The tumor suppressor PTEN regulates T cell survival and antigen receptor signaling by acting as a phosphatidylinositol 3-phosphatase.
The tumor suppressor gene PTEN encodes a 55-kDa enzyme that hydrolyzes both protein phosphotyrosyl and 3-phosphorylated inositol phospholipids in vitro. We have found that the latter activity is physiologically relevant in intact T cells. Expression of active PTEN lead to a 50% loss of transfected cells due to increased apoptosis, which was completely prevented by coexpression of a constitutively active, membrane-bound form of protein kinase B. A mutant of PTEN selectively lacking lipid phosphatase activity, but retaining protein phosphatase activity, had no effects on cell number. Active (but not mutant) PTEN also decreased TCR-induced activation of the mitogen-activated protein kinase ERK2 (extracellular signal-related kinase 2), as seen after inhibition of phosphatidylinositol 3-kinase. Our data indicate that PTEN is a phosphatidylinositol 3-phosphatase in T cells, and we suggest that PTEN may play a role in the regulation of T cell survival and TCR signaling by directly opposing phosphatidylinositol 3-kinase.
Wang
X
X
The Burnham Institute, La Jolla Cancer Research Center, La Jolla, CA 92037, USA.
Gjörloff-Wingren
A
A
Saxena
M
M
Pathan
N
N
Reed
J C
JC
Mustelin
T
T
D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006801:Humans; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019814:Myristic Acid / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D017252:CD3 Complex; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D019814:Myristic Acid; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C061816:phosphatidylinositol-3-phosphatase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human