January 16, 2026
New work was published this week by recent MB&B graduate student Kimberly Vish, Boggon lab, and colleagues. In the study, the first structure of an understudied MAP kinase, MEKK2, is determined. The findings reveal the mechanism by which MEKK2 recognizes its substrates offers insights into signaling pathways altered in vascular disease.
When Dr. Vish determined the crystal structure of MEKK2 kinase domain she found an unexpected feature that provided the hypothesis for the study. In the structure is a dimer of the kinase domains that uses residues completely conserved in MEKK2 and the closely related MEKK3. The surface is in a region known as the αG helix, which she and colleagues found to be necessary for both dimerization and autophosphorylation of MEKK2, demonstrated using mobility shift and split luciferase techniques. Dr. Vish then asked whether the high conservation might indicate additional functions for this surface, and indeed it does. The authors show that downstream substrates MEK5 and MKK6 are both recognized by the same region but interestingly found differences in recruitment, potentially implicating this surface in pathway determination. In addition to revealing the MEKK2 dimerization surface, the crystal structure is in complex with a kinase inhibitor named ponatinib. This clinically used inhibitor may be useful in treating patients with cerebral vascular disease, and the structure will help in future drug discovery studies.
Overall Kimmie hopes this work will help reveal the importance of αG-based dimerization in kinase signaling pathways, especially MAPK pathways. The study is published this week in the journal Nature Communications.
Link to paper: https://www.nature.com/articles/s41467-025-66884-5