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© The Rockefeller University Press, 0021-9525/1997//481 $5.00
The Journal of Cell Biology, Volume 137, Number 2, , 1997 481-492

Article

Regulation of Cell Motility by Mitogen-activated Protein Kinase



Richard L. Klemke*, Shuang Cai{ddagger}, Ana L. Giannini*, Patricia J. Gallagher§, Primal de Lanerolle*, and David A. Cheresh*

* Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037; {ddagger} Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612; and § Department of Physiology and Biophysics, University of Indiana, School of Medicine, Indianapolis, Indiana 46202-5120

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.

1. Abbreviations used in this paper: HA, influenza hemagglutinin epitope; MAP, mitogen-activated protein; MBP, myelin basic protein; MLC, myosin light chain(s); MLCK, myosin light chain kinase.

D.A. Cheresh was supported by grants HL-54444, CA-50286, and CA45726 from the National Institutes of Health (NIH) and a Faculty Research Award from the American Cancer Society. R.L. Klemke was supported by National Institutes of Health fellowship grant 1F32CA67442-07. P. de Lanerolle was supported by National Science Foundation grant (MCB9631833) and the Hannet Brooks fund of the University of Illinois, Chicago, IL. S. Cai was supported by an NIH training grant HL076922. This is manuscript #10200-IMM from The Scripps Research Institute.

Address all correspondence to D.A. Cheresh, The Scripps Research Institute, (IMM-24), 10555 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (619) 784-8281. Fax: (619) 784-8926.


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