1. MEKK2 mediates aberrant ERK activation in neurofibromatosis type I
- Author
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Mark Eiseman, Matthew B. Greenblatt, Jae-Hyuck Shim, Jun Sun, Alisha R. Yallowitz, Dong Yeon Shin, Na Li, Michelle Cung, Bing Su, Seoyeon Bok, Ren Xu, Alfred L. Williams, and John E. Scott
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Male ,General Physics and Astronomy ,Diseases ,0302 clinical medicine ,Phosphorylation ,lcsh:Science ,Extracellular Signal-Regulated MAP Kinases ,Extracellular Matrix Proteins ,Multidisciplinary ,Neurofibromin 1 ,Kinase ,Chemistry ,Imidazoles ,Phenotype ,Pyridazines ,030220 oncology & carcinogenesis ,Female ,Cell signalling ,Cell signaling ,congenital, hereditary, and neonatal diseases and abnormalities ,Neurofibromatosis 1 ,Transgene ,Science ,Mice, Transgenic ,MAP Kinase Kinase Kinase 2 ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Enzyme activator ,Animals ,Humans ,Bone ,neoplasms ,Protein Kinase Inhibitors ,Osteoblasts ,MAP kinase kinase kinase ,Skull ,General Chemistry ,eye diseases ,nervous system diseases ,Enzyme Activation ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,lcsh:Q ,Peripheral nervous system - 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 (Nf1fl/fl;Dmp1-Cre) and Mekk2−/− each displaying skeletal defects, Nf1fl/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., Neurofibromatosis type I (NF1) is characterized by prominent skeletal abnormalities mediated in part by aberrant ERK pathway activation due to NF1 loss-of-function. Here, the authors report the MEKK2 is a key mediator of this aberrant ERK activation and that MEKK2 inhibitors, including ponatinib, ameliorate skeletal defects in a mouse model of NF1.
- Published
- 2020