Regulation of Cell Migration by the Calcium-dependent Protease Calpain*
- Anna Huttenlocher‡§,
- Sean P. Palecek¶,
- Qin Lu‖,
- Wenli Zhang‖,
- Ronald L. Mellgren‖,
- Douglas A. Lauffenburger¶,
- Mark H. Ginsberg** and
- Alan F. Horwitz‡
- From the ‡Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, the¶Department of Chemical Engineering and Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, the ‖Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo, Ohio 43699, and the**Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037
Abstract
Integrin receptors play an important role during cell migration by mediating linkages and transmitting forces between the extracellular matrix and the actin cytoskeleton. The mechanisms by which these linkages are regulated and released during migration are not well understood. We show here that cell-permeable inhibitors of the calcium-dependent protease calpain inhibit both β1 and β3 integrin-mediated cell migration. Calpain inhibition specifically stabilizes peripheral focal adhesions, increases adhesiveness, and decreases the rate of cell detachment. Furthermore, these inhibitors alter the fate of integrin receptors at the rear of the cell during migration. A Chinese hamster ovary cell line expressing low levels of calpain I also shows reduced migration rates with similar morphological changes, further implicating calpain in this process. Taken together, the data suggest that calpain inhibition modulates cell migration by stabilizing cytoskeletal linkages and decreasing the rate of retraction of the cell’s rear. Inhibiting calpain-mediated proteolysis may therefore be a potential therapeutic approach to control pathological cell migration such as tumor metastasis.
Footnotes
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↵* This work was supported by National Institutes of Health grants (to A. F. H., D. A. L., M. H. G., and R. M.), an Arthritis Foundation grant (to A. H.), and a Whitaker Foundation Graduate Fellowship in Biomedical Engineering (to S. P. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ To whom correspondence should be addressed: Dept. of Cell and Structural Biology, B107 Chemistry and Life Sciences Lab., 601 S. Goodwin Ave., Urbana, IL 61801. E-mail: Huttenlo{at}uiuc.edu.
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↵1 The abbreviations used are: CHO, Chinese hamster ovary; BDK, benzoylcarbonyl-Leu-Leu-Tyr diazomethyl ketone.
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↵2 R. Mellgren, unpublished observations.
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- Received July 25, 1997.
- Revision received October 27, 1997.
