Harada, H., Quearry, B., Ruiz-Vela, A. & Korsmeyer, S. J. Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc. Natl Acad. Sci. USA 101, 15313-15317

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2004; 101(43):15313-7. DOI: 10.1073/pnas.0406837101
Source: PubMed


The "BH3-only" proapoptotic BCL-2 family members initiate the intrinsic apoptotic pathway. A small interfering RNA knockdown of BIM confirms this BH3-only member is important for the cytokine-mediated homeostasis of hematopoietic cells. We show here that the phosphorylation status of BIM controls its proapoptotic activity. IL-3, a hematopoietic survival factor, induces extracellular signal-regulated kinase/mitogen-activated protein kinase-mediated phosphorylation of BIM on three serine sites (S55, S65, and S100). After IL-3 withdrawal, only nonphosphorylated BIM interacts with the multidomain proapoptotic effector BAX. Phosphorylation of BIM on exposure of cells to IL-3 dramatically reduces the BIM/BAX interaction. A nonphosphorylatable BIM molecule (S55A, S65A, and S100A) demonstrates enhanced interaction with BAX and enhanced proapoptotic activity. Thus, ERK/mitogen-activated protein kinase-dependent phosphorylation of BIM in response to survival factor regulates BIM/BAX interaction and the pro-death activity of BIM.

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Available from: Hisashi Harada
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    • "The pro-apoptotic BIM-EL can be phosphorylated and subsequently degraded in the proteasome when ERK signaling is activated.[32, 33] In addition, phosphorylation of BIM by ERK reduces its pro-apoptotic activity by preventing binding of BIM to BAX.[34] On the other hand, phosphorylation of BIM by JNK at a different site activates the apoptotic activity of BIM and induces BAX-dependent apoptosis[35]. Our treatment of pancreatic cancer cells with IRE1α inhibitors decreased levels of phosphorylated ERK and increased levels of phosphorylated JNK. "
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    • "This may be explained by the finding that the combination of afatinib and selumetinib leads to a more complete inhibition of the phosphorylation of two key inhibitory residues on the proapoptotic BH3- only proteins BAD and BIM. It has been shown previously that phosphorylation of BAD at serine residues 112 and 136 sequesters BAD in 14-3-3 protein complexes at the plasma membrane, thereby inhibiting its proapoptotic action, and a similar model of inhibition by phosphorylation has been proposed for BIM (Datta et al., 1997; Harada et al., 2004; Scheid et al., 1999; Zha et al., 1996). Our data are consistent with a model in which selumetinib and afatinib synergize to unleash the proapoptotic activity of BAD and BIM, resulting in cell death. "
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    • "n the cell cycle and / or lymphocyte development as well as carcinogenesis . BCL2L11 is a key pro - apoptotic member of the BCL2 family that initiates apoptosis in lymphocytes . BCL2L11 gene is balancing the proliferative and anti - apoptotic effects of BCL2 ( Bouillet et al . , 1999 ) . The BCL2L11 isoforms have varying pro - apoptotic activity ( Harada et al . , 2004 ) . In the present study upregulation in BCL2L gene in NHL samples compared to normal lymph node . Other studies showed BCL2L11 gene with little expression with melanoma progression , renal cell carcinoma , and glioblastoma ( Zantl et al . , 2007 ) . BCL7A is participated in chromosomal translocation with MYC and IgH in a Burkitt lympho"
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