Structural Analysis of <i>Drosophila</i> Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization

LaJeunesse, Dennis; McCartney, Brooke M.; Fehon, Richard G.

doi:10.1083/jcb.141.7.1589

Cited by 141 publications

(170 citation statements)

References 37 publications

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“…The accumulation of Merlin at cell-to-cell junctions in confluent epithelial and endothelial cells [5,7], within lamellipodia in various types of cell [62][63][64], and on the surface of endocytic vesicles in Drosophila epithelial tissues [53,65] is consistent with this general hypothesis (Sidebar C).…”

Section: Merlin Localizationsupporting

confidence: 65%

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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Section: Merlin Localizationsupporting

confidence: 65%

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

et al. 2012

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“…It is worth mentioning that the methione residue at position 177 in the Blue Box is conserved among all merlin proteins, but not in the ERM proteins. These results further corroborate the functional importance of these amino acids in the Blue Box [46].…”

Section: Construction Of a Phylogenetic Tree For The Ermfamily Ofprotsupporting

confidence: 80%

“…In addition, the human NF2 gene could rescue the lethal merlin mutant allele in Drosophila, implying a functional conservation (LaJeunesse et al, 1998).…”

Section: Security Classificationmentioning

confidence: 97%

The Role of Drosophila Merlin in the Control of Mitosis Exit and Development

Chang¹

2006

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Pu reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the dal, needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, Including suggestions for reducing this4urden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-41o2. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid 0MB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command FortDetrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S)12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES14. ABSTRACT: Merlin, the NF2 gene product, shares a substantial homology with the ezrin-radixin-moesin (ERM) proteins. The merlin and ERM proteins are thought to be key regulators of interactions between the actin cytoskeleton and the plasma membrane in Schwann cells and polarized cells. They act as important members of signal transduction pathways that control cell growth and participate in the sorting of membrane proteins during exocytic traffic. Unlike ERM. Merlin has a distinct function as a tumor suppressor; however, the mechanism by which marline functions as a tumor suppressor is poorly understood. Drosophila melanogaster provides a genetic and developmental system that is amenable to experiment manipulation and has been very valuable to the study of tumor genetics. The Drosophila homolog of merlin shares sequence and functional similarity to the human protein. We have shown that merlin plays an important role in the control of mitosis exit and in the determination of dorsal/ventral compartment border during wing Imaginal disc development. Although merlin mutation did not seem to significantly affect the overall cell-cycle duration, merlin mutant displayed prolonged proliferation during the cell cycle. We showed that merlin is required for the determination of the wing morphology, and demonstrated a genetic interaction between merlin and porcupine, which controls the acetylation of the Wingless morphogen during the development of the wing imaginal disc. In addition, we showed a potential interaction between merlin and shibire, which is involved in wingless protein trafficking during early embryogenesis. Also, we found a role for merlin in spermatogenesis. Finally, we analyzed the origin and evolution of merlin, and identified a monophyletic origin of the merlin prot...

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“…It is widely held that tumor-suppressor mutants often act in a dominant-negative fashion to promote tumorigenesis (Nigro et al, 1989). Various merlin deletion mutants have been shown to promote tumorigenesis (Koga et al, 1998;Lajeunesse et al, 1998;Giovannini et al, 2000), but whether their effects are the result of a dominantnegative or a gain-of-function prooncogenic activity has not been resolved. Tr6BC1 cells express merlin endogenously (Figure 1a), and the results of RT-PCR together with DNA sequencing indicated that both merlin isoforms I and II are expressed (data not shown).…”

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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Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization

Cited by 141 publications

References 37 publications

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

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

The Role of Drosophila Merlin in the Control of Mitosis Exit and Development

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

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