How is the mTOR pathway involved in metabolic regulation?

Today we are referring to the mTOR pathway, the signal path hundreds, the mTOR pathway, because of its physiological and pathological significance, in many pathways stand out.
mTOR, full name mammalian target of rapamycin, rapamycin receptor protein, and currently the main research focuses on mammals, so add a mammalian.
life activities require energy, cells also need some growth and metabolism necessary structures and proteins, so also need some simple small molecules to synthesize the desired substances, energy and these small molecules are the result of carbohydrate decomposition. the metabolism of
energy is usually accompanied by the metabolism of matter, the material cycle is accompanied by the production and utilization of energy, such a process needs to be in accordance with the cell and the body's material and energy demand state of fine regulation to maintain the stability of life activities.
and the star molecule mTOR is a hub molecule that regulates growth and metabolism, so how exactly is it involved in metabolic regulation? The response to insulin and insulin-like growth factors PI3K-AKT-mTOR is a classic response to insulin signaling.
when eaten, the decomposed glucose enters the blood to promote the release of insulin, which, as a signal in response to nutrient surplus, guides cells to absorb and utilize these nutrients.
Insulin first binds cell surface receptors to activate the PI3K-AKT pathway through IRS1, AKT directly promotes the absorption of Glucose, while activating the activity of mTORC1 through AKT-TSC1/2-RheB-mTORC1, and mTORC1 further directs the synthesis of glucose-related enzymes for nutrient storage.
RheB is a small G protein, small G protein activated can directly regulate mTORC1, mediated hormone class that signals to mTORC1, which is one of many mTORC1 regulation methods.
this process includes both absorption and absorption after the use of adjustment, such a one-stop adjustment, is usually understood by many researchers as mTORC1 is activated, can be both synthetic glycogen, can promote translation, can also promote growth.
such a general understanding is obviously biased, but also we often understand the literature a misunderstanding.
actually insulin activation of mTORC1 is mostly associated with sugar metabolism, while IGF (insulin-like growth factor) activation of mTORC1 is mainly related to cell growth.
the basis of the separate regulation after the activation of mTORC1 is theoretically different, very specific regulation and substrate information still need to be further studied.
the response of amino acids to nutrients of the three major nutrients of which sugar, has been mentioned mainly through Insulin and cell surface receptorindirect lying to regulate the activity of mTORC1.
and amino acids can be absorbed directly to activate the activity of mTORC1.
Sabatini found that mTORC1 is activated in two main steps: first, in the presence of amino acids, the small G protein Rags is activated, combined with mTOR to assist it in the position of the lysozyme membrane surface.
the small G protein Rheb protein, which is then positioned on the membrane surface, is activated by signals from growth factors before activating mTOR activity.
here by amino acids directly activated mTOR regulatory mode, although not through the signal from the cell surface, but also by the small G protein Rags mediated.
since mTOR can be fully activated in the presence of factorand and amino acids, that is, in the case of excess material and energy, the conditions for activation of mTOR.
this point shows that mTOR has the function of information integration as a hub of metabolic regulation.
Imagine if, in the case of glucose surplus and amino acid shortage, what material stakes in cells to synthesize to complete growth? So this time glucose is more used to convert into amino acids than energy storage, so mTOR is not activated.
on the contrary, in the case of amino acid surplus and insufficient glucose, the synthesis of the required energy supply is insufficient, amino acids at this time more may be used to break down and provide the energy required for cell activity, so mTOR must not be activated.
this is a sign that the mTOR regulation pattern also reflects the strategy of cell metabolic balance wit.
interesting is that both lines are signaled by small G proteins, so how do the signals of the cell's metabolic stability, such as biochemical transformation between amino acids and sugars, perceive? Does the small G protein play an important role in participating? It's fascinating. the effect of
on autophagy mTOR is essentially the regulation between growth and metabolism.
there are nutritional and energy factors.
autophagy is when the cell's nutrients or energy is insufficient, in order to maintain their basic survival needs, the cell will be the lysosome degradation of some relatively minor proteins, as well as some relatively redundant organelles, to supply substances and energy.
in addition to the energy of the main carrier ATP relative lying insufficient, that is, AMP /ATP rise, nutritional supply is insufficient, mTORC1 activity will also be insufficient, so mTORC1 released the inhibition of autophagy starting regulation.
on the other hand from PI3K-AKT, MAPK cascades signal regulation of mTORC1 also reflects the link between growth regulation and metabolism.
, the stability of the P53/genome can directly regulate the activity of mTORC1, which also adds evidence in this regard.
the effect of tumor treatment Since mTOR has such a large impact on metabolism, it is well known that the tumor is a large energy consumption, that inhibits the mTOR pathway can affect the growth of tumors? In this study, rapamycin is a classic mTOR inhibitor that inhibits the activity of two large blocks of mTORC1 and mTORC2 in the pathway at the same time.
Is it good to limit the tumor just by using it? It's not that simple, and a negative feedback diagram below illustrates the reason.
when mTOR is long-term inhibition, S6K1 activity will also be reduced, S6K1 feedback inhibition circuit of RTK will be lifted, then, there will be more compensation circuit to compensate For AKT and AGKs these pro-survival factors, in addition to S6K1 can also inhibit the MEK-ERK signaling pathway, the same rapamycin can be de-inhibited MEK-ERK inhibition, clinical inhibition of rapinmycin resistance.
studies have shown that rapamycin does not completely inhibit the full activity of mTORC1, and may vary from substrate to substrate.
for 4E-BP1 is only a short or partial inhibition of its phosphorylation, when the negative feedback loop of S6K1-IRS1 causes the activation of PI3K-AKT, may eventually lead to the overphosofs of 4E-BP1 and other tumor-promoting functions.
scientists are trying to design mTOR inhibitors to fight tumors.
competing ATP-combined inhibitors Torin 1 and PP242 have good clinical efficacy, but the feedback loop of S6K1-IRS1 is still unavoidable.
think again, if the activity of mTORC1 is maintained to maintain the integrity of negative feedback on AKT activity, only inhibit the activity of mTORC2.
this can inhibit AKT's Ser473 phosphorylation inhibits its activity, but the follow-up study found that although AKT's Ser473 phosphorylation is inhibited, in theory Thr308 phosphorylation will not be triggered, the actual situation is in this context Thr308 bit may be compensated by other paths, mTORC2 inhibition on AKT activity may only affect some of the substrates such as FOXO1 and FOXO3.
strategy in recent years has focused on mTOR and PI3K double inhibitors, both protein kinases belonging to the PI3K protein kinase family.
principle, it not only inhibits the activity of mTOR, but also directly inhibits the activity of AKT, so it is very good to avoid the S6K1-IRS1 feedback loop.
double inhibitor PI-103 has also shown good effects on killing lymphoma, but such double inhibitors have the same toxic side effects on normal lymphatic tissue.
cancer treatment for mTOR still has a long way to go.
's attempts at mTOR targeted treatment of tumors have also been a good confirmation that tumors are a systemic disease that moves the entire system, which is probably the most important reason why tumors are difficult to deal with.
for simple-cause tumors, treatment is relatively easy.
for tumors caused by complex etiology, may initially be caused by a single factor of the internal cell to the growth and proliferation of self-restraint mechanism of destruction, and simple point of destruction may be self-healing, may also cause the chain of positive feedback constraints of escape, causing tumors.
this is like in a cellular society, if the body is hurt by external factors can not resist, then the individual cell will not rely on the overall collaboration and strive to survive as an individual.
Source: Dehelix.