The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death



: Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ, Lilly M

Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

: 2003

Journal of Biological Chemistry

JOURNAL OF BIOLOGICAL CHEMISTRY

: J BIOL CHEM

: 278

: 46

: 45358

: 45367

: 10

: 0021-9258

DOI: https://doi.org/10.1074/jbc.M307933200


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.

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