Regulation of Cell Motility by Mitogen-activated Protein Kinase

TLDR

Cell interaction with extracellular matrix proteins activates Ras/MAP kinase signaling. The study aims to define a MAP kinase–dependent signaling pathway that regulates cell migration on the extracellular matrix. MAP kinase phosphorylates myosin light chain kinase, which then phosphorylates myosin light chains to drive cell migration. Inhibition of MAP kinase decreases MLCK activity, MLC phosphorylation, and migration, while active MAP kinase enhances these events, and ERK‑phosphorylated MLCK shows higher activity and calmodulin sensitivity.

Abstract

Cell interaction with adhesive proteins or growth factors in the extracellular matrix initiates Ras/ mitogen-activated protein (MAP) kinase signaling. Evidence is provided that MAP kinase (ERK1 and ERK2) influences the cells' motility machinery by phosphorylating and, thereby, enhancing myosin light chain kinase (MLCK) activity leading to phosphorylation of myosin light chains (MLC). Inhibition of MAP kinase activity causes decreased MLCK function, MLC phosphorylation, and cell migration on extracellular matrix proteins. In contrast, expression of mutationally active MAP kinase kinase causes activation of MAP kinase leading to phosphorylation of MLCK and MLC and enhanced cell migration. In vitro results support these findings since ERK-phosphorylated MLCK has an increased capacity to phosphorylate MLC and shows increased sensitivity to calmodulin. Thus, we define a signaling pathway directly downstream of MAP kinase, influencing cell migration on the extracellular matrix.