PTEN inhibits CXCR4-mediated chemotaxis 1 Negative regulation of CXCR4-mediated chemotaxis by the lipid phosphatase activity of tumor suppressor PTEN

PTEN, a multifunctional tumor suppressor, has been shown to play a regulatory role in cell migration. D. discoideum cells lacking PTEN exhibited impaired migration towards chemoattractant gradients. In the present study, we investigated the involvement of PTEN in chemotaxis of mammalian cells by examining PTEN-null Jurkat T cells. We observed that, in contrast to observations made in D. discoideum, PTEN-null Jurkat T cells exhibited potent chemotactic responses to the chemokine, SDF-1α, indicating that PTEN was not requisite for CXCR4-mediated chemotaxis of Jurkat cells. Conversely, reconstitution of PTEN in Jurkat cells by using a Tet-on inducible expression system down-regulated CXCR4-mediated chemotaxis. Furthermore, we established the lipid phosphatase activity of PTEN as essential for its inhibitory effect on chemotaxis. In addition, using PTEN-expressing T cell lines and primary T cells; we demonstrated that down-regulation of PTEN expression with vector-based siRNAs enhanced CXCR4-mediated chemotaxis. Based on these results, we conclude that PTEN expression negatively regulates chemotaxis of lymphoid mammalian cells via its lipid phosphatase activity. Our findings may account for the reported increase in metastatic activity of PTEN-null tumor cells.