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

Bai, Yang; Yj, Liu; H, Wang; Xu, Yiming; Stamenkovic, Ivan; Q, Yu

doi:10.1038/sj.onc.1209849

Cited by 83 publications

(78 citation statements)

References 62 publications

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“…Ezrin is the essential molecule that stimulates proliferation and migration, whereas merlin is the molecule that inhibits cell proliferation. Several investigations revealed that the expression and activation of ezrin and merlin can be regulated by HA [16,17]. Therefore, it has been proposed that merlin and ezrin are probably involved in the different regulatory processes in vascular endothelial cells (VECs) associated with glycans and oligosaccharides [18]; however, there is no definitive evidence for this assertion.…”

Section: Introductionmentioning

confidence: 86%

The influence of hyaluronic acid on vascular endothelial cell proliferation and the relationship with ezrin/merlin expression

Mo¹,

Yang²,

Liu³

et al. 2011

ABBS

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It has been established that hyaluronic acid (HA) glycans (nHA) and oligosaccharide (oHA) exert different effects on the biological function of the vascular endothelial cell (EC), resulting in altered regulation of angiogenesis. However, the specific mechanism is still unclear. Our study focused on the effects of nHA and oHA on the ezrin and merlin proteins in EC. The expression of ezrin and merlin was silenced by siRNA, and the regulation on EC growth as well as the mRNA expression and activation ( phosphorylation) of ezrin and merlin stimulated by oHA and nHA was investigated. The results revealed that when treated with nHA, there was no significant change in ezrin expression or activation. After being treated with oHA, the expression and activation of ezrin were definitively increased whereas there were no obvious changes in merlin expression (including its phosphorylation). With ezrin expression silenced, the expression of merlin as well as its phosphorylation levels in nHA-stimulated human umbilical vein endothelial cells were notably elevated, while there was no significant change induced by oHA. With merlin expression silenced, no obvious change was found in the expression of ezrin (including its phosphorylation) induced by nHA. Conversely, the expression of ezrin and its activation was significantly improved after being treated with oHA. The results suggest that the mechanism for the promotion of EC proliferation by oHA is likely related to the expression and activation of ezrin, and the inhibition of EC proliferation by nHA is likely related to the expression and activation of merlin.

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Section: Introductionmentioning

confidence: 86%

The influence of hyaluronic acid on vascular endothelial cell proliferation and the relationship with ezrin/merlin expression

Mo¹,

Yang²,

Liu³

et al. 2011

ABBS

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“…Interestingly, Bai et al (2007) recently showed that the first 50 amino acids of merlin contain regulatory residues that affect the interplay between merlin, ezrin, actin and CD44. Phosphorylation of serine 10 could be involved in regulating the formation of these complexes.…”

Section: Pka Phosphorylation Of Merlin M Laulajainen Et Almentioning

confidence: 99%

Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton

et al. 2007

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“…47 Moreover, merlin overexpression inhibits CD44 mediated cell linkage to HA, in turn inhibiting the interaction of CD44 with both ezrin and actin. 48 We thus evaluated also merlin interaction with ezrin and CD44. The experiments showed that merlin co-immunoprecipitated with both ezrin and CD44 (Fig.…”

Section: Ezrin-related Metastatic Functionsmentioning

confidence: 99%

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

Cited by 83 publications

References 62 publications

The influence of hyaluronic acid on vascular endothelial cell proliferation and the relationship with ezrin/merlin expression

The influence of hyaluronic acid on vascular endothelial cell proliferation and the relationship with ezrin/merlin expression

Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton

Pleiotropic function of ezrin in human metastatic melanomas

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