TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1

Shin, Ju Hyun; Min, Sang Hyun; Kim, Seong‐Jin; Kim, Young Il; Park, Junsoo; Lee, Kyung-Mi; Yoo, Ook Joon

doi:10.1038/srep01561

Cited by 36 publications

(32 citation statements)

References 47 publications

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“…Although the well-defined role of S6K1, a direct substrate of mTOR, in autophagy regulation is not yet know, previous reports have suggested that S6K1 negatively regulates autophagy (33). It has also been reported that the phosphorylation of S6K1 correlates with the suppression of autophagy (33). Our results showed that there was an increase in the phosphorylation of S6K1 kinase at Thr 389 site after treatment with trastuzumab for 24 and 48 hours in human cardiomyocytes (Fig.…”

Section: Trastuzumab Downregulates Autophagosome-associated Proteinssupporting

confidence: 62%

“…5C). Although the well-defined role of S6K1, a direct substrate of mTOR, in autophagy regulation is not yet know, previous reports have suggested that S6K1 negatively regulates autophagy (33). It has also been reported that the phosphorylation of S6K1 correlates with the suppression of autophagy (33).…”

Section: Trastuzumab Downregulates Autophagosome-associated Proteinsmentioning

confidence: 99%

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Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes

Mohan

Shen

Endo

et al. 2016

Molecular Cancer Therapeutics

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Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment of HER2-positive breast cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocyte development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Our data reveal a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy.

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Section: Trastuzumab Downregulates Autophagosome-associated Proteinssupporting

confidence: 62%

Section: Trastuzumab Downregulates Autophagosome-associated Proteinsmentioning

confidence: 99%

Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes

Mohan

Shen

Endo

et al. 2016

Molecular Cancer Therapeutics

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“…Having shown that S6K1 has an inhibitory effect on TLR2-or TLR4-mediated signaling and the production of proinflammatory cytokines, we next explored the molecular mechanism of this phenomenon. It has recently been shown that TAK1 interacts with S6K1 and that this interaction inhibits S6K1 activation (11). We therefore hypothesized that S6K1 is able to negatively regulate TAK1 activity.…”

Section: S6k1 Is Negatively Involved In the Tlr2-or Tlr4-mediated Sigmentioning

confidence: 96%

“…A previous report showed that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, inhibits the activation of NF-B induced by IL-1 through disruption of TRAF6-TAK1 interaction (10). Moreover, it has recently been proposed that TAK1 inhibits S6 kinase1 (S6K1) phosphorylation by interfering with the interaction between raptor and S6K1, inducing autophagy (11). Nevertheless, the mechanisms that allow TAK1 to be regulated by so many different stimuli and tissue types and the kinetics of the regulatory response are not completely understood.…”

mentioning

confidence: 99%

S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway

Kim

Baik

Baek

et al. 2014

Molecular and Cellular Biology

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dTransforming growth factor ␤ (TGF-␤)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-B and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1؊/؊ and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1؊/؊ mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-B-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.T ransforming growth factor ␤-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) family (1). TAK1 is essential for the production of tumor necrosis factor (TNF-␣) and other inflammatory mediators by activating several MAPKs, such as p38␣ MAPK, Jun N-terminal protein kinases 1 and 2 (JNK1 and JNK2), and extracellular signal-regulated kinases 1 and 2 (ERK1/2). TAK1 also plays a key regulatory role in several cytokine-mediated innate immunity signal transduction cascades, including interleukin-1 (IL-1) and the downstream signaling of Toll-like receptors (TLRs) and NOD1/2 (2, 3). In these pathways, various proinflammatory cytokines and TLR agonists trigger TAK1 activity, leading to its autophosphorylation and subsequent recruitment to the IB kinase (IKK) complex, ultimately resulting in the activation of the transcription factor NF-B and the upregulation of genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes.Several binding partners of TAK1, including TAK1-binding protein 1 (TAB1), TAB2, and TAB3, have been implicated in the regulation of TAK1 activity in response to various stimuli (1, 4). Previous reports demonstrated that the native forms of TAK1 comprise a catalytic kinase subunit in complex with the regulatory subunit TAB1 and either of two homologous proteins, TAB2 and TAB3 (2, 5, 6). Importantly, it has been reported that TAB1 might play a key role in the regulation of the TAK1 complex (7,8). Studies with TAB1-deficient mouse embryonic fibroblasts (TAB1 Ϫ/Ϫ MEFs) demonstrated that TAB1 is able to recruit p38␣ MAPK to the TAK1 complex f...

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“…It has been reported that TAK1 participates in regulatory mechanisms of acute injury in several tissue types 7. TAK1 has also been implicated in oxidative stress, apoptosis and autophagy 8. However, the role of TAK1 in response to cisplatin‐induced AKI has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Zhou

Fan

Zhong

et al. 2018

J Cellular Molecular Medi

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The ability of cisplatin (cis‐diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor‐β (TGF‐β)‐activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen‐activated protein kinase) and ERK regulate autophagy in response to various stimuli. Therefore, our hypothesis is that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells and thus exacerbating kidney damage. Here, BALB/c mice were intraperitoneally injected with a TAK1 inhibitor and were then administrated with sham or cisplatin at 20 mg/kg by intraperitoneal injection. Compared with mice in the vehicle cisplatin group, mice intraperitoneally injected with a TAK1 inhibitor were found to have lower serum creatinine and less tubular damage following cisplatin‐induced AKI. Furthermore, inhibition of TAK1 reduced p38 and Erk phosphorylation, decreased expression of LC3II and reversed the down‐regulation of P62 expression induced by cisplatin. The hypothesis was verified with tubular epithelial cells administrated with cisplatin in vitro. Finally, p38 inhibitor or ERK inhibitor abated autophagy activation and cell viability reduction in tubular epithelial cells treated with cisplatin plus TAK1 overexpression vector. Taken together, our results show that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells that exacerbates kidney damage.

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TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1

Cited by 36 publications

References 47 publications

Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes

Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes

S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

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