Division of Rheumatology, Department of Medicine
Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Musculoskeletal Diseases | Nervous System Diseases
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.
Cell signalling, Bone, Peripheral nervous system, Diseases
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DOI of Published Version
Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim JH, Greenblatt MB. MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Nat Commun. 2020 Nov 11;11(1):5704. doi: 10.1038/s41467-020-19555-6. PMID: 33177525; PMCID: PMC7658220. Link to article on publisher's site
Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim J, Greenblatt MB. (2020). MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Open Access Publications by UMMS Authors. https://doi.org/10.1038/s41467-020-19555-6. Retrieved from https://escholarship.umassmed.edu/oapubs/4475
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This work is licensed under a Creative Commons Attribution 4.0 License.