Meta's contracts with Entergy are largely cloaked from public scrutiny

Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.

The key sensor of energy status in mammalian cells, AMP-activated protein kinase (AMPK), can also be activated by the AMP analog aminoimidazolecarboxamide nucleoside monophosphate (ZMP) generated directly from aminoimidazolecarboxamide ribonucleoside (AICAR) or from inhibition of purine synthesis by the antifolate pemetrexed (PTX), a drug used extensively in the treatment of lung cancers. Despite this common mechanism, signaling downstream of AMPK activated by PTX or AICAR differed. AICAR-activated AMPK inhibited mTORC1 both directly by phosphorylation of the mTORC1 subunit Raptor and indirectly by phosphorylation of the regulator TSC2. In contrast, PTX-activated AMPK inhibited mTORC1 solely through Raptor phosphorylation. This dichotomy was due to p53 function. Transcription of p53 target genes, including TSC2, was activated by AICAR but not by PTX. Although both PTX and AICAR stabilized p53, only AICAR activated Chk2 phosphorylation, stimulating p53-dependent transcription. However, Raptor phosphorylation by AMPK was independent of p53 and was sufficient, after PTX treatment, to inhibit mTORC1. We concluded that PTX effects on mTORC1 were independent of TSC2 and p53 and that the activation of a p53 transcriptional response by AICAR was due to an activation of Chk2 that was not elicited by PTX. https://ancillary-proxy.atarimworker.io?url=https%3A%2F%2Fpmc.ncbi.nlm.nih.gov%2Fa...

In the last installments of this series we have begun to dig deeper into the signaling mechanisms that are / could be involved in the beneficial effects intermittent fasting is hailed for in the (unreal) world of the Internet blogosphere. We have identified AMPK and mTOR as the two players in the constructive and de-/re-constructive orchestrate of mammalian organisms and we have learned that their relationship - despite all its antagonistic aspects - is, after all, a complementary one. This means that, as you can observe it time and again in nature, health, vitality, yes even sustainable changes in body composition require balance!

The delicate balance between mTOR and AMPK, this was another result of our considerations, is oftentimes broken in these days of nutritional abundance, where the rebuild and repair mechanisms of AMPK hardly get a chance to control the growth processes a constantly elevated mTOR pathway is triggering. The forced feeding-breaks on an intermittent fasting regime break this rampantly anabolic cycle. They let AMPK come into it's own and allow for

.....broken DNA strands to be fixed, before their (re-)use results in cancerous growth (Habib. 2010),

...cancer and defect cells to initiate apoptosis, i.e. to kill themselves (Chen. 2011)

...life extension via reduction of dietary glucose to work (Schulz. 2007)

...fat to be used as a substrate (Hardy. 2002),

...inhibiting adipogenesis = fat cell differntiation (Lee. 2011)

...mitochondrial biogenesis to be initiated (Zong. 2002),

...muscular GLUT4 activity and thus glucose uptake to be restored/increased (Holmes. 1999),

...gluconeogensis in the liver to be suppressed (Rutter. 2003

In the previous episode, we have also identified energy availability or, to be precise, the ratio of the high energy ATP (adenosine triphosphate) to the lower energy ADP (adenosine diphosphate; -7.3kcal/mol) and AMP (adenosine monophosphate; -10.9kcal), as a crucial determinant of AMPK activation. In one of the most recent reviews on the topic (Carlin. 2011), David Carlin and colleagues from the Imperial College in London state that

[...] the finding that ADP, as well as AMP, protects AMPK against dephosphorylation influences the way we look at the physiological regulation of AMPK. To the best of our current understanding, the concentration of ADP in mammalian cells is much higher (10- to 100-fold) than that of free AMP, and so it is likely to be the main regulator of AMPK activity under normal energy-stress conditions. The extent of the tighter binding of ADP to AMPK, relative to MgATP, essentially offsets the higher physiological concentration of MgATP. An interesting possibility is that under most conditions AMPK is regulated by the ATP:ADP ratio through changes in Thr172 phosphorylation state. Under severe stress conditions, however, when the concentration of AMP might increase markedly, the additional allosteric activation mediated by AMP could act as a type of fail-safe device, ensuring that all AMPK substrates are maximally phosphorylated.

In other words, under normal conditions ADP, i.e. the higher energy variety of the dephosphorylated ATP molecule, and not AMP is the main determinant of AMPK activity. And, and this is a pretty novel finding, both ADP and AMP do not actually activate 5' adenosine monophosphate-activated protein kinase (AMPK), but rather prevent it from being deactivated. While it may seem that this does not really matter, looking at things this way let's the "deactivation of AMPK by energy abundance" - a state we have accepted as a norm - suddenly look like the exception; and when we come to think of it, all the "diabesity"-related ailments an ever-increasing percentage of our society is experiencing can be tracked back to the reversal of norm (=AMPK phosphorylated = restore and repair using stored energy) and exception (=mTOR phosphorylated = build, grow, store) that is triggered by the persistent abundance of energy.

heros of international freedom

The local media provided no evidence supporting these allegations

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