Epidermal growth factor regulates protein kinase A activity in murine fibrosarcoma cells: differences between...

The interplay between cyclic AMP (cAMP)-dependent protein kinase A (PKA)- and p21ras-mediated signaling pathways is expected to determine further loss, maintenance, or modulation of differentiation and proliferation of a particular cell. Therefore, the relationship and nature of the cross-talk between these two major signaling systems are of utmost importance to the understanding of these processes in both normal and neoplastic cells. In view of their paramount physiological importance, one would expect the existence of a well-controlled bidirectional interaction between these pathways, which would be more appropriate and in agreement with basic principles of cellular homeostasis. However, based on the discovery that activated PKA may inhibit ras-mediated translocation of c-Raf-1 to the plasma membrane, it is generally accepted that the cross-talk between cAMP/PKA and p21ras-mediated signal transduction pathways is unilateral, i.e., that the activation of PKA regulates growth factor receptor protein tyrosine kinase-mediated signaling. To challenge the validity of a unilateral approach, we decided to test the possible existence of cross-talk of a bidirectional nature between the aforementioned signaling pathways at different stages of malignant differentiation. For that purpose, we investigated the nature of the cross-talk existing between a known receptor protein tyrosine kinase-epidermal growth factor receptor (EGFR) and PKA in highly metastatic and nonmetastatic cloned variants of a murine fibrosarcoma (T-10). Our study revealed the existence of principal differences in PKA activity between metastatic and nonmetastatic cloned fibrosarcoma variants that may be due to the differential expression and membrane translocation of the p21(Ki-ras) small mass G-protein. Most importantly, our experiments have demonstrated the existence of a novel character of interactions between EGFR and PKA, because the ligation of the EGFR by epidermal growth factor in the metastatic variant induced a high activity of PKA. These findings are of prime importance, because they reveal the existence of a new relationship between two major signal transduction pathways in mammalian cells, i.e., the existence of a bilateral interaction between the ras- and cAMP/PKA-mediated signal transduction pathways. Furthermore, the fact that two tumor cell variants originating in the same tumor and differing in their metastatic capacity differ as well in the nature of the cross-talk between major signal generation systems imposes new challenges for the future use of biological response modulators to cure cancer and restrict metastatic spread.