Abstract
MAP kinase cascades play a pivotal role in many aspects of cellular functions, and are evolutionarily conserved from yeast to mammals. MAP kinase pathways are composed of three kinases: a MAP kinase (MAPK), MAPK kinase (MAPKK), and a MAPK kinase kinase (MAPKKK). MEKK1 is a 196-kD protein serine-threonine kinase that has been cloned as a mammalian homologue of Ste11 and Byr2 MAPKKK in yeast. MEKK1 gene disruption by homologous recombination defined its role of JNK and ERK activations and cell survival by some specific stimuli. MEKK1 deficient cells also showed unexpected roles of cell migration. MEKK1 is associated with actin fibers and focal adhesions, localizing MEKK1 to sites critical in the control of cell adhesion and migration. MEKK1 is required for activation of the cysteine protease calpain and cleavage of spectrin and talin, proteins linking focal adhesions to the cytoskeleton. In MEKK1 knockout mice, the absence of this kinase was sufficient to prevent the cardiac hypertrophy induced by G a q and elevated levels of apoptosis and inflammatory lesions by pressure overload. Thus, MEKK1 is a logical target for drug development in pathological conditions including heart diseases.
