Moesin Dependent Cytoskeleton Remodeling Is Associated With an Anaplastic Phenotype of Pancreatic Cancer

Abiatari, Ivane; Espósito, Irene; Oliveira, Tiago De; Felix, Klaus; Hong, Xin; Penzel, Roland; Giese, Thomas; Frieß, Helmut; Kleeff, Jörg

doi:10.1111/j.1582-4934.2009.00772.x

Cited by 27 publications

(34 citation statements)

References 35 publications

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“…As shown by other studies (41,42), phosphorylation of ERM proteins is an important regulatory mechanism that has been related to cell motility, migration, and cell invasion. We found that SL are not just involved in ERM inactivation but are also involved in a rapid activation driven by S1P.…”

Section: Discussionmentioning

confidence: 61%

Differential Effects of Ceramide and Sphingosine 1-Phosphate on ERM Phosphorylation

Canals

Jenkins

Roddy

et al. 2010

Journal of Biological Chemistry

103

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ERM proteins are regulated by phosphorylation of the most C-terminal threonine residue, switching them from an activated to an inactivated form. However, little is known about the control of this regulation. Previous work in our group demonstrated that secretion of acid sphingomyelinase acts upstream of ERM dephosphorylation, suggesting the involvement of sphingomyelin (SM) hydrolysis in ERM regulation. To define the role of specific lipids, we employed recombinant bacterial sphingomyelinase (bSMase) as a direct probe of SM metabolism at the plasma membrane. bSMase induced a rapid dose-and timedependent decrease in ERM dephosphorylation. ERM dephosphorylation was driven by ceramide generation and not by sphingomyelin depletion, as shown using recombinant sphingomyelinase D. The generation of ceramide at the plasma membrane was sufficient for ERM regulation, and no intracellular SM hydrolysis was required, as was visualized using Venustagged lysenin probe, which specifically binds SM. Interestingly, hydrolysis of plasma membrane bSMase-induced ceramide using bacterial ceramidase caused ERM hyperphosphorylation and formation of cell surface protrusions. The effects of plasma membrane ceramide hydrolysis were due to sphingosine 1-phosphate formation, as ERM phosphorylation was blocked by an inhibitor of sphingosine kinase and induced by sphingosine 1-phosphate. Taken together, these results demonstrate a new regulatory mechanism of ERM phosphorylation by sphingolipids with opposing actions of ceramide and sphingosine 1-phosphate. The approach also defines a tool kit to probe sphingolipid signaling at the plasma membrane.Ezrin (82 kDa), radixin (80 kDa), and moesin (75 kDa), known as the ERM proteins, link the plasma membrane to the cortical cytoskeleton. These proteins have been found to be enriched in specialized plasma membrane domains such as microvilli, lamellipodia, membrane ruffles, and other membrane protrusions (1). ERM proteins have been implicated in regulation of cell shape (2), cell polarization (3, 4), membrane enzyme localization, membrane transport, cell adhesion/migration (5-7), and signal transduction (8). The function of ERM proteins is regulated by a two-step process based on an open (active) and closed (inactive) conformation. In the closed conformation, the N terminus domain (FERM) and the C terminus domain (C-ERMAD) interact with each other in a self-folded, dormant state, and the proteins rest in the cytosol. This folding is regulated by phosphorylation on the very C-terminal threonine residue (ezrin Thr 567 , radixin Thr 564 , and moesin Thr 558 ), which leads to the open, active conformation. In the active conformation, the FERM domain interacts with the plasma membrane, and with several membrane-associated proteins (CD95, CD44, intercellular adhesion molecule (I-CAM), CD43, cystic fibrosis transmembrane conductance regulator (CFTCR), and NHE1), and the C-ERMAD domain interacts with actin filaments in the submembrane cortex (9 -13). Several kinases have been shown to phosphorylate the C ter...

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Section: Discussionmentioning

confidence: 61%

Differential Effects of Ceramide and Sphingosine 1-Phosphate on ERM Phosphorylation

Canals

Jenkins

Roddy

et al. 2010

Journal of Biological Chemistry

103

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“…This transition is fundamental in tumour development and metastasis and allows epithelial cells to develop a mesenchymal and, therefore, more invasive phenotype. Moesin has been predicted to be a potential EMT marker in breast and pancreatic cancer (Abiatari et al, 2010;Haynes et al, 2011;Wang et al, 2012). Furthermore, expression profiles of both breast and basal breast carcinomas have shown strong upregulation of moesin (Charafe-Jauffret et al, 2007;Condeelis et al, 2005;Kobayashi et al, 2004;Wang et al, 2012).…”

Section: Moesinmentioning

confidence: 99%

ERM proteins in cancer progression

Clucas

Valderrama

2014

Journal of Cell Science

223

152

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Members of the ezrin–radixin–moesin (ERM) family of proteins are involved in multiple aspects of cell migration by acting both as crosslinkers between the membrane, receptors and the actin cytoskeleton, and as regulators of signalling molecules that are implicated in cell adhesion, cell polarity and migration. Increasing evidence suggests that the regulation of cell signalling and the cytoskeleton by ERM proteins is crucial during cancer progression. Thus, both their expression levels and subcellular localisation would affect tumour progression. High expression of ERM proteins has been shown in a variety of cancers. Mislocalisation of ERM proteins reduces the ability of cells to form cell–cell contacts and, therefore, promotes an invasive phenotype. Similarly, mislocalisation of ERM proteins impairs the formation of receptor complexes and alters the transmission of signals in response to growth factors, thereby facilitating tumour progression. In this Commentary, we address the structure, function and regulation of ERM proteins under normal physiological conditions as well as in cancer progression, with particular emphasis on cancers of epithelial origin, such as those from breast, lung and prostate. We also discuss any recent developments that have added to the understanding of the underlying molecular mechanisms and signalling pathways these proteins are involved in during cancer progression.

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“…Moesin expression has been associated with papillary thyroid carcinomas (Brown et al, 2006), oral squamous cell carcinomas (Kobayashi et al, 2004), basal breast carcinoma (Charafe-Jauffret et al, 2007), pancreatic cancer (Abiatari et al, 2010), colorectal carcinoma (Kim et al, 2012), and prostatic adenocarcinoma (Bartholow et al, 2011). In pancreatic adenocarcinoma, moesin-positive cases have been associated with shorter survival times than moesin-negative cases (Abiatari et al, 2010), with moesin-positive tumors showing higher histopathological grades and perineural and lymphovascular invasion rates (Torer et al, 2007). Our results indicated that 78.3% (47/60) of LSCC and 87.9% (29/33) of metastatic lymph nodes expressed high levels of moesin.…”

Section: Discussionmentioning

confidence: 99%

Expression of ezrin and moesin related to invasion, metastasis and prognosis of laryngeal squamous cell carcinoma

2014

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ABSTRACT. We examined the expression of ezrin and moesin in laryngeal squamous cell carcinoma (LSCC) and their correlation with patient clinicopathological characteristics and overall survival. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) for ezrin and moesin were applied to 60 carcinoma tissues, adjacent normal tissues, and 33 metastatic lymph nodes. Survival functions were estimated using the Kaplan-Meier method and compared by the log-rank test. RT-PCR demonstrated that the intensity ratios of ezrin and moesin to β-actin were higher in LSCC than in adjacent normal mucous membrane (P < 0.05). Furthermore, intensity ratios were higher in cervical metastatic lymph nodes than in LSCC (P < 0.05). Immunohistochemical staining showed that ezrin and moesin were well distributed in the cell membrane and cytoplasm. Expression was significantly different between LSCC and adjacent normal tissues (P < 0.05); moreover, expression in the cervical metastatic lymph nodes was higher than in LSCC (P < 0.05). Expression of ezrin and moesin was significantly related to clinical stage, T stage, and cervical lymph node metastasis (P < 0.05), except that moesin showed Expression of ezrin and moesin in LSCC no significant relationship with clinical stage (P > 0.05). Patients with negative ezrin and moesin expression had a significantly longer overall survival time compared to patients with moderate and intense ezrin and moesin expression (P < 0.001, P < 0.05). Ezrin and moesin expression is related to LSCC invasion and metastasis, and may be important molecular markers for predicting prognosis and therapeutic targets in LSCC patients.

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Moesin Dependent Cytoskeleton Remodeling Is Associated With an Anaplastic Phenotype of Pancreatic Cancer

Cited by 27 publications

References 35 publications

Differential Effects of Ceramide and Sphingosine 1-Phosphate on ERM Phosphorylation

Differential Effects of Ceramide and Sphingosine 1-Phosphate on ERM Phosphorylation

ERM proteins in cancer progression

Expression of ezrin and moesin related to invasion, metastasis and prognosis of laryngeal squamous cell carcinoma

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