Negative regulation of CXCR4-mediated chemotaxis by the lipid phosphatase activity of tumor suppressor PTEN.
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 1alpha (SDF-1alpha), 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.
Gao
Ping
P
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, PO Box B, Bldg 560, Rm 31-19, Frederick, MD 21702-1201, USA.
Wange
Ronald L
RL
Zhang
Ning
N
Oppenheim
Joost J
JJ
Howard
O M Zack
OM
D000818:Animals; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004023:Dictyostelium; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D019169:Jurkat Cells; D050356:Lipid Metabolism; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D025521:Tumor Suppressor Proteins; C515255:CXCL12 protein, human; C494929:PTEN protein, human