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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2619-2626.
Prepublished online as a Blood First Edition Paper on June 30, 2005; DOI 10.1182/blood-2004-08-3362.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Negative regulation of CXCR4-mediated chemotaxis by the lipid phosphatase activity of tumor suppressor PTEN
Ping Gao,
Ronald L. Wange,
Ning Zhang,
Joost J. Oppenheim, and
O. M. Zack Howard
From the Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD; and Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a multifunctional tumor suppressor, has been shown to play a regulatory role in cell migration. Dictyostelium discoideum cells lacking PTEN exhibited impaired migration toward 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 stromal cell–derived factor 1 (SDF-1), indicating that PTEN was not requisite for CXC chemokine receptor 4 (CXCR4)–mediated chemotaxis of Jurkat cells. Conversely, reconstitution of PTEN in Jurkat cells by using a tetracycline (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 small interfering RNAs (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.
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