Other
13 Authors
- Cung M,
- Su B,
- Eiseman M,
- Greenblatt MB,
- Scott JE,
- Bok S,
- Sun J,
- Xu R,
- Shim JH,
- Williams AL,
- Yallowitz AR,
- Shin DY,
- Li N
| First Author | Bok S | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 5704 |
| PubMed ID | 33177525 | Mgi Jnum | J:297927 |
| Mgi Id | MGI:6479416 | Doi | 10.1038/s41467-020-19555-6 |
| Citation | Bok S, et al. (2020) MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Nat Commun 11(1):5704 |
| abstractText | 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. |
