The Tumor Suppressor Merlin Controls Growth in Its Open State, and Phosphorylation Converts It to a Less-Active More-Closed State

Sher, Ifat; Hanemann, C. Oliver; Karplus, P. Andrew; Bretscher, Anthony

doi:10.1016/j.devcel.2012.03.008

Cited by 57 publications

(119 citation statements)

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“…by truncation of a part of its C-terminal tail) constitutively activates Merlin (8), indicating that the FERM domainmediated activities of Merlin requires the release of the C-terminal tail-mediated auto-inhibition. Interestingly, phos- phorylation of Ser-518 or substitutions of Ser-518 with Glu/ Asp in the predicted helical region between the FERM domain and the inhibitory tail domain convert Merlin into a functionally less active state (36). This functionally less active state of Merlin is often equated to a conformationally more closed state, although no direct biochemical or structural evidences exist.…”

Section: Discussionmentioning

confidence: 99%

“…The FERM domain of Merlin interacts with its own tail, and this intra-molecular interaction is believed to keep Merlin in an auto-inhibited conformation (36). Release of the auto-inhibition (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Merlin is believed to adopt a closed conformation in solution, in which the C-terminal regulatory tail binds to the FERM domain and keeps the full-length Merlin in an auto-inhibited conformation (36). Based on the structure of auto-inhibited Moesin (24,37) and in view of the very high amino acid sequence identity between Merlin and Moesin, it is generally accepted that the C-terminal tail of Merlin is likely to binding to its own FERM domain with a mode similar to that found in Moesin.…”

Section: The Auto-inhibited and Structurally Closed Form Of Merlin Camentioning

confidence: 99%

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Structural Basis of the Binding of Merlin FERM Domain to the E3 Ubiquitin Ligase Substrate Adaptor DCAF1

Wei

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: Merlin controls organ size by binding to target proteins both in cytoplasm and nucleus. Results: The structure of Merlin FERM domain in complex with its binding domain of DCAF1 is determined. Conclusion: DCAF1 folds into a ␤-hairpin structure and binds to the F3 lobe of Merlin FERM domain. Significance: The structure of the Merlin⅐DCAF1 complex provides a template for understanding the interactions of Merlin with its binding partners.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Auto-inhibited and Structurally Closed Form Of Merlin Camentioning

confidence: 99%

See 1 more Smart Citation

Structural Basis of the Binding of Merlin FERM Domain to the E3 Ubiquitin Ligase Substrate Adaptor DCAF1

Wei

Zhang

et al. 2014

Journal of Biological Chemistry

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“…22,23 However, a recent biochemical study suggested that phosphorylation converts Merlin into a less active and more closed form. 24 To avoid confusion, however, we defined the unphosphorylated form as closed and active (see Discussion). Interestingly, S518A mutant of Merlin (Merlin-SA, mimetic of unphosphorylated) interacted more strongly with LRP6 than did wild-type Merlin, whereas S518D mutant (Merlin-SD, phospho-mimetic) showed almost no interaction ( Figure 1d).…”

Section: Resultsmentioning

confidence: 99%

“…22 However, a recent biochemical study suggested that phosphorylation converts Merlin into a less active and more closed form. 24 Our model shown in Figure 7 can be modified according to whether a closed or open form of Merlin interacts with LRP6 in the absence of Wnt.…”

Section: Discussionmentioning

confidence: 99%

Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation

Kim

et al. 2016

Cell Death Differ

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Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP 2 -dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease.

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CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies

Widemann

Acosta²,

Ammoun

et al. 2014

American J of Med Genetics Pt A

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The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a “state-of-the-field” for NF research in 2012.

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The Tumor Suppressor Merlin Controls Growth in Its Open State, and Phosphorylation Converts It to a Less-Active More-Closed State

Cited by 57 publications

References 10 publications

Structural Basis of the Binding of Merlin FERM Domain to the E3 Ubiquitin Ligase Substrate Adaptor DCAF1

Structural Basis of the Binding of Merlin FERM Domain to the E3 Ubiquitin Ligase Substrate Adaptor DCAF1

Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies

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