Regulation of cell motility by mitogen-activated protein kinase.
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.
Klemke
R L
RL
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Cai
S
S
Giannini
A L
AL
Gallagher
P J
PJ
de Lanerolle
P
P
Cheresh
D A
DA
D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002277:Carcinoma; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016023:Integrins; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D038981:Receptors, Collagen; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016023:Integrins; D018994:Myosin Light Chains; D038981:Receptors, Collagen; D003094:Collagen; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one