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 (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 11, 2020
- Source ID
- 10.1038/s41467-020-19555-6
Entities
People
- Alfred L Williams
- Alisha R. Yallowitz
- Bing Su
- Dong Yeon Shin
- Jae-Hyuck Shim
- John E Scott
- Jun Sun
- Mark Eiseman
- Matthew B Greenblatt
- Michelle Cung
- Na Li
- Ren Xu
- Seoyeon Bok
Organizations
- Burroughs Wellcome Fund
- National Institutes of Health
- National Research Foundation of Korea
- United States Department of Defense