MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Nat Commun. 2020 Nov 11;11(1):5704. doi: 10.1038/s41467-020-19555-6.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Enzyme Activation
  • Extracellular Matrix Proteins / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Humans
  • Imidazoles / pharmacology*
  • MAP Kinase Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 2 / genetics
  • MAP Kinase Kinase Kinase 2 / metabolism*
  • Male
  • Mice, Transgenic
  • Neurofibromatosis 1 / drug therapy
  • Neurofibromatosis 1 / etiology*
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism
  • Osteoblasts / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Pyridazines / pharmacology*
  • Skull / cytology


  • Dmp1 protein, mouse
  • Extracellular Matrix Proteins
  • Imidazoles
  • NF1 protein, human
  • Neurofibromin 1
  • Protein Kinase Inhibitors
  • Pyridazines
  • ponatinib
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinase 2
  • Map3k2 protein, mouse