ERM proteins in cancer progression

Clucas, Jarama; Valderrama, Ferran

doi:10.1242/jcs.170027

Cited by 91 publications

(132 citation statements)

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“…45 Several studies suggest that ezrin may play a key role in tumor development, invasion, and metastasis, possibly regulating adhesion molecules, cell signal transduction, and signaling to other cell membrane channels in the tumor. 28 Together with ezrin, we found a significant expression increase of moesin, another ERM protein which has been equally involved in EMT, metastatization and cancer progression. 46,47,28 ANXA1 biological effects could differ according to its intra-or extra-cellular localization.…”

Section: Discussionmentioning

confidence: 72%

“…28 Together with ezrin, we found a significant expression increase of moesin, another ERM protein which has been equally involved in EMT, metastatization and cancer progression. 46,47,28 ANXA1 biological effects could differ according to its intra-or extra-cellular localization. 29 Cytosolic ANXA1 for example has been frequently implicated in cytoskeletal organization in several cellular models.…”

Section: Discussionmentioning

confidence: 72%

“…27 ERM protein members such as ezrin and moesin have been frequently described to have a role in the progression of many types of human malignancies since their overexpression alters cell shape, adhesion, and motility and correlates with the metastatic behavior of many human cancers. 28 Therefore, we hypothesized a modulation of ERM protein expression in LNCaP, DU145 and PC3 PCa cell lines during low oxygen stress adaptation. Our results showed an intriguing increase of both ezrin and moesin proteins starting from 24 hours of hypoxic treatment in PCa cells (Fig.…”

Section: Anxa1 Expression Increases In Hypoxic Conditionsmentioning

confidence: 99%

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Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Bizzarro

Belvedere

Migliaro

et al. 2016

Cell Adhesion & Migration

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Annexin A1 (ANXA1) is a Ca 2C -binding protein overexpressed in the invasive stages of prostate cancer (PCa) development; however, its role in this tumor metastatization is largely unknown. Moreover, hypoxic conditions in solid tumors have been related to poor prognosis in PCa patients. We have previously demonstrated that ANXA1 is implicated in the acquisition of chemo-resistant features in DU145 PCa cells conferring them a mesenchymal/metastatic phenotype. In this study, we have investigated the mechanisms by which ANXA1 regulates metastatic behavior in LNCaP, DU145 and PC3 cells exposed to hypoxia. ANXA1 was differentially expressed by PCa cell lines in normoxia whereas hypoxic stimuli resulted in a significant increase of protein expression. Additionally, in low oxygen conditions ANXA1 was extensively secreted out-side the cells where its binding to formyl peptide receptors (FPRs) induced cell invasion. Loss and gain of function experiments performed by using the RNA interfering siANXA1 and an ANXA1 over-expressing plasmid (MF-ANXA1), also confirmed the leading role of the protein in modulating LNCaP, DU145 and PC3 cell invasiveness. Finally, ANXA1 played a crucial role in the regulation of cytoskeletal dynamics underlying metastatization process, such as the loss of adhesion molecules and the occurrence of the epithelial to mesenchymal transition (EMT). ANXA1 expression increased inversely to epithelial markers such as E-cadherin and cytokeratins 8 and 18 (CKs) and proportionally to mesenchymal ones such as vimentin, ezrin and moesin. Our results indicated that ANXA1 may be a key mediator of hypoxia-related metastasis-associated processes in PCa.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 72%

Section: Anxa1 Expression Increases In Hypoxic Conditionsmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Bizzarro

Belvedere

Migliaro

et al. 2016

Cell Adhesion & Migration

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“…Because Ezrin-Moesin-Radixin (ERM) proteins are general crosslinkers between cortical actin filaments and plasma membranes essential for apical differentiation, [30][31][32][33] and that they are highly expressed in the uterine epithelium at periimplantation, 34 we next explored whether ERM signaling would take part in uterine epithelial transformation upon Rac1 activation. As shown in Figure 5a, Rac1 and p-ERM (active ERM) were well colocalized in the apical side of uterine luminal epithelium on days 4 and 5 of pregnancy, indicating the possibility that ERM activation may mediate Rac1's function during epithelial transformation.…”

Section: Resultsmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

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“…ERM proteins organize membrane domains by binding to the cytoplasmic tails of integral membrane proteins [1,2], for example in the immune synapse and in vesicular trafficking, processing and phagocytosis. The ERM protein ezrin is directly involved in tumor metastasis, particularly in the pediatric cancers: rhabdomyosarcoma and osteosarcoma [3].…”

Section: Introductionmentioning

confidence: 99%

Structural characterization suggests models for monomeric and dimeric forms of full-length ezrin

Phang

Harrop

Duff

et al. 2016

Biochemical Journal

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Ezrin is a member of the ERM (ezrin–radixin–moesin) family of proteins that have been conserved through metazoan evolution. These proteins have dormant and active forms, where the latter links the actin cytoskeleton to membranes. ERM proteins have three domains: an N-terminal FERM [band Four-point-one (4.1) ERM] domain comprising three subdomains (F1, F2, and F3); a helical domain; and a C-terminal actin-binding domain. In the dormant form, FERM and C-terminal domains form a stable complex. We have determined crystal structures of the active FERM domain and the dormant FERM:C-terminal domain complex of human ezrin. We observe a bistable array of phenylalanine residues in the core of subdomain F3 that is mobile in the active form and locked in the dormant form. As subdomain F3 is pivotal in binding membrane proteins and phospholipids, these transitions may facilitate activation and signaling. Full-length ezrin forms stable monomers and dimers. We used small-angle X-ray scattering to determine the solution structures of these species. As expected, the monomer shows a globular domain with a protruding helical coiled coil. The dimer shows an elongated dumbbell structure that is twice as long as the monomer. By aligning ERM sequences spanning metazoan evolution, we show that the central helical region is conserved, preserving the heptad repeat. Using this, we have built a dimer model where each monomer forms half of an elongated antiparallel coiled coil with domain-swapped FERM:C-terminal domain complexes at each end. The model suggests that ERM dimers may bind to actin in a parallel fashion.

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ERM proteins in cancer progression

Cited by 91 publications

References 0 publications

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Structural characterization suggests models for monomeric and dimeric forms of full-length ezrin

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