The Nf2 Tumor Suppressor, Merlin, Functions in Rac-Dependent Signaling

Shaw, Reuben J.; Páez, J. Guillermo; Curto, Monica; Yaktine, Ann L.; Pruitt, Wendy M.; Saotome, Ichiko; O’Bryan, John P.; Gupta, Vikas A.; Ratner, Nancy; Der, Channing J.; Jacks, Tyler; McClatchey, Andrea I.

doi:10.1016/s1534-5807(01)00009-0

Cited by 317 publications

(348 citation statements)

References 56 publications

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“…Phosphorylation of Merlin at Ser518 was previously reported to play an important role in regulating Merlin tumor suppressor activity (Shaw et al, 2001;Alfthan et al, 2004;Jin et al, 2006a). Interestingly, the interaction between Merlin and VprBP is independent of Ser518 phosphorylation of Merlin (data not shown), suggesting that the Merlin-VprBP interaction might represent a new means for Merlin regulation in vivo.…”

Section: Identification Of Vprbp and Ddb1 As Merlin-associated Proteinsmentioning

confidence: 85%

“…Merlin has been suggested to restrain tumor growth through inhibiting Rac and ERK activities (Shaw et al, 2001;Kissil et al, 2003;Okada et al, 2005;Morrison et al, 2007). To further substantiate a role of VprBP in Merlin function regulation, we tested whether Rac and ERK activities might be altered in VprBP-depleted cells.…”

Section: Vprbp Targets Merlin For Degradation J Huang and J Chenmentioning

confidence: 99%

“…Phosphorylation of a C-terminal serine (S518) by p21-activated kinase (PAK)-or cAMP-dependent protein kinase A weakens Merlin's self-association and is believed to inactivate its growth-suppressing activity. On the other hand, the phosphatase MYPT-1-PP1-d activates the tumor suppression activity of Merlin through S518 dephosphorylation, which subsequently inhibits the Ras/ERK (extracellular signal-regulated kinase) pathway (Shaw et al, 2001;Alfthan et al, 2004;Jin et al, 2006a). In addition, Merlin can also be regulated at the protein level by growth arrest stimuli.…”

Section: Introductionmentioning

confidence: 99%

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VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

Huang

Chen

2008

Oncogene

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Inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene function has been observed not only in familial schwannomas and other central nervous system tumors, but also in malignant tumors unrelated to the NF2 syndrome, indicating a broader role of NF2 in human tumorigenesis. The NF2-encoded protein Merlin is closely related to the Ezrin-Radixin-Moesin family of membrane/ cytoskeleton linker proteins, and has been demonstrated to suppress tumor growth by inhibiting extracellular signal-regulated kinase (ERK) and Rac1 activation. Interestingly, serum deprivation has been shown to regulate Merlin at the protein level, however, exactly how such condition affects Merlin remains elusive. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasomemediated degradation. Consistently, VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation. Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin.

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Section: Identification Of Vprbp and Ddb1 As Merlin-associated Proteinsmentioning

confidence: 85%

Section: Vprbp Targets Merlin For Degradation J Huang and J Chenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

Huang

Chen

2008

Oncogene

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“…The results of the present study indicate that the first 50 amino acids of merlin are necessary for the recruitment of merlin to the plasma membrane and that merlinDel-1 is capable of forming a head-to-tail association. Thus, merlinDel-1 may disrupt both the head-to-tail intramolecular association and the intermolecular association (oligomerization) seen in wt merlin and also abrogate the interaction that occurs between wt merlin and its downstream binding partner(s)/targets such as Rac and p21-activated kinase (Pak 1, Shaw et al, 2001;Kissil et al, 2003), which may provide the underlying basis for the tumor-promoting activity of merlinDel-1. Furthermore, CD44-HA binding can induce the formation of large CD44-HA complexes that localize in the lipid rafts (Oliferenko et al, 1999).…”

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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“…Promitogenic signals-which are initiated by integrins and receptor tyrosine kinases and transduced by Cdc42 [7,25]. Conversely, engagement of cadherins or loss of mitogenic signalling inactivates PAK, leading to an accumulation of the closed form of Merlin [56].…”

Section: Merlin Structure and Modificationsmentioning

confidence: 99%

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4 DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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The Nf2 Tumor Suppressor, Merlin, Functions in Rac-Dependent Signaling

Cited by 317 publications

References 56 publications

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

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

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

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