34. Cell signalling and kinases

Last updated on November 19, 2018 at 17:16

Summary

  • AMPK is activated when a cell has low [ATP], and activates and inhibits enzymes to try to raise [ATP]
  • mTORC1 is a protein that is activated by growth factors and nutrients, that stimulates cell growth
  • Erythropoietin affects gene expression through the JAK/STAT pathway and MAPK
  • Protein kinase C is activated by many hormones, and regulates the cell cycle and stimulates inflammation
  • HIF-1α is a protein that is activated in hypoxia. It increases glycolysis and inhibits TCA, while trying to make the oxidative phosphorylation more effective. It also activates transcription of erythropoietin and VEGF.
  • ChREBP is carbohydrate response element binding protein, and is stimulated by the end-products of the pentose phosphate pathway and activates anabolic enzymes
  • SREBP is sterol regulatory element binding protein. It activates cholesterol synthesis when cholesterol is low. It’s explained in the cholesterol chapter.
  • FOXO1 is a transcription factor that is inactivated by PKB.

There exist many types of receptor

G-protein coupled receptor, receptor tyrosine kinase, receptor guanylyl cyclase, gates ion channel, adhesion receptor and nuclear receptor are the general types of receptors.

AMPK affects many things

AMP-dependant kinase, or AMPK for short, is an enzyme that is activated when the cells concentration of AMP is high (because that means that [ATP] is low), or by exercise. It is also activated by adiponectin, a hormone that is released by adipose tissue during periods of starvation. AMPK then activates many processes that will elevate the level of ATP, while inactivating many processes that would use ATP. The table below shows what AMPK affects.

Cardiac glycolysis Activated
Glucose uptake through GLUT4 and GLUT1 Activated
Fatty acid oxidation Activated
Fatty acid synthesis Inactivated
Cholesterol synthesis Inactivated
Triacylglycerol synthesis Inactivated
Glycogen synthesis Inactivated
Protein synthesis Inactivated
Insulin secretion Inactivated

AMPK also affects cognitive functions. It will stimulate feeding behaviour, and inhibit behaviour that uses unnecessary energy.

mTORC1 increases cell growth and proliferation

mTORC1 is a protein complex that is activated by nutrients and growth factors. It increases energy production and the activity of the pentose phosphate pathway, to create materials needed for protein synthesis. It also increases transcription of genes involved in angiogenesis and adipogenesis, to provide materials needed for membranes. Finally, the cell uses these materials to grow and proliferate. Too high or too low activity of mTORC1 causes age-related diseases.

Erythropoietin

EPO is a hormone that stimulates RBC production. The hormone binds to its receptor, EPO receptor. This receptor is bound to a protein called Janus kinase, or JAK. When EPO is bound, JAK is activated. JAK then activates two pathways, the MAPK cascade, and the STAT protein. Both affect gene expression.

Protein kinase C

PKC is activated by increased [Ca2+] and [diacylglycerols], which means it’s activated by many hormones, like oxytocin, angiotensin, histamine, vasopressin and so on. Activated PKC is involved in many functions, like learning, memory, regulating cell growth and mediating immune responses. It also regulates transcription through a protein called NF-κB, which also stimulates inflammation.

HIF-1α

Hypoxia-inducible factor 1-α, or HIF-1α, is a protein that is used to sense O2 in humans. When activated, it activates processes that yield energy without needing oxygen, while inhibiting processes that do need oxygen. It also activates processes like angiogenesis and through the mechanism of EPO.

HIF-1α is constantly hydroxylated by O2, a process which requires vitamin C and Fe2+. After hydroxylation, it binds to a protein called Von Hippel–Lindau protein, or pVHL. The HIF-1α-pVHL complex is then ubiquitinated and broken down.

However, when O2-saturation is low, HIF-1α can’t be hydroxylated, because hydroxylation requires O2. By itself, HIF-1α is a transcription factor, but when there is sufficient oxygen present, it is hydroxylated and therefore degraded before it can affect transcription. However, when O2 is low and it’s not hydroxylated but instead phosphorylated, and it does its job as a transcription factor.

HIF-1α increases expression of genes that are involved in glycolysis and lactate dehydrogenase. Because glycolysis doesn’t need O2, but the TCA and oxidative phosphorylation do, glycolysis is activated while the latter two are inhibited. It also inhibits pyruvate dehydrogenase complex.

Lastly, HIF-1α modifies complex IV of the oxidative phosphorylation. It switches out one of its subunits with another subunit that is more effective when O2 is low.

ChREBP

Carbohydrate response element binding protein, or ChREBP, is a transcription factor that is activated by xylulose 5-phosphate, a product of the pentose phosphate pathway, and PP2A. ChREBP increases expression of pyruvate kinase (in the liver), acetyl-CoA carboxylase and fatty acid synthase in the liver, adipose tissue and the kidney.

FOXO

Forkhead box other, or FOXO, is a class of transcription factors. They target genes that negatively regulate cell growth and survival. We know from before that FOXO1 activates PEPCK and G6Phase, but FOXO genes also inhibit expression of enzymes related to glycolysis, pentose phosphate pathway and triacylglycerol synthesis. It can bind another protein called 14-3-3.

NF-κB

Nuclear factor kappa B, or NF-κB, is a transcription factor that is activated by several stimuli, like stress, free radicals, cytokines, infection or UV radiation. It responds to these stimuli by increasing expression of genes related to immune response and inflammation, amongst others.


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33. Insulin

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35. NO and CO as signal molecules

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