Activation of the ERK1/2 Signaling Pathway Promotes Phosphorylation and Proteasome-dependent Degradation of the BH3-only Protein, Bim*

By R. Ley, K. Balmanno, K. Hadfield, C. Weston, S. Cook. Journal of Biological Chemistry, 2003

661 citations recorded by the source corpus.

Both the ERK and phosphatidylinositol 3′-kinase (PI3K) signaling pathways can protect cells from apoptosis following withdrawal of survival factors. We have previously shown that the ERK1/2 pathway acts independently of PI3K to block expression of the BH3-only protein, BimEL, and prevent serum withdrawal-induced cell death, although the precise mechanism by which ERK reduced BimEL levels was unclear. By comparing Bim mRNA and Bim protein, expression we now show that the rapid expression of BimEL following serum withdrawal cannot be accounted for simply by increases in mRNA following inhibition of PI3K. In cells maintained in serum BimEL is a phosphoprotein. We show that activation of the ERK1/2 pathway is both necessary and sufficient to promote BimEL phosphorylation and that this leads to a substantial increase in turnover of the BimEL protein. ERK1/2-dependent degradation of BimEL proceeds via the proteasome pathway because it is blocked by proteasome inhibitors and is defective at the restrictive temperature in cells with a temperature-sensitive mutation in the E1 component of the ubiquitin-conjugating system. Finally, co-transfection of BimEL and FLAG-ubiquitin causes the accumulation of polyubiquitinated forms of Bim, and this requires the ERK1/2 pathway. Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/efa37fcd565a0221297c11bb7496020a4a94e517

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Citations in the corpus

Pathological roles of MAPK signaling pathways in human diseases. (2010, background): “the transcription factor FOXO3A, which results in proteasomedependent degradation of the phosphorylated FOXO3A [156] and”
The Bcl-2 apoptotic switch in cancer development and therapy (2007, background): “The level of Bim can be regulated by phosphorylation by Erk, which triggers its degradation by the proteasome (Akiyama et al., 2003; Ley et al., 2003; Luciano et al., 2003), whereas its phosphorylation by c-Jun N-terminal kinase may potentiate its pro-apoptotic activity (Putcha et al., 2003).”
Life in the balance: how BH3-only proteins induce apoptosis. (2005, background): “Current Opinion in Cell Biology 2005, 17:617–625 such as phorbol ester or growth factors provoke Erk1/2 to phosphorylate Bim on one or more serines (including Ser 55, 65 and 100), inducing its degradation via the proteasome [29,31,32].”
Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms (2009, background): “the mechanisms by which ERK1/2 activation promote survival are not fully characterized, a number of antiapoptotic effector proteins have been identified, including increased expression of antiapoptotic proteins such as c-FLIP (Allan et al., 2003; Ley et al., 2003; Mori et al., 2003; Qiao et al., 200”
The role of BH3-only proteins in the immune system (2005, background): “It has also been shown that stimulation with growth factors can post-translationally inactivate BIM through ERK (extracellular signal-regulated kinase)-mediated phosphorylation, which targets BIM for UBIQUITYLATION and proteasomal degradatio”
Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. (2006, background): “For example, while ERK phosphorylates and thereby destabilizes proapoptotic BIM upon growth factor stimulation (Ley et al., 2003; Luciano et al., 2003), GSK-3 phosphorylates and destabilizes antiapoptotic MCL-1 when growth factor is low or withdrawn.”
`The stress of dying': the role of heat shock proteins in the regulation of apoptosis (2004, background): “Intriguingly, the ubiquitin-dependent turnover of several key regulators of the apoptotic pathway, including Bid (Breitschopf et al., 2000), Bcl-2 (Dimmeler et al., 1999) and Bim (Akiyama et al., 2003; Ley et al., 2003), has been described recently.”
Cell Death Signaling. (2015, background): “…ERK1/2 and RSK1/2 Cell survival Ley et al. 2003; Hubner et al. 2008; Dehan et al. 2009 Ubiquitylation bTrCP Cell survival Akiyama et al. 2003; Ley et al. 2003; Dehan et al. 2009 mRNA stability Hsc70 Cell survival Matsui et al. 2007 ? mRNA stability miR-17-92 Cell survival Xiao et al. 2008…”