERM and C-terminal domains, we probed in Vitro conformational changes impacted by the presence of the R-domain using fluorescence resonance energy transfer (FRET). Furthermore, deletion of this unusually long R-helical structure (radixin residues 314-411) prevents ERM membrane targeting in ViVo.

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Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation

Cited by 166 publications

References 97 publications

Pleiotropic function of ezrin in human metastatic melanomas

Pleiotropic function of ezrin in human metastatic melanomas

Merlin, a Tumor Suppressor, Interacts with Transactivation-responsive RNA-binding Protein and Inhibits Its Oncogenic Activity

Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

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