MEKK1 Displays Destructive PHD

Abstract

The mitogen-activated protein (MAP) kinase MEKK1 sits at the top of of a cascade of protein kinases that leads to phosphorylation and consequent activation of MAP kinases. Reversal of these phosphorylation events by phosphatases is an obvious mechanism for restraining MAP kinase activity, but the actual mechanism now appears to be more complicated. Lu et al. report that in NIH3T3 cells, MEKK1 acts not only as a kinase, but also associates with the MAP kinase ERK2 and has E3 ubiquitin ligase activity toward the ERK2 protein. Exposure of cells to osmotic stress (500 mM sorbitol) caused a prolonged activation of ERK2 (up to 8 hours) that was eventually reversed by destruction of ERK2 rather than dephosphorylation. Such destruction required interaction of ERK2 with MEKK1 and ubiquitin ligase activity present in the PHD (plant homeodomain) domain of MEKK1. Expression of a mutant form of ERK2 with a disrupted docking site for binding MEKK1 protected cells from sorbitol-induced apoptosis, probably by preventing ubiquitination and subsequent destruction of ERK2 (activity of which is known to protect cells from apoptosis). The authors note that PHD domains are found in many proteins and that mutations in PHD domains are associated with several human diseases. If other PHD domains share E3 ubiquitin ligase activity as demonstrated for the domain in MEKK1, the association of mutations with disease may reflect the importance of proper E3 ligase function. Z. Lu, S. Xu, C. Joazerio, M. H. Cobb, T. Hunter, The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol. Cell 9 , 945-956 (2002). [Online Journal]