Key points are not available for this paper at this time.
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. 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. Hematopoietic cells are dependent on peptide growth factors for survival and proliferation. The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor, and the related cytokines interleukin-3 (IL-3) 1The abbreviations used are: IL, interleukin; GST, glutathione S-transferase; CS, calf serum; neo, neomycin; SCF, stem cell factor; ELISA, enzyme-linked immunosorbent assay; Chaps, 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid; Pipes, 1,4-piperazinediethanesulfonic acid; DTT, dithiothreitol; Mops, 4-morpholinepropanesulfonic acid. and IL-5, can induce a spectrum of responses in target cells, including proliferation, differentiation, and prevention of apoptosis. The signaling events that regulate these several phenotypic responses are of great interest, and many mediators of these responses are being characterized. Among the signaling intermediates implicated in hematopoietic cell survival is the pim-1 serine/threonine kinase (1Selten G. Cuypers H.T. Boelens W. Robanus-Maandag E. Verbeek J. Domen J. van Beveren C. Berns A. Cell. 1986; 46: 603-611Abstract Full Text PDF PubMed Scopus (143) Google Scholar). pim-1 expression is regulated by hematopoietic growth factors (2Dautry F. Weil D. Yu J. Dautry-Varsat A. J. Biol. Chem. 1988; 263: 17615-17620Abstract Full Text PDF PubMed Google Scholar, 3Lilly M. Le T. Holland P. Hendrickson S.L. Oncogene. 1992; 7: 727-732PubMed Google Scholar). Furthermore, the kinase enhances factor-independent survival of hematopoietic cells, in part through a bcl-2-dependent pathway (4Lilly M. Kraft A. Cancer Res. 1997; 57: 5348-5355PubMed Google Scholar, 5Lilly M. Sandholm J. Cooper J.J. Koskinen P. Kraft A. Oncogene. 1999; 18: 4022-4031Crossref PubMed Scopus (153) Google Scholar). The pim-1 gene product is a true oncogene, in that its enforced expression in transgenic mice leads to an increased incidence of tumors (6van Lohuizen J. Verbeek S. Krimpenfort P. Domen J. Saris C. Radaszkiewicz T. Berns A. Cell. 1989; 56: 673-682Abstract Full Text PDF PubMed Scopus (441) Google Scholar, 7Breuer M. Wientjens E. Verbeek S. Slebos R. Berns A. Cancer Res. 1991; 51: 958-963PubMed Google Scholar). Potential PIM-1 substrates include proteins active in cell cycle regulation and transcription, such as Cdc25 (8Mochizuk I.T. Kitanaka C. Noguchi K. Muramatsu T. Asia A. Kuchino Y. J. Biol. Chem. 1999; 274: 18659-18666Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar), PAP-1 (9Maita H. Harada Y. Nagakubo D. Kitaura H. Ikeda M. Tamai K. Takahashi K. Ariga H. Iguchi-Ariga S.M. Eur. J. Biochem. 2000; 267: 5168-5178Crossref PubMed Scopus (55) Google Scholar), HP1 (10Koike N. Maita H. Taira T. Ariga H. Iguchi-Ariga S.M. FEBS Lett. 2000; 467: 17-21Crossref PubMed Scopus (98) Google Scholar), NFATc1 (11Rainio E.M. Sandholm J. Koskinen P.J. J. Immunol. 2002; 168: 1524-1527Crossref PubMed Scopus (109) Google Scholar), PTP-U2S (12Wang Z.P. Bhattacharya N. Meyer M.K.E. Seimiya H. Tsuruo T. Tonani J.A. Magnuson N.S. Arch. Biochem. Biophys. 2001; 390: 9-18Crossref PubMed Scopus (45) Google Scholar), and the c-myb transcriptional co-activator p100 (13Leverson J.D. Koskinen P.J. Orrico P.C. Rainio E.M. Jalkanen K.J. Dash A.B. Eisenman R.N. Ness S.A. Mol. Cell. 1998; 2: 417-425Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). pim-1 belongs to a kinase family that has three members: pim-1 (1Selten G. Cuypers H.T. Boelens W. Robanus-Maandag E. Verbeek J. Domen J. van Beveren C. Berns A. Cell. 1986; 46: 603-611Abstract Full Text PDF PubMed Scopus (143) Google Scholar), pim-2 (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar), and pim-3 (15Feldman J.D. Vician L. Crispino M. Tocco G. Marcheselli V.L. Bazan N.G. Baudry M. Herschman H.R. J. Biol. Chem. 1998; 273: 16535-16543Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). These related enzymes show substantial homology, but differ in their tissue expression (16Eichmann A. Yuan L. Breant C. Alitalo K. Koskinen P.J. Oncogene. 2000; 19: 1215-1224Crossref PubMed Scopus (95) Google Scholar). It is unknown to what extent the various family members differ in their biochemical effects. The pim-2 gene was identified as a frequent site for retroviral insertion in experimental lymphomas, both in normal and pim-1-deficient mice (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar). The pim-2 gene also encodes a cytoplasmic serine threonine kinase whose expression is regulated by hematopoietic cytokines (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar, 15Feldman J.D. Vician L. Crispino M. Tocco G. Marcheselli V.L. Bazan N.G. Baudry M. Herschman H.R. J. Biol. Chem. 1998; 273: 16535-16543Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 16Eichmann A. Yuan L. Breant C. Alitalo K. Koskinen P.J. Oncogene. 2000; 19: 1215-1224Crossref PubMed Scopus (95) Google Scholar, 17Allen J.D. Verhoeven E. Domen J. vanderValk M. Berns A. Oncogene. 1997; 15: 1133-1141Crossref PubMed Scopus (140) Google Scholar). Like the PIM-1 kinase, there are multiple isoforms of PIM-2 protein (three in the mouse and potentially two in humans) due to the use of the alternative translation start codon, CTG (18Saris C.J. Domen J. Berns A. EMBO J. 1991; 10: 655-664Crossref PubMed Scopus (265) Google Scholar). Functional similarity between pim-1 and pim-2 gene products has been inferred from studies of transgenic mice. Both pim-1 and pim-2 induce lymphomas alone or in synergy with c-myc (6van Lohuizen J. Verbeek S. Krimpenfort P. Domen J. Saris C. Radaszkiewicz T. Berns A. Cell. 1989; 56: 673-682Abstract Full Text PDF PubMed Scopus (441) Google Scholar, 14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar). Furthermore, the relatively weak phenotype associated with disruption of the pim-1 gene (19Laird P.W. van der Lugt N.M. Clarke A. Domen J. Linders K. McWhir J. Berns A. Hooper M. Nucleic Acids Res. 1993; 21: 4750-4755Crossref PubMed Scopus (107) Google Scholar) suggests that its functions may be largely assumed by related molecules, such as the highly homologous pim-2 gene. Little is known, however, of the biochemical and molecular events through which the PIM-2 kinase may act. We have therefore sought to characterize the effect of PIM-2 protein in immortalized hematopoietic cells and identify potential molecular events modulated by this kinase. Our data indicate that PIM-2 kinase inhibits apoptosis induced by various stimuli. Furthermore, we implicate phosphorylation of BAD as a possible mechanism through which the enzyme may inhibit apoptosis. These data that enforced expression of the pim-2 gene effects to identified for pim-1 in immortalized hematopoietic cells. and murine hematopoietic cell FDCP1 from and from Cancer used for this in with calf and by the cell of cells in with calf All cells at in and cells in calf and for the short form of murine PIM-2 protein (PIM-2(34 kDa)) was from an FDCP1 cell by the for The for kDa)) and kDa)) forms by a from a murine The for PIM-2 was by a the for both short and forms of murine PIM-2 or short by a the start was to and was by an All the expression to the of expression for a BAD protein was from and in an by molecular was by expression for pim-1 was by the from (4Lilly M. Kraft A. Cancer Res. 1997; 57: 5348-5355PubMed Google Scholar) expression of the the for the short form of PIM-2 was the as was the for the short form of of and murine cells in cells of and to the the was with an of the cells and for cell cells also for expression of of a to cells in by and The cells in for and by for expression of the of and cell pim-2 by expression of the PIM-2 isoforms was by FDCP1 cells or kDa) by with and to produce cell for expression by for biochemical and cell growth and of cells, cells in of in with a was by an with both an and The of cells that but was to be the by a to murine PIM-2 protein was as mice with murine kDa) The was produced in as a the expression The protein was by on a and was to of a on and by that with murine PIM-2 protein but not or murine PIM-1 by and was for its ability to murine PIM-2 protein by both of these for pim-1 and pim-2 by of on to and with pim-2 the of a murine pim-2 The pim-1 of an of the from (4Lilly M. Kraft A. Cancer Res. 1997; 57: 5348-5355PubMed Google Scholar). of the was as the with a in and in by or in Chaps, DTT, by three protein was and with an of of protein to for in and to with by with The caspase for BAD mouse for and and BAD cells with an expression for PIM-2(34 kDa) cells in DTT, PIM-2 proteins produced by in and a by of the products in PIM-2 was with with with and with and in in kinase DTT, protein kinase peptide with of and of protein as a substrate. at for to with and the to of in a with at for with for three The on the was in and by The by kinase in with but this the protein was by with The PIM-2 kinase was also in of a with with kDa) or kDa) protein was in the kinase with The kinase was to for at was by of for at The was a on an at of enzyme with the kinase in with of of kinase protein was with the was by the the of the also to that the was for at enzyme and the results by the data by the to the of and of pim-2 mRNA and by in a to of ability of pim-2 to for the of pim-1 (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar) suggests also that the expression of these two be regulated in a this we FDCP1 cells for and with a of cytokines for an that both pim-1 and pim-2 induced by and to a extent by stem cell and to induce expression of PIM-2 protein with pim-2 mRNA we a The identified PIM-2 protein with of PIM-1 in of cells FDCP1 cells three PIM-2 as (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar), with the form being most PIM-2 protein the in mRNA FDCP1 cells of cytokine little induced a in the kinase of the that induced expression of but stem cell and to expression of the kinase of Hematopoietic with pim-2 identify potential effects by we the various as as an kinase, in two factor-dependent murine hematopoietic cells, FDCP1 and enforced expression in a in the protein cell data not of the kDa) protein in both cell for the other two of the was also of the products not after in the cells or in cell The of the proteins in FDCP1 cells was after of protein and The kDa) protein an short the kDa) was PIM-2(34 kDa) a in of PIM-2 proteins not due to the short for the PIM-2 of Hematopoietic after or and cells in the of pim-2 also but at a cell data not with cells for several The three isoforms of PIM-2 survival effects. The form (PIM-2(34 kDa)) was the most active at cell in little in cell for to of cytokine However, the and forms of PIM-2 active at cell death. a not factor-independent survival and to the this the similarly to a PIM-1 which also cell cytokine M. Sandholm J. Cooper J.J. Koskinen P. Kraft A. Oncogene. 1999; 18: 4022-4031Crossref PubMed Scopus (153) Google Scholar). The pim-1 kinase has been implicated in to such as and Oncogene. 2000; 19: PubMed Scopus (55) Google Scholar). We that enforced expression of the active PIM-2(34 kDa) kinase also to in FDCP1 cells, to a in the for that not with cells. PIM-2 and the of with in hematopoietic cells cytokine is to from or cell death. We have that the pim-1 kinase inhibits the of apoptosis in FDCP1 cells (4Lilly M. Kraft A. Cancer Res. 1997; 57: 5348-5355PubMed Google Scholar). we the survival effects of PIM-2 protein from apoptosis. the pro-survival effects associated with enforced expression of the PIM-2(34 kDa) studies on this kinase cells by in and kDa) cells withdrawal. cells an increased of cells which and with an in apoptosis mechanism of caspase is in apoptosis induced by and growth withdrawal. We have of PIM-2 can regulate the of caspase to a in the caspase in cells, by a in the active of caspase was by the of PIM-2 in kDa) cells. These data that pim-2 cells from apoptosis by caspase activation. PIM-2 BAD Both in and in and of the mechanism of pim-2 inhibits caspase we its effects on the expression or of several members of the family of survival proteins. and kDa) cells by after in the or of enforced expression of pim-2 to in expression of or was associated with expression of and increased expression of BIM, but PIM-2 not their expression not We have that the PIM-1 protein can the effects of BAX protein of expression M. Sandholm J. Cooper J.J. Koskinen P. Kraft A. Oncogene. 1999; 18: 4022-4031Crossref PubMed Scopus (153) Google Scholar). This that PIM-1 regulate the of other pro-apoptotic family such as BAD M. Sandholm J. Cooper J.J. Koskinen P. Kraft A. Oncogene. 1999; 18: 4022-4031Crossref PubMed Scopus (153) Google Scholar). we have that PIM-1 kinase can phosphorylate T. J. K. J. H. P. M. and P. J. We therefore the PIM-2 kinase and the BAD as leads to of and of apoptosis in factor-dependent hematopoietic cells P. F. S.M. 2000; PubMed Google Scholar). The phosphorylation for pim kinases are to of and kinase kinases M. S. R. Magnuson N.S. Arch. Biochem. Biophys. 1992; PubMed Scopus Google Scholar). these kinases can phosphorylate possible that PIM-2 as PIM-2 proteins by from cells with expression for or kinase PIM-2(34 kDa) proteins. The enzymes in an kinase for their ability to phosphorylate from kinase to phosphorylate to protein alone was not by the kinase. characterize the we protein to with protein by PIM-2(34 kDa) protein with BAD on serine from cells with a a short phosphorylate the due to of other BAD kinases with a form of PIM-2 similarly not PIM-2 to phosphorylate on serine 112, the not with for serine or serine the PIM-2 isoforms in their ability to survival of FDCP1 cells, we their kinase for the three PIM-2 isoforms by in translation by used in an in kinase to phosphorylate on serine The kinase of the form that was about that of the a for the protein kinase that the in was due to The form also ability to phosphorylate BAD not We have that PIM-1 protein can phosphorylate T. J. K. J. H. P. M. and P. J. the of the two kinases for the we kDa) protein with The kinases in an kinase with as the substrate. The PIM-2 protein in the that the was for at with the of was with of in the The the was with by The that the enzyme with It was also from the that the for PIM-2 and PIM-1 and therefore the This suggests that PIM-1 and PIM-2 may be kinases for not be from the the is in of of the The and can be used as to PIM-1 and PIM-2 but not for with for other kinases, as in the of the data in the and for the two kinases in of the two not We the phosphorylation of BAD by PIM-2 in a and cells with expression for PIM-2(34 kDa) and alone or in the of was on serine in both cell in cells there was phosphorylation of serine and serine in cells serine was in the of of the pim-2 product was in the cells, We also and kDa) cells with a expression and a protein was we to BAD proteins. the protein has the BAD to be for expression of by with an Several of and cells and three of Enforced expression of in cells with cells However, enforced expression of PIM-2 protein was to the effect of We therefore the extent of phosphorylation in the after cells in phosphorylation of on serine after of The cells increased phosphorylation of which little after withdrawal. of BAD on serine or serine was not these we sought to of PIM-2 phosphorylate BAD FDCP1 cells neo, PIM-2(34 kDa) or protein of for cell used for The BAD protein was in three BAD but phosphorylation on serine in cells. kDa) increased phosphorylation of cells with PIM-2 phosphorylation of PIM-2 in through of BAD on phosphorylation of BAD on serine a in the ability of PIM-2 to inhibit cell we sought to PIM-2 and a that not be on serine However, we to cell with these The proteins not We therefore to PIM-2 and or in This cell was used can be FDCP1 and has been used for studies of BAD also with an expression for the protein to cells. the cells by and of cells with a alone highly the expression the of cells, that the two proteins induced cell in the cells. with a pim-2 expression increased the of cells, the ability of the kinase to survival of the also with PIM-2(34 kDa) and or with the expression Enforced expression of PIM-2(34 kDa) protein was at cell in the of with its ability to reverse the effects of the protein for These data that of by PIM-2(34 kDa) at in part on the ability of the kinase to phosphorylate on serine granulocyte-macrophage colony-stimulating factor, and related growth factors induce proliferation and of hematopoietic cells and from apoptosis. We have that this family of cytokines the expression of pim family kinases in hematopoietic cells. The pim kinases show expression (16Eichmann A. Yuan L. Breant C. Alitalo K. Koskinen P.J. Oncogene. 2000; 19: 1215-1224Crossref PubMed Scopus (95) Google Scholar). studies have or biochemical the pim-1 and pim-2 appear to be regulated similarly (2Dautry F. Weil D. Yu J. Dautry-Varsat A. J. Biol. Chem. 1988; 263: 17615-17620Abstract Full Text PDF PubMed Google Scholar, 3Lilly M. Le T. Holland P. Hendrickson S.L. Oncogene. 1992; 7: 727-732PubMed Google Scholar, 17Allen J.D. Verhoeven E. Domen J. vanderValk M. Berns A. Oncogene. 1997; 15: 1133-1141Crossref PubMed Scopus (140) Google Scholar). these kinases (6van Lohuizen J. Verbeek S. Krimpenfort P. Domen J. Saris C. Radaszkiewicz T. Berns A. Cell. 1989; 56: 673-682Abstract Full Text PDF PubMed Scopus (441) Google Scholar, 14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar, 17Allen J.D. Verhoeven E. Domen J. vanderValk M. Berns A. Oncogene. 1997; 15: 1133-1141Crossref PubMed Scopus (140) Google Scholar), is that may also through biochemical that both PIM-1 and PIM-2 can phosphorylate the protein J.A. S. E. S. D. V.L. P. S. A. 2002; PubMed Scopus Google Scholar). this however, studies have identified potential PIM-2 We that PIM-2 can phosphorylate and BAD and that its as a BAD kinase that of we that PIM-1 and PIM-2 are for these data suggest that for the kinases may from their tissue expression (16Eichmann A. Yuan L. Breant C. Alitalo K. Koskinen P.J. Oncogene. 2000; 19: 1215-1224Crossref PubMed Scopus (95) Google Scholar). Three PIM-2 isoforms are in FDCP1 and cells. The kDa) protein is the other This the results from in translation of the pim-2 (14van der Lugt N.M. Domen J. Verhoeven E. Linders K. van der Gulden H. Allen J. Berns A. EMBO J. 1995; 14: 2536-2544Crossref PubMed Scopus (170) Google Scholar). as a kDa) was the these protein expression in part kinase with the form of PIM-2 being and at a these data suggest that transcriptional and regulation may both an in the of the various isoforms in the the pim-2 mRNA the start site for PIM-2(34 kDa) is by the alternative start for kDa) is by kDa) the start is by with the the start for kDa) and PIM-2(34 kDa) are by This with the that the for kDa) is in a may to the of PIM-2 The and biochemical effects of these three isoforms differ as the proteins with an in kinase the and forms the was and the enzymes It is not the form is active the the in the form an the and forms at in the FDCP1 cells, is that the in kinase accounts for the survival effect of the kinase. The and PIM-2 proteins ability to phosphorylate BAD in the enzyme was active at survival in FDCP1 cells. this the of expression of the cells, with that of PIM-2(34 may for the survival effect of the kinase. The mechanisms through which pim-2 to cell survival and inhibit cell have not been characterized. Our studies of the pim-1 kinase the of family members M. Sandholm J. Cooper J.J. Koskinen P. Kraft A. Oncogene. 1999; 18: 4022-4031Crossref PubMed Scopus (153) Google Scholar). of the between the two kinases, may through biochemical We have that the PIM-1 kinase can phosphorylate and that the PIM-2 kinase can PIM-2 kinase, from cells, was to phosphorylate a in on serine in cells with both pim-2 and expression the was on serine 112, serine and serine These may be the of PIM-2 other kinases, a effect of PIM-2 protein the in kinase which are known to not show serine or serine we have that of a with pim-2 and the serine phosphorylation of the not We that this potential of serine by PIM-2 is to be of serine or serine phosphorylation was in an in which of the in cells. we of serine or serine phosphorylation in FDCP1 cells the two that serine is the phosphorylation site on for the PIM-2 kinase. phosphorylation at other does not mediate a part of the PIM-2 of BAD to be the site for kinase both and The serine several but a phosphorylation site M. S. R. Magnuson N.S. Arch. Biochem. Biophys. 1992; PubMed Scopus Google Scholar). Several other known PIM-1 substrates also have phosphorylation is not the are for PIM-2 several other enzymes as known kinases for BAD These include protein kinase M. M. J.D. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), kinase J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), kinase C. L. N. G. P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and kinase A. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). It is not of of these other kinases can phosphorylate BAD data show that enforced expression of a PIM-2 protein both phosphorylation of BAD and cell survival to that of cells BAD we can identify BAD as a legitimate for PIM-2 kinase at as as in a Enforced expression of PIM-2 was to the effects of in both and cells. However, to FDCP1 PIM-2 and a that phosphorylation of by the PIM-2 kinase on serine was for this This was in the Enforced expression of or similarly the of cells, PIM-2 increased of the the effects of both of the However, of the was of the the of PIM-2 to phosphorylate BAD on serine for these data also suggest that other molecular may be studies the of BAD in survival of hematopoietic cells J. Immunol. 1999; Google Scholar, A.B. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). The between phosphorylation of BAD in the of enforced expression of and cell suggest that BAD in survival of these cells, and that part of the survival effect of We however, that pim kinases regulate a of survival PIM-1 has been to phosphorylate and regulate the of the a of cell Bhattacharya N. W. J. Magnuson N.S. Biophys. 2002; PubMed Scopus Google Scholar). We have a of for substrates and and have many several of which can be implicated in survival is that many between family kinases and survival be identified in the
Yan et al. (Sat,) studied this question.