Squamous cell carcinoma (SCC) antigen, including intracellular serine protease inhibitors, is widely used as a laboratory marker for cancers of squamous cell origin. Clinical evidences suggest that increased tissue-expression of SCC antigen predicts an invasive phenotype of cancer cells. Herein, we demonstrated that over-expression of SCC antigen increased the rate of EGF-stimulated cell migration. In the search for the underlying molecular mechanism, we have discovered that SCC antigen was translocated to the plasma membrane upon EGF stimulation and co-localized with polymerized-actin at lamellipodia. We further showed that, co-expression of Cdc42, a downstream target of the EGF receptor, enhanced translocation of the SCC antigen, while co-expression of dominant-inhibitory Cdc42 diminished its translocation. These results suggest that EGF-Cdc42 signal regulates the translocation of SCC antigen to the plasma membrane. Lamellipodia at the leading edge might be a site of action of SCC antigen. (c) 2008 Elsevier Inc. All rights reserved.