The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death.
Hematopoietic growth factors mediate the survival and proliferation of blood-forming cells, but the mechanisms through which these proteins produce their effects are incompletely known. Recent studies have identified the pim family of kinases as mediators of cytokine-dependent survival signals. Several studies have identified substrates for the pim-1 kinase, but little ... is known about the other family members, pim-2 and pim-3. We have investigated potential functions for the pim-2 kinase in factor-dependent murine hematopoietic cells. We find that pim-2 mRNA and protein expression are regulated by cytokines similarly to pim-1. Three PIM-2 protein isoforms are produced in cytokine-treated cells. All three forms are active kinases, and the short (PIM-2(34 kDa)) form is the most active at enhancing survival of FDCP1 cells after cytokine withdrawal. This pro-survival function involves inhibition of apoptosis and caspase activation. Enforced expression of PIM-2(34 kDa) kinase does not appear to regulate expression of BCL-2, BCL-xL, BIM, or BAX proteins. However, the kinase can phosphorylate the pro-apoptotic protein BAD on serine 112, which accounts in part for its ability to reverse Bad-induced cell death. Our results indicate that pim-2 functions similarly to pim-1 as a pro-survival kinase and suggest that BAD is a legitimate PIM-2 substrate.
Mesh Terms:
Animals, Antibodies, Monoclonal, Apoptosis, Blotting, Northern, Blotting, Western, Carrier Proteins, Cell Line, Cell Line, Tumor, Cell Survival, Cycloheximide, Cytokines, DNA, Complementary, Glutathione Transferase, Hela Cells, Humans, Interleukin-3, Jurkat Cells, Kinetics, Mice, NIH 3T3 Cells, Phosphorylation, Plasmids, Protein Isoforms, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, RNA, Messenger, Serine, Time Factors, Transfection, Transgenes, bcl-Associated Death Protein
Animals, Antibodies, Monoclonal, Apoptosis, Blotting, Northern, Blotting, Western, Carrier Proteins, Cell Line, Cell Line, Tumor, Cell Survival, Cycloheximide, Cytokines, DNA, Complementary, Glutathione Transferase, Hela Cells, Humans, Interleukin-3, Jurkat Cells, Kinetics, Mice, NIH 3T3 Cells, Phosphorylation, Plasmids, Protein Isoforms, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, RNA, Messenger, Serine, Time Factors, Transfection, Transgenes, bcl-Associated Death Protein
J. Biol. Chem.
Date: Nov. 14, 2003
PubMed ID: 12954615
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