Hippo and Hyperplasia.
Hippo and Hyperplasia.
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河马和增生。
DOI：
10.1161/circresaha.119.314968
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发表时间：
2019
影响因子：
20.1
通讯作者：
Martin,KathleenA
中科院分区：
文献类型：
--
作者：
Ostriker,AllisonC;Martin,KathleenA
在体外直接结合并反式激活启动子。4 SLC 1A 5是mTORC 1的L-谷氨酰胺依赖性激活所必需的。12此外，谷氨酰胺对癌细胞至关重要，因为其代谢物不仅提供能量来源，而且还为核酸和氨基酸生物合成提供氮，从而允许快速增殖。值得注意的是，TEAD 1-SLC 1A 5-谷氨酰胺摄取信号传导轴显示出在体外调节SMC mTORC 1活性、去分化和增殖。TEAD 1的过表达激活mTORC 1至与PDGF-BB刺激相当的水平，并增强PDGF-BB（血小板衍生生长因子-BB）的作用。用SLC 1A 5抑制剂GPNA治疗证明，这种转运蛋白是TEAD 1诱导的SMC mTORC 1活化和增殖所必需的。主要的新机制发现是TEAD 1在Hippo通路和谷氨酰胺驱动的mTORC 1信号激活之间提供了直接的转录联系，为我们对这些通路之间相互作用的理解增加了新的深度。这项工作揭示了一种新的代谢机制，通过这种机制，快速增殖和高度合成的SMC获得一种关键的营养物质谷氨酰胺，谷氨酰胺协调调节并为血管修复和新生内膜形成的生物合成需求提供燃料。本研究提出了几个问题，以供未来研究。TEAD 1活性放大了mTORC 1信号传导，该信号传导可能是由血管损伤部位的生长因子（例如PDGF）启动的，但促进血管损伤中上游Hippo激酶抑制的刺激因素尚不清楚。取决于细胞类型和环境，生长因子、细胞因子、G蛋白偶联受体配体、细胞应激和细胞接触的破坏可激活雅普/TAZ（综述见Ma et al 9）。潜在刺激的复杂性和缺乏明确定义的激动剂和受体需要依赖于过表达和敲低方法来研究Hippo途径功能，这增加了由于高水平过表达和/或在缺乏天然刺激的情况下缺乏其他伴随的信号传导相互作用而产生伪影的可能性。损伤后介导TEAD 1上调的机制仍有待确定，但TEAD因子可通过磷酸化、棕榈酰化来调节，并且与雅普/TAZ类似，TEAD可在高细胞密度条件下从细胞核中排除。14 TEAD 1与之合作调节SLC 1A 5和SMC表型的特异性辅因子也尚不清楚。雅普和TEAD 1之间共享的相似表型，以及癌细胞中SLC 1A 5的雅普调节15表明它们可能在血管损伤反应中共同作用。然而，TEAD还可以与Hippo独立的辅因子合作。在损伤环境中TEAD 1依赖性靶基因的完整谱尚不清楚，但RNA-Seq与ChIP-seq理想配对，可能会提供未来的见解。从翻译的角度来看，这项工作表明，抑制TEAD 1活性和/或下游谷氨酰胺转运，可能与mTORC 1抑制协同作用，代表了一种新的组合策略，用于治疗血管病变。靶向谷氨酰胺代谢是深入研究的领域，因为“谷氨酰胺成瘾”可以赋予肿瘤对mTOR抑制剂的抗性。然而，谷氨酰胺摄取的抑制一直是有问题的，因为GPNA（L-γ-谷氨酰基-对硝基苯胺）和其他SLC 1A 5抑制剂在癌症临床试验中失败，因为健康细胞中谷氨酰胺剥夺的不良作用（在Choi和Park中综述13）。谷氨酰胺酶（将谷氨酰胺转化为谷氨酸的酶）的抑制剂在2018年就已进入早期临床试验，...
directly binding and transactivating the promoter in vitro. 4 SLC1A5 is required for L-glutamine-dependent activation of mTORC1. 12 Furthermore, glutamine is essential to cancer cells as its metabolites provide not only a source of energy but also nitrogen for nucleic and amino acid biosynthesis, allowing for rapid proliferation. 13 Notably, the TEAD1-SLC1A5-glutamine uptake signaling axis was shown to regulate SMC mTORC1 activity, dedifferentiation and proliferation in vitro. Overexpression of TEAD1 activated mTORC1 to a level comparable to PDGF-BB stimulation and potentiated the effects of PDGF-BB (platelet-derived growth factor-BB). Treatment with the SLC1A5 inhibitor GPNA demonstrated that this transporter is required for TEAD1-induced SMC mTORC1 activation and proliferation. The major novel mechanistic finding is that TEAD1 provides a direct transcriptional link between the Hippo pathway and glutamine-driven activation of mTORC1 signaling, adding new depth to our understanding of the interplay between these pathways. This work reveals a new metabolic mechanism by which rapidly proliferating and highly synthetic SMC obtain a key nutrient, glutamine, which coordinately regulates and provides fuel for the biosynthetic demands of vascular repair and neointima formation. Several questions arise from this study for future research. TEAD1 activity amplifies the mTORC1 signaling that is likely initiated by growth factors such as PDGF at sites of vascular injury, but the stimuli that promote repression of upstream Hippo kinases in vascular injury are unknown. Depending on cell type and context, growth factors, cytokines, G-protein–coupled receptor ligands, cellular stresses, and disruption of cellcell contacts can activate YAP/TAZ (reviewed in Ma et al9). The complexity of potential stimuli and lack of clearly defined agonists and receptors necessitates reliance on overexpression and knockdown approaches to study Hippo pathway functions, which raises the possibility of artifacts due to high-level overexpression, and/or lack of other concomitant signaling interactions in the absence of native stimuli. The mechanisms that mediate TEAD1 upregulation post-injury remain to be determined, but TEAD factors can be regulated by phosphorylation, palmitoylation, and, similar to YAP/TAZ, TEADs can be excluded from the nucleus under conditions of high cell density. 14 The specific cofactors with which TEAD1 partners to regulate SLC1A5 and SMC phenotype are also not yet known. The similar phenotypes shared between YAP and TEAD1, as well as YAP regulation of SLC1A5 in cancer cells15 suggests that they likely act in concert in vascular injury response. TEADs, however, can additionally partner with Hippo-independent cofactors. 14 The full spectrum of TEAD1-dependent target genes in the injury setting is not yet known, but RNA-Seq, ideally paired with ChIP-seq, may provide future insights. From a translational standpoint, this work suggests that inhibition of TEAD1 activity and/or downstream glutamine transport, may synergize with mTORC1 inhibition, representing a novel combinatorial strategy for treating vasculopathies. Targeting glutamine metabolism is an area of intensive research as “glutamine addiction” can confer tumor resistance to mTOR inhibitors. Inhibition of glutamine uptake, however, has been problematic, as GPNA (L-γ-glutamyl-p-nitroanilide) and other SLC1A5 inhibitors have failed in cancer clinical trials because of adverse effects of glutamine deprivation in healthy cells (reviewed in Choi and Park13). Inhibitors of glutaminase, the enzyme that converts glutamine to glutamate, were in early clinical trials as of 2018, and …