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J. Biol. Chem., Vol. 276, Issue 51, 47895-47900, December 21, 2001
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From the Division of Cancer Biology and Angiogenesis, Department of
Pathology, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, Massachusetts 02115
Members of the Rho family of small GTPases, such
as Rho and Rac, are required for actin cytoskeletal reorganization
during the migration of carcinoma cells. Phosphodiesterases are
necessary for this migration because they alleviate
cAMP-dependent protein kinase (PKA)-mediated inhibition of
RhoA (O'Connor, K. L., Shaw, L. M., and Mercurio, A. M. (1998) J. Cell Biol. 143, 1749-1760; O'Connor
K. L., Nguyen, B.-K., and Mercurio, A. M. (2000),
J. Cell Biol. 148, 253-258). In this study, we report
that the migration of breast and squamous carcinoma cells toward either
lysophosphatidic acid or epidermal growth factor involves not only
phosphodiesterase activity but also cooperative signaling from PKA.
Furthermore, we demonstrate that Rac1 activation in response to
chemoattractant or
Protein Kinase A Regulates Rac and Is Required for the Growth
Factor-stimulated Migration of Carcinoma Cells*
and
1 integrin clustering is
regulated by PKA and that Rac1 is required for this migration. Also, we
find that 1 integrin signaling stimulates the rapid and
transient activation of PKA. A novel implication of these findings is
that carcinoma cell migration is controlled by
cAMP-dependent as well as cAMP inhibitory signaling mechanisms.
*
This work was supported by National Institutes of Health
Grant CA80789 (to A. M. M.) and United States Army Medical Research and Materiel Command Grants DAMD17-98-1-8033 (to K. L. O.) and DAMD17-96-1-6199 (to A. M. M.).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.
Present address: Dept. of Surgery, Division of General Surgery,
University of Texas Medical Branch, 301 University Blvd., Galveston, TX
77555-0527.
§
To whom correspondence should be addressed: Beth Israel Deaconess
Medical Center, Dept. of Pathology, Research North, 99 Brookline Ave.,
Boston, MA 02215. Tel.: 617-667-7714; Fax: 617-975-5531; E-mail:
amercuri@caregroup.harvard.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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