MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Seoyeon Bok, Dong Yeon Shin, Alisha R. Yallowitz, Mark Eiseman, Michelle Cung, Ren Xu, Na Li, Jun Sun, Alfred L. Williams, John E. Scott, Bing Su, Jae-Hyuck Shim and Matthew B. Greenblatt ()
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Seoyeon Bok: Weill Cornell Medicine
Dong Yeon Shin: Weill Cornell Medicine
Alisha R. Yallowitz: Weill Cornell Medicine
Mark Eiseman: Weill Cornell Medicine
Michelle Cung: Weill Cornell Medicine
Ren Xu: Xiamen University
Na Li: Xiamen University
Jun Sun: Weill Cornell Medicine
Alfred L. Williams: North Carolina Central University
John E. Scott: North Carolina Central University
Bing Su: Shanghai JiaoTong University School of Medicine
Jae-Hyuck Shim: University of Massachusetts Medical School
Matthew B. Greenblatt: Weill Cornell Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19555-6

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