MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Academic Article uri icon

Overview

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.

publication date

  • November 11, 2020

Research

keywords

  • Extracellular Signal-Regulated MAP Kinases
  • Imidazoles
  • MAP Kinase Kinase Kinase 2
  • Neurofibromatosis 1
  • Pyridazines

Identity

PubMed Central ID

  • PMC7658220

Scopus Document Identifier

  • 85095830501

Digital Object Identifier (DOI)

  • 10.1038/s41467-020-19555-6

PubMed ID

  • 33177525

Additional Document Info

volume

  • 11

issue

  • 1