Bidirectional signals transduced by DAPK?ERK interaction promote the apoptotic effect of DAPK

Chen, Chun Hau; Wang, Won Jing; Kuo, Jean Cheng; Tsai, Hsiao Chien; Lin, Jia-Ren; Chang, Zee Fen; Chen, Ruey‐Hwa

doi:10.1038/sj.emboj.7600510

Cited by 196 publications

(237 citation statements)

References 40 publications

(76 reference statements)

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“…24 The pCMV/MEK plasmids were a gift from Dr. Zee-Fen Chang (Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University). 25 The empty pCIS2 and pCMV vectors were used as control vectors, respectively.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

Hsu

Che

Liao

et al. 2011

The American Journal of Pathology

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Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for 8% to 10% of all pediatric malignancies. 1 This tumor arises from primitive neuroepithelial cells of the neural crest. 2 The behavior of NB is markedly heterogeneous, ranging from highly undifferentiated tumors with very poor outcomes to welldifferentiated benign ganglioneuroma or NB that may spontaneously regress with favorable prognosis. 3 Half of all patients with newly diagnosed NB are in a high-risk subset with poor overall survival despite intensive therapy. Therefore, it is important to develop useful prognostic tools and to understand NB pathogenesis to help design improved NB therapies.Glycosylation is regulated spatiotemporally during development of the nervous system. 4 Altered carbohydrate structures on tumors are often associated with tumor metastasis and progression. Tumor-associated carbohydrate epitopes commonly found in cancers include GM2,

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Section: Cell Culture and Transfectionmentioning

confidence: 99%

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

Hsu

Che

Liao

et al. 2011

The American Journal of Pathology

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“…[93] Likewise, the inhibition of ERKs cytoplasmic component, by preventing ERK dimerization, is sufficient to abrogate fibroblast transformation and proliferation, and tumor formation in vivo by lung, colorectal, and bladder carcinoma cells. [90] These data indicate that both spatial components of ERKs signals are necessary for tumor development and that interfering with either of them can have remarkable anti-tumor effects.…”

Section: Local Intervention For the Prevention Of Global Malignancy?mentioning

confidence: 99%

“…As mentioned before, sequestering ERKs at the cytoplasm, whereby ERKs nuclear signals are impeded, is sufficient for abrogating growth and/ or potentiating apoptosis. [91][92][93] Recently, a nuclear translocation signal: Ser-Pro-Ser, has been identified within ERKs ''insert.'' These serines are phosphorylated upon stimulation, promoting ERKs translocation to the nucleus.…”

Section: Local Intervention For the Prevention Of Global Malignancy?mentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

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“…Several proteins, which interact with the DAPk death domain, have been identified by using different approaches (Chen et al, 2005;Llambi et al, 2005). In order to extend the search and identify proteins that interact with DAPk through its death domain in an unbiased manner, we performed several rounds of yeast two-hybrid screens.…”

Section: Resultsmentioning

confidence: 99%

“…The death domain of DAPk is essential for some of its cell-death-promoting responses (Cohen et al, 1999;Chen et al, 2005;Llambi et al, 2005;Goldschneider and Mehlen, 2010). We therefore used a yeast twohybrid screen as an unbiased approach to identify proteins that interact with the death domain of DAPk.…”

Section: Introductionmentioning

confidence: 99%

Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase

et al. 2011

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Death-associated protein kinase (DAPk), a multi-domain serine/threonine kinase, regulates numerous cell death mechanisms and harbors tumor suppressor functions. In this study, we report that DAPk directly binds and functionally activates pyruvate kinase M2 (PKM2), a key glycolytic enzyme, which contributes to the regulation of cancer cell metabolism. PKM2 was identified as a novel binding partner of DAPk by a yeast two-hybrid screen. This interaction was validated in vitro by enzyme-linked immunosorbent assay using purified proteins and in vivo by co-immunoprecipitation of the two endogenous proteins from cells. In vitro interaction with full-length DAPk resulted in a significant increase in the activity of PKM2. Conversely, a fragment of DAPk harboring only the functional kinase domain (KD) could neither bind PKM2 in cells nor activate it in vitro. Indeed, DAPk failed to phosphorylate PKM2. Notably, transfection of cells, with a truncated DAPk lacking the KD, elevated endogenous PKM2 activity, suggesting that PKM2 activation by DAPk occurs independently of its kinase activity. DAPk-transfected cells displayed changes in glycolytic activity, as reflected by elevated lactate production, whereas glucose uptake remained unaltered. A mild reduction in cell proliferation was detected as well in these transfected cells. Altogether, this work identifies a new role for DAPk as a metabolic regulator, suggesting the concept of direct interactions between a tumor suppressor and a key glycolytic enzyme to limit cell growth. Moreover, the work documents a unique function of DAPk that is independent of its catalytic activity and a novel mechanism to activate PKM2 by protein-protein interaction.

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Bidirectional signals transduced by DAPK?ERK interaction promote the apoptotic effect of DAPK

Cited by 196 publications

References 40 publications

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase

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