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 (Nf1^fl/fl;Dmp1-Cre) and Mekk2^-/- each displaying skeletal defects, Nf1^fl/fl;Mekk2^-/-;Dmp1-Cre

SUBMITTER: Bok S 

PROVIDER: S-EPMC7658220 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature