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MEKK2 mediates aberrant ERK activation in neurofibromatosis type I.

ABSTRACT: Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1^fl/fl;Dmp1-Cre) and Mekk2^-/- each displaying skeletal defects, Nf1^fl/fl;Mekk2^-/-;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.

SUBMITTER: Bok S

PROVIDER: S-EPMC7658220 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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MEKK2 mediates aberrant ERK activation in neurofibromatosis type I.

Bok Seoyeon S Shin Dong Yeon DY Yallowitz Alisha R AR Eiseman Mark M Cung Michelle M Xu Ren R Li Na N Sun Jun J Williams Alfred L AL Scott John E JE Su Bing B Shim Jae-Hyuck JH Greenblatt Matthew B MB

Nature communications 20201111 1

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ...[more]

PMID: 33177525

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Project description:BackgroundFatal neurodegenerative disorders such as Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases in humans, scrapie and bovine spongiform encephalopathy in animals, are characterized by the accumulation in the brain of a pathological form of the prion protein (PrP) denominated PrPSc. The latter derives from the host cellular form, PrPC, through a process whereby portions of its alpha-helical and coil structures are refolded into beta-sheet structures.ResultsIn this work, the widely known in vitro model of prion replication, hypothalamic GT1-1 cell line, was used to investigate cellular and molecular responses to prion infection. The MAP kinase cascade was dissected to assess the phosphorylation levels of src, MEK 1/2 and ERK 1/2 signaling molecules, both before and after prion infection. Our findings suggest that prion replication leads to a hyper-activation of this pathway. Biochemical analysis was complemented with immunofluorescence studies to map the localization of the ERK complex within the different cellular compartments. We showed how the ERK complex relocates in the cytosol upon prion infection. We correlated these findings with an impairment of cell growth in prion-infected GT1-1 cells as probed by MTT assay. Furthermore, given the persistent urgency in finding compounds able to cure prion infected cells, we tested the effects on the ERK cascade of two molecules known to block prion replication in vitro, quinacrine and Fab D18. We were able to show that while these two compounds possess similar effects in curing prion infection, they affect the MAP kinase cascade differently.ConclusionsTaken together, our results help shed light on the molecular events involved in neurodegeneration and neuronal loss in prion infection and replication. In particular, the combination of chronic activation and aberrant localization of the ERK complex may lead to a lack of essential neuroprotective and survival factors. Interestingly, these data seem to define some common traits with other neurodegenerative disorders such as, for example, Alzheimer's disease.

Dataset Information

MEKK2 mediates aberrant ERK activation in neurofibromatosis type I.

Publications

MEKK2 mediates aberrant ERK activation in neurofibromatosis type I.

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