Colorectal cancer is the second most frequent cancer in the Western world, often lethal when invasion and/or metastasis occur. In addition to hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins, especially the E₂ series (PGE₂), generated by the cyclooxygenase‐2 (Cox‐2) enzyme. While concentration of PGE₂ as well as expression of Cox‐2, HGF receptor (c‐Met‐R), epidermal growth factor receptor (EGFR), and β‐catenin are all dramatically increased in colon cancers and implicated in their growth and invasion, the precise role of PGE₂ in the latter process remains unclear. Here we provide evidence that PGE₂ transactivates c‐Met‐R (contingent upon functional EGFR), increases tyrosine phosphorylation and nuclear accumulation of β‐catenin, and induces urokinase‐type plasminogen activator receptor (uPAR) mRNA expression. This is accompanied by increased β‐catenin association with c‐Met‐R and enhanced colon cancer cell invasiveness. Inactivation of EGFR and c‐Met‐R significantly reduced PGE₂‐induced cancer cell invasiveness. Clinical relevance of these findings is confirmed by our immunohistochemical studies demonstrating that cancer cells in the invasive front overexpress Cox‐2, c‐Met‐R, and β‐catenin. Our findings explain a functional relationship between prostaglandins, EGFR, and c‐Met‐R in colon cancer growth and invasion.—Pai, R., Nakamura, T., Moon, W. S., Tarnawski, A. S. Prostaglandins promote colon cancer cell invasion; signaling by cross‐talk between two distinct growth factor receptors. FASEB J. 17, 1640–1647 (2003)