Title | MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Bok S, Shin DYeon, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim J-H, Greenblatt MB |
Journal | Nat Commun |
Volume | 11 |
Issue | 1 |
Pagination | 5704 |
Date Published | 2020 11 11 |
ISSN | 2041-1723 |
Keywords | Animals, Disease Models, Animal, Enzyme Activation, Extracellular Matrix Proteins, Extracellular Signal-Regulated MAP Kinases, Female, Humans, Imidazoles, Male, MAP Kinase Kinase Kinase 2, Mice, Transgenic, Neurofibromatosis 1, Neurofibromin 1, Osteoblasts, Phosphorylation, Protein Kinase Inhibitors, Pyridazines, Skull |
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;Dmp1-Cre) and Mekk2 each displaying skeletal defects, Nf1;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. |
DOI | 10.1038/s41467-020-19555-6 |
Alternate Journal | Nat Commun |
PubMed ID | 33177525 |
PubMed Central ID | PMC7658220 |
Grant List | DP5 OD021351 / OD / NIH HHS / United States R01 AR075585 / AR / NIAMS NIH HHS / United States |
Related Lab:
Related Faculty:
Matthew B. Greenblatt, M.D., Ph.D.