The role of the CD44/ezrin complex in cancer metastasis

Martin, Tracey Amanda; Harrison, Gregory; Mansel, Robert Edward; Jiang, Wen Guo

doi:10.1016/s1040-8428(02)00172-5

Cited by 207 publications

(194 citation statements)

References 164 publications

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“…It is well established that CD44 plays an important role in promoting tumor growth and metastasis, mainly by mediating tumor cell adhesion to HA (for reviews see Sherman et al, 1994;Stamenkovic, 2000;Martin et al, 2003). Overproduction of HA promotes anchorageindependent growth of the CD44-expressing breast epithelial cells by inducing an epithelial-mesenchymal transition (Zoltan-Jones et al, 2003) and increasing evidence suggests that ezrin is a key regulator of tumor metastasis Yu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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“…Ezrin, another member of the ERM family, is reported to participate in Src signaling and to induce FAK activation (Poullet et al, 2001;Srivastava et al, 2005) Although ezrin and merlin have similarities in structure and common interacting partners, such as CD44, NHERF and N-WASP (Bretscher et al, 2000;Morrison et al, 2001;Martin et al, 2003;Manchanda et al, 2005), they possess opposite functions in cell growth and proliferation. As we observed an inhibitory effect of merlin on cell migration and invasion, we sought to determine if merlin could downregulate FAK.…”

Section: Re-expression Of Merlin Attenuates Fak Phosphorylation At Tymentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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“…Studies from a number of laboratories have focused on how CD44 integrates these adhesive and signalling activities to modulate cell migration, proliferation, differentiation and survival. Given this coordinating role of CD44, it is unsurprising that aberrant CD44 expression has been associated with a number of pathophysiological processes including tumour progression and chronic inflammation (Pure and Cuff, 2001;Martin et al, 2003;Ponta et al, 2003). In particular, there is increasing in vitro and in vivo evidence for a role for CD44 in tumour cell invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

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The role of the CD44/ezrin complex in cancer metastasis

Cited by 207 publications

References 164 publications

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

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