mTORC2 Regulates Cardiac Response to Stress by Inhibiting MST1

Sciarretta, Sebastiano; Zhai, Peiyong; Maejima, Yasuhiro; Re, Dominic P. Del; Nagarajan, Narayani; Yee, Derek; Liu, Tong; Magnuson, Mark A.; Volpe, Massimo; Frati, Giacomo; Li, Hong; Sadoshima, Junichi

doi:10.1016/j.celrep.2015.03.010

Cited by 115 publications

(88 citation statements)

References 51 publications

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“…Rapamycin, a drug that strongly inhibits mTORC1 but to a lesser level mTORC2, blunts cardiac hypertrophy development in response to pressure overload 44 and improves cardiac function in mice with decompensated hypertrophy 45 . It was recently reported that cardiac-specific mTORC2 disruption through Rictor deletion leads to impaired cardiac growth and response to pressure overload, cardiac dilation and cardiac dysfunction 46 , features that we similarly found after Stim1 silencing.…”

Section: Discussionsupporting

confidence: 79%

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Bénard

Cacheux

et al. 2016

Circulation

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Background STromal Interaction Molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiac myocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma but the pathways underpinning this effect have not been examined. Methods and Results To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiac myocytes using in vivo gene delivery of specific short hairpin RNAs. In three different models, we found that Stim1 silencing prevents the development of pressure-overload induced hypertrophy but also reverses pre-established cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the anti-hypertrophic and pro-apoptotic GSK-3β molecule. Pharmacological inhibition of GSK-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of AktS473, a hydrophic motif of Akt that is directly phosphorylated by mTORC2. We found that Stim1 silencing directly impaired mTORC2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTORC2 complex. Conclusions These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiac myocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2 (mTORC2), which further results in repression of GSK-3β activity.

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Section: Discussionsupporting

confidence: 79%

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Bénard

Cacheux

et al. 2016

Circulation

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“…For instance, the nutrient-sensing kinases salt-induced kinase 2 and kinase 3 phosphorylate Sav at Ser413 to promote Yki target gene expression (Wehr et al 2013). Both mTORC1 and mTORC2 are reported to positively regulate YAP in perivascular epithelioid cell tumors and glioblastomas (Liang et al 2014;Artinian et al 2015;Sciarretta et al 2015). It is worth noting that mTORC1 is highly sensitive to nutrient availability and cellular energy status.…”

Section: Stress Signalsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…Some studies suggest that Mst1/Mst2 homodimerization is required for autophosphorylation and activation of these kinases [8, 15, 16] while others indicate that homodimer formation is not required for its activity [8, 17]. In addition to forming homodimers, Mst1 and Mst2 have also been shown to heterodimerize with other SARAH domain containing proteins, such as, RASSF family of proteins [8, 18–20].…”

Section: Resultsmentioning

confidence: 99%

H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization

et al. 2016

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Summary The protein kinases Mst1 and Mst2 have tumor suppressor activity, but their mode of regulation is not well established. Mst1 and Mst2 are broadly expressed and may have certain overlapping functions in mammals, as deletions of both Mst1 and Mst2 together are required for tumorigenesis in mouse models [1–3]. These kinases act via a three-component signaling cascade comprising Mst1/2, the protein kinase Lats1/2, and the transcriptional coactivators Yap and Taz [4–6]. Mst1/2 contain C-terminal SARAH domains that mediate their homodimerization as well as heterodimerization with other SARAH-domain containing proteins, which may regulate Mst1/2 activity. Here, we show that, in addition to forming homodimers, Mst1 and Mst2 heterodimerize in cells, that this interaction is mediated by their SARAH domains and is favored over homodimers, and that these heterodimers have much reduced protein kinase activity compared to Mst1 or Mst2 homodimers. Mst1/Mst2 heterodimerization is strongly promoted by oncogenic H-ras, and this effect requires activation of the Erk pathway. Cells lacking Mst1, in which Mst1/Mst2 heterodimers are not possible, are resistant to H-ras-mediated transformation and maintain active hippo pathway signaling compared to wild-type cells or cells lacking both Mst1 and Mst2. Our results suggest that H-ras, via an Erk-dependent mechanism, down-regulates Mst1/2 activity by inducing the formation of inactive Mst1/Mst2 heterodimers.

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mTORC2 Regulates Cardiac Response to Stress by Inhibiting MST1

Cited by 115 publications

References 51 publications

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Mechanisms of Hippo pathway regulation

H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization

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