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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation
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Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation

机译：钙氧化剂信号网络调节基质剥夺后的AMP激活的蛋白激酶（AMPK）激活

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The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKβ. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca2+/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells.
机译：AMP激活的蛋白激酶（AMPK）最近与耐厌碱症有关。但是，尚未探讨在基质脱离时激活AMPK的分子机制。在这项研究中，我们表明AMPK激活是基质剥夺后的一种快速而持续的现象，而重新附着于基质会导致其去磷酸化和失活。因为基质分离导致整合素信号的丢失，所以我们研究了整合素信号是否负调节AMPK激活。然而，整合素信号传导的主要下游成分即粘着斑激酶或Src的调节未能引起AMPK信号传导的相应变化。进一步的研究表明，上游的AMPK激酶肝脏激酶B1（LKB1）和Ca 2 + /钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）促进了分离后AMPK的激活。在LKB1缺陷细胞中，我们发现AMPK激活主要依赖于CaMKKβ。我们在早期的时间点观察到在分离条件下ATP水平没有变化，这表明分离后快速AMPK激活不是由能量压力触发的。我们证明基质剥夺导致细胞内钙以及氧化剂信号的尖峰，并且这两个细胞内信使均对分离后的快速AMPK活化有贡献。我们进一步表明，内质网钙释放诱导的存储操作钙进入有助于细胞内钙的增加，导致活性氧的产生和AMPK的激活。我们还显示，LKB1 / CaMKK-AMPK轴和细胞内钙水平在不依赖锚定的癌球形成中起关键作用。因此，Ca 2 + /活性氧触发的LKB1 / CaMKK-AMPK信号级联反应可能提供快速，适应性强的开关来促进转移性癌细胞的存活。

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