REGULATION OF CELL MOTILITY BY MITOGEN-ACTIVATED PROTEIN-KINASE

Cell interaction with adhesive proteins or growth factors in the extra cellular matrix initiates Pas! mitogen-activated protein (MAP) kinase signaling. Evidence is provided that MAP kinase (ERK1 and ERK2) influe nces the cells' motility machinery by phosphorylating and, thereby, en hancing myosin light chain kinase (MLCK) activity leading to phosphory lation of myosin light chains (MLC). Inhibition of MAP kinase activity causes decreased MLCK function, MLC phosphorylation, and cell migrati on on extracellular matrix proteins. In contrast, expression of mutati onally active MAP kinase kinase causes activation of MAP kinase leadin g to phosphorylation of MLCK and MLC and enhanced cell migration. In v itro results support these findings since ERK-phosphorylated MLCK has an increased capacity to phosphorylate MLC and shows increased sensiti vity to calmodulin. Thus, we de fine a signaling pathway directly down stream of MAP kinase, influencing cell migration on the extracellular matrix.