Abstract:
:The pro-apoptotic protein BIM(EL) is phosphorylated by ERK1/2 and this targets the protein for poly-ubiquitination and degradation by the proteasome as a survival mechanism. To define in greater detail the sequence determinants required for BIM(EL) turnover we have compared various BIM splice variants and truncation mutants. Of the naturally occurring splice variants BIMbeta1, which lacks the C-terminal hydrophobic domain, the BH3 domain and is cytosolic, exhibited the fastest turnover rate. Indeed, neither the C-terminus, the BH3 domain nor the DLC1 binding region was required for poly-ubiquitination and turnover of BIM. However, we demonstrate that a region consisting of the ERK1/2 docking domain, ERK1/2 phosphorylation sites and either of the two potential ubiquitin-acceptor lysine residues is sufficient to allow poly-ubiquitination and turnover of BIM. In the process we demonstrate that the C-terminal hydrophobic domain, previously suggested to be important in membrane localisation, is as important as the BH3 domain for BIM to induce cell death; similarly, the pro-death BH3-domain can also confer correct mitochondrial localisation in the absence of the C-terminus. These results refine the minimal sequence for ERK1/2-driven degradation and further define the functional importance of key regions within BIM(EL), highlighting the complexity of this pro-apoptotic protein.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Wiggins CM,Johnson M,Cook SJdoi
10.1016/j.cellsig.2010.01.004subject
Has Abstractpub_date
2010-05-01 00:00:00pages
801-8issue
5eissn
0898-6568issn
1873-3913pii
S0898-6568(10)00010-0journal_volume
22pub_type
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1016/j.cellsig.2011.12.001
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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pub_type: 杂志文章
doi:10.1016/j.cellsig.2012.12.009
更新日期:2013-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.cellsig.2019.109467
更新日期:2020-02-01 00:00:00
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更新日期:2016-05-01 00:00:00
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更新日期:2016-09-01 00:00:00
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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更新日期:2005-03-01 00:00:00
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journal_title:Cellular signalling
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doi:10.1016/j.cellsig.2012.10.009
更新日期:2013-01-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2015.08.009
更新日期:2015-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
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更新日期:1992-05-01 00:00:00
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