Protein kinase A regulates Rac and is required for the growth factor-stimulated migration of carcinoma cells.
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 beta(1) integrin clustering is regulated by PKA and that Rac1 is required for this migration. Also, we find that beta(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.
O'Connor
K L
KL
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Mercurio
A M
AM
D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002633:Chemotaxis / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019012:Integrin beta1; D008246:Lysophospholipids; D004815:Epidermal Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein