SWAP-70 is a protein that has been suggested to be involved in regulation of actin rearrangement. Having discovered that an artificially-derived mutant of SWAP-70 can transform mouse embryo fibroblasts, we searched for naturally-occurring mutations in the SWAP-70 gene, finding listings for several on the Web at www.sanger.ac.uk/genetics/CGP/cosmic/, including three mutations found in ovarian cancers. (The number of such mutations has now reached 13 out of 228 tumors). We created expression vectors for the mutant SWAP-70 proteins and introduced these into NIH3T3 cells. The cells expressing the mutant SWAP-70 constructs exhibited faster growth than the parental or wild-type SWAP-70-expressing cells. In most instances, cells that are able to grow in soft agar will form tumors in nude mice. While SWAP-70-transformed cells grew in soft agar, they failed to form tumors in nude mice. This result implies that transformation by the SWAP-70 mutants is unique. The cells bearing the mutant SWAP-70 genes were sensitive to nutrient starvation, supporting the idea that they are transformed cells. However, they failed to pile up and demonstrated contact inhibition, unlike most normal transformed cells. Upon expression of human SWAP-70 genes, MEK1 was activated. This activation appeared to contribute to the saturation density of the cells. As SWAP-70 has been shown to be the last protein to receive signals from cytokines, it is likely that there is a putative feedback signaling pathway, and that disorder of this signaling pathway can transform cells. Accordingly, this may explain why SWAP-70-transformed cells have different characteristics than most transformed cells.