Inhibition of Cdc42-mediated activation of mixed lineage kinase 3 by the tumor suppressor protein merlin.

Mammalian mitogen-activated protein kinase (MAPK) signaling pathways respond to diverse extracellular signals and coordinate a range of cellular responses. Mixed lineage kinase 3 (MLK3) is a member of the mixed lineage kinase family of MAPK kinase kinases (MAP3Ks) that functions to regulate multiple MAPK signaling pathways. Activated forms of the Rho GTP ases, Rac and Cdc42, interact with MLK3 through the Cdc42/Rac-interactive binding (CRIB) motif and promote MLK3 catalytic activity. Our recent findings demonstrate that merlin, the product of the neurofibromatosis type 2 (NF2) tumor suppressor gene, is a physiological inhibitor of MLK3. Our results suggest that merlin inhibits MLK3 activity by blocking the Cdc42-MLK3 interaction. In this commentary, the effect of merlin on Cdc42-mediated activation of MLK3 and MAPK signaling will be discussed.