title: The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death.
abstract: 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.
authors.affiliation: Center for Molecular Biology & Gene Therapy, the Department of Microbiology, Loma Linda University School of Medicine, Loma Linda, California 92354, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Marina
authors.initials: M
authors.lastname: Zemskova
authors.forename: Sheldon
authors.initials: S
authors.lastname: Holder
authors.forename: Vernon
authors.initials: V
authors.lastname: Chin
authors.forename: Andrew
authors.initials: A
authors.lastname: Kraft
authors.forename: Paivi J
authors.initials: PJ
authors.lastname: Koskinen
authors.forename: Michael
authors.initials: M
authors.lastname: Lilly
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D019169:Jurkat Cells; D007700:Kinetics; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D051025:bcl-Associated Death Protein
chemical_list: D000911:Antibodies, Monoclonal; C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D016207:Cytokines; D018076:DNA, Complementary; D007377:Interleukin-3; C490587:PIM2 protein, human; C094167:Pim2 protein, mouse; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051025:bcl-Associated Death Protein; D012694:Serine; D003513:Cycloheximide; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases