MEK/ERK-Mediated Phosphorylation of Bim Is Required to Ensure Survival of T and B Lymphocytes during Mitogenic Stimulation

Survival and death of lymphocytes are regulated by the balance between pro- and antiapoptotic members of the Bcl-2 family; this is coordinated with the control of cell cycling and differentiation. Bim, a proapoptotic BH3-only member of the Bcl-2 family, can be regulated by MEK/ERK-mediated phosphorylation, which affects its binding to pro–survival Bcl-2 family members and its turnover. We investigated Bim modifications in mouse B and T lymphoid cells after exposure to apoptotic stimuli and during mitogenic activation. Treatment with ionomycin or cytokine withdrawal caused an elevation in BimEL, the most abundant Bim isoform. In contrast, in mitogenically stimulated T and B cells, BimEL was rapidly phosphorylated, and its levels declined. Pharmacological inhibitors of MEK/ERK signaling prevented both of these changes in Bim, reduced proliferation, and triggered apoptosis of mitogen-stimulated T and B cells. Loss of Bim prevented this cell killing but did not restore cell cycling. These results show that during mitogenic stimulation of T and B lymphocytes MEK/ERK signaling is critical for two distinct processes, cell survival, mediated (at least in part) through phosphorylation and consequent inhibition of Bim, and cell cycling, which proceeds independently of Bim inactivation.

[1]  A. Strasser,et al.  Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim. , 2009, Immunity.

[2]  R. Flavell,et al.  Multisite phosphorylation regulates Bim stability and apoptotic activity. , 2008, Molecular cell.

[3]  A. Strasser,et al.  Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells. , 2007, Blood.

[4]  Tomomi Gotoh,et al.  ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim , 2007, Cell.

[5]  Ceri M. Wiggins,et al.  ERK1/2‐dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl‐1 and Bcl‐xL , 2007, The EMBO journal.

[6]  A. Strasser,et al.  The BH3-Only Protein Bid Is Dispensable for DNA Damage- and Replicative Stress-Induced Apoptosis or Cell-Cycle Arrest , 2007, Cell.

[7]  Erinna F. Lee,et al.  Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak , 2007, Science.

[8]  A. Strasser,et al.  Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction , 2006, The Journal of experimental medicine.

[9]  H. Harada,et al.  TLR-dependent Bim phosphorylation in macrophages is mediated by ERK and is connected to proteasomal degradation of the protein. , 2006, International immunology.

[10]  A. Strasser,et al.  Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic , 2006, Proceedings of the National Academy of Sciences.

[11]  A. Strasser,et al.  BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. , 2005, Blood.

[12]  E. Clark,et al.  BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway , 2005, The Journal of experimental medicine.

[13]  S. Cook,et al.  Regulatory phosphorylation of Bim: sorting out the ERK from the JNK , 2005, Cell Death and Differentiation.

[14]  M. Grãos,et al.  Growth-factor-dependent phosphorylation of Bim in mitosis. , 2005, The Biochemical journal.

[15]  A. Strasser.  The role of BH3-only proteins in the immune system , 2005, Nature Reviews Immunology.

[16]  Susan R. Wilson,et al.  Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. , 2004, Immunity.

[17]  D. Green,et al.  The Pathophysiology of Mitochondrial Cell Death , 2004, Science.

[18]  P. Insel,et al.  The Pro-apoptotic Protein Bim Is a Convergence Point for cAMP/Protein Kinase A- and Glucocorticoid-promoted Apoptosis of Lymphoid Cells* , 2004, Journal of Biological Chemistry.

[19]  S. Cook,et al.  Extracellular Signal-regulated Kinases 1/2 Are Serum-stimulated “BimEL Kinases” That Bind to the BH3-only Protein BimEL Causing Its Phosphorylation and Turnover* , 2004, Journal of Biological Chemistry.

[20]  V. Levitsky,et al.  Regulation of expression of Bcl-2 protein family member Bim by T cell receptor triggering. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Shi Yan,et al.  The MAP kinase pathway is required for entry into mitosis and cell survival , 2004, Oncogene.

[22]  Y. Kadono,et al.  Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3‐only Bcl‐2 family member Bim , 2003, The EMBO journal.

[23]  A. Strasser,et al.  Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. , 2003, Annual review of immunology.

[24]  A. Strasser,et al.  Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Andreas Villunger,et al.  p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa , 2003, Science.

[26]  A. Strasser,et al.  Loss of the Pro-Apoptotic BH3-only Bcl-2 Family Member Bim Inhibits BCR Stimulation–induced Apoptosis and Deletion of Autoreactive B Cells , 2003, The Journal of experimental medicine.

[27]  G. Pagès,et al.  Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function , 2003, Oncogene.

[28]  J. Cleveland,et al.  Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. , 2003, Cancer cell.

[29]  S. R. Datta,et al.  Bad-deficient mice develop diffuse large B cell lymphoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Aebersold,et al.  Phosphorylation of the pro-apoptotic protein Bim in lymphocytes is associated with protection from apoptosis. , 2003, Molecular immunology.

[31]  S. Cook,et al.  Activation of the ERK1/2 Signaling Pathway Promotes Phosphorylation and Proteasome-dependent Degradation of the BH3-only Protein, Bim* , 2003, Journal of Biological Chemistry.

[32]  K. Lei,et al.  JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Strasser,et al.  Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. , 2002, Immunity.

[34]  A. Strasser,et al.  Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins , 2002, Cell Death and Differentiation.

[35]  A. Strasser,et al.  BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes , 2002, Nature.

[36]  A. Strasser,et al.  Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. , 2001, Developmental cell.

[37]  K. Moulder,et al.  Induction of BIM, a Proapoptotic BH3-Only BCL-2 Family Member, Is Critical for Neuronal Apoptosis , 2001, Neuron.

[38]  A. Strasser,et al.  BH3-Only Proteins—Essential Initiators of Apoptotic Cell Death , 2000, Cell.

[39]  J. Lammers,et al.  Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 , 2000, Current Biology.

[40]  C. Print,et al.  The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells. , 2000, The American journal of pathology.

[41]  A. Strasser,et al.  Apoptosis signaling. , 2000, Annual review of biochemistry.

[42]  C. Print,et al.  Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Strasser,et al.  Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. , 1999, Science.

[44]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[45]  A. Strasser,et al.  Bim: a novel member of the Bcl‐2 family that promotes apoptosis , 1998, The EMBO journal.

[46]  E. Manos,et al.  The p38 mitogen-activated protein kinase pathway in activated and anergic Th1 cells. , 1997, Cellular immunology.

[47]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[48]  M. Raff,et al.  Size Control: The Regulation of Cell Numbers in Animal Development , 1996, Cell.

[49]  H. Karasuyama,et al.  Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors , 1988, European journal of immunology.