Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP

Park, Byoung Duck; Ham, Young Mi; Jeong, Hyun Ji; Cho, Seung Ju; Je, Young; Yoo, Kyu Dong; Lee, Seung-Ki

doi:10.1016/j.bbrc.2007.07.121

Cited by 12 publications

(4 citation statements)

References 22 publications

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“…Addition of a phosphate moiety, like substitution of a hydrophobic residue by an aspartate or glutamate, would be expected to similarly affect recognition by the Smac antibody. Recently Park et al reported that recombinant Smac can be phosphorylated by JNK3 in vitro [41]. Although the stoichiometry of Smac phosphorylation was not reported, phosphorylation decreased Smac interaction with XIAP similarly to our results with Smac56 following persistent cytosolic expression.…”

Section: Discussionsupporting

confidence: 89%

Monomerization of Cytosolic Mature Smac Attenuates Interaction with IAPs and Potentiation of Caspase Activation

Burke

Smith

2010

PLoS ONE

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The four residues at the amino-terminus of mature Smac/DIABLO are an IAP binding motif (IBM). Upon exit from mitochondria, mature Smac interacts with inhibitor of apoptosis proteins (IAPs), abrogating caspase inhibition. We used the ubiquitin fusion model to express mature Smac in the cytosol. Transiently expressed mature Smac56-239 (called Smac56) and Smac60-239 (called Smac60), which lacks the IBM, interacted with X-linked inhibitor of apoptosis protein (XIAP). However, stable expression produced wild type Smac56 that failed to homodimerize, interact with XIAP, and potentiate caspase activation. Cytosolic Smac60 retained these functions. Cytosolic Smac56 apparently becomes posttranslationally modified at the dimer interface region, which obliterated the epitope for a monoclonal antibody. Cytosolic Smacδ, which has the IBM but lacks amino acids 62–105, homodimerized and weakly interacted with XIAP, but failed to potentiate apoptosis. These findings suggest that the IBM of Smac is a recognition point for a posttranslational modification(s) that blocks homodimerization and IAP interaction, and that amino acids 62–105 are required for the proapoptotic function of Smac.

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Section: Discussionsupporting

confidence: 89%

Monomerization of Cytosolic Mature Smac Attenuates Interaction with IAPs and Potentiation of Caspase Activation

Burke

Smith

2010

PLoS ONE

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“…For example, phosphorylation of p21 WAF1/CIP1 by PKC δ was proposed as a possible mechanism that can activate the dormant Cdk2 activity by unleashing the inhibitor protein from the Cdk2 complexes during apoptotic cell death . In a previous study, we found that c‐Jun N‐terminal kinase 3(JNK3) plays an anti‐apoptotic role by attenuating the interaction between Smac and XIAP by phosphorylation of Smac during etoposide‐induced apoptotic HeLa cells .…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Smac by Akt promotes the caspase-3 activation during etoposide-induced apoptosis in HeLa cells

et al. 2013

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The Akt, family of serine/threonine protein kinases functions as key regulators of multiple aspects of cell behavior, such as survival, proliferation, migration, and carcinogenesis. Notably, Akt exerts its anti-apoptotic effects through the phosphorylation of numerous substrates related with cell cycle, genome stability, and cancer development. In this report, nevertheless, we focused our view on the novel role of Akt which involves in a pro-apoptotic action by phosphorylating second mitochondria derived activator of caspases (Smac) protein during etoposide-induced apoptotic processes. Our data reveals that Akt could bind to and phosphorylate Smac at serine residue 67, which enhances the ability of Smac to interact with the cytosolic X-chromosome linked IAP (XIAP) protein. The cellular interaction of wild-type Smac with XIAP was enhanced with similar activation kinetics of Akt activity, while this interaction was markedly attenuated in cells expressing the phosphorylation-defective mutant S67A-Smac during etoposide-induced apoptosis. Moreover, we provide the evidence indicating that the phosphorylation of Smac at ser-67 markedly upregulates the caspase-3 activity by promoting the interaction of Smac with XIAP. Taken together, we propose that the phosphorylation of Smac by Akt might be a novel mechanism that involves in amplification of caspase cascade pathway during etoposide-induced apoptosis in HeLa cells.

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“…The N-terminus of Smac is phosphorylated by JNK1. It has previously been reported that the phosphorylation of Smac by JNK3 attenuates the apoptotic progression induced by the anticancer drug etoposide (18). Subsequently, the present study investigated the role of Smac phosphorylation in the release of Smac by JNK1.…”

Section: A B a B Cmentioning

confidence: 83%

JNK1-mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF-α-induced apoptosis of HeLa cells

Park

2014

Molecular Medicine Reports

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The second mitochondria‑derived activator of caspases (Smac/DIABLO), is a mitochondrial protein that is released along with cytochrome c during apoptosis and promotes caspase activity. It has been reported that c‑Jun N‑terminal kinase (JNK) is involved in the regulation of Smac release during apoptosis; however, the specific role of JNK is not well understood. The aim of the present study was to investigate whether JNK1 is activated during apoptosis induced by tumor necrosis factor‑α (TNF‑α) and whether the activation of JNK1 is functionally associated with Smac release from the mitochondria in HeLa cells. It was determined that during apoptotic progression induced by TNF‑α, JNK1 is activated and translocated into the mitochondria. It was also shown that Smac release is markedly promoted by transient expression of JNK1, while it is suppressed by the expression of a dominant negative version of JNK1. Furthermore, expression of JNK1 also increases the levels of TNF‑α‑induced caspase‑3 activity. To determine whether JNK1 activity is directly involved in the release of Smac, an in vitro phosphorylation assay was performed with the N‑terminal 10‑mer peptide fragment of Smac (pep0110). The results indicated that pep0110 is phosphorylated in dose and time‑dependent manners by active JNK1, and that the phosphorylation of Smac at the N‑terminal serine 6 residue is functionally linked to Smac release during TNF‑α‑induced apoptosis. In conclusion, this suggests that Smac is a major physiological substrate of JNK1 in the regulation of apoptosis.

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Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP

Cited by 12 publications

References 22 publications

Monomerization of Cytosolic Mature Smac Attenuates Interaction with IAPs and Potentiation of Caspase Activation

Monomerization of Cytosolic Mature Smac Attenuates Interaction with IAPs and Potentiation of Caspase Activation

Phosphorylation of Smac by Akt promotes the caspase-3 activation during etoposide-induced apoptosis in HeLa cells

JNK1-mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF-α-induced apoptosis of HeLa cells

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