Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells.
Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells.
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DOI：
10.1016/j.matbio.2013.12.011
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发表时间：
2014-02
期刊：
影响因子：
6.9
通讯作者：
Iozzo, Renato V.
中科院分区：
文献类型：
--
作者：
Goyal, Atul;Neill, Thomas;Owens, Rick T.;Schaefer, Liliana;Iozzo, Renato V.
宏自噬的高度保守的真核过程(自噬)是一种非特异性的批量降解程序，对于维持适当的细胞内环境平衡和清除老化和受损的细胞器至关重要。这一决定与细胞的代谢需求和能量需求密不可分。可溶性单体核心蛋白粘附素是一种天然的肿瘤抑制因子，可拮抗多种受体酪氨酸激酶。最近，我们发现核心蛋白Decorin可诱导血管内皮细胞自噬，位于VEGFR2下游。这一过程完全依赖于Peg3，这是一种核心蛋白聚糖诱导的基因组印迹肿瘤抑制基因。然而，对此负责的信号级联仍然难以捉摸。在这份报告中，我们发现Vps34是一种III类磷酸肌醇激酶，是Peg3诱导所需的上游激酶。此外，核心蛋白聚糖触发Vps34/Beclin 1复合体的差异形成，并伴随着抑制性的Bcl2/Beclin 1复合体的溶解。此外，核心蛋白聚糖通过抑制Akt/mTOR/p70S6K活性同时激活AMPK介导的亲自噬信号通路来抑制反自噬信号转导。从机制上讲，AMPK位于VEGFR2下游，抑制AMPK信号可抑制核心蛋白聚糖诱导的自噬。总而言之，这些发现暗示了Decorin诱导的内皮细胞自噬所必需的潜在分子继而的复杂性，并揭示了增强自噬和对抗肿瘤血管生成的重要治疗靶点。
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
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影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
影响因子：
5.5
作者：
Du, Jianhai;Teng, Ru-Jeng;Shi, Yang
通讯作者：
Shi, Yang
DOI：
10.1083/jcb.200901129
发表时间：
2009-05-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goldoni S;Humphries A;Nyström A;Sattar S;Owens RT;McQuillan DJ;Ireton K;Iozzo RV
通讯作者：
Iozzo RV
影响因子：
6.9
作者：
Dunkman, Andrew A.;Buckley, Mark R.;Mienaltowski, Michael J.;Adams, Sheila M.;Thomas, Stephen J.;Satchell, Lauren;Kumar, Akash;Pathmanathan, Lydia;Beason, David P.;Iozzo, Renato V.;Birk, David E.;Soslowsky, Louis J.
通讯作者：
Soslowsky, Louis J.
影响因子：
20.3
作者：
Ichii, Michiko;Frank, Mark Barton;Kincade, Paul W.
通讯作者：
Kincade, Paul W.