Cell Signaling Unit 4 Flashcards
Explain local vs. long distance strategies of cell-communication:
Describe Ion-channels:
Ion-channel-coupled receptors, also known as transmitter-gated ion channels or ionotropic receptors, are involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells such as nerve and muscle cells. This type of signaling is mediated by a small number of neurotransmitters that transiently open or close an ion channel formed by the protein to which they bind, briefly changing the ion permeability of the plasma membrane and thereby the excitability of the postsynaptic target cell. Most ion-channel-coupled receptors belong to a large family of homologous, multipass transmembrane proteins.
Describe GPCRs:
G-protein-coupled receptors act by indirectly regulating the activity of a separate plasma-membrane-bound target protein, which is generally either an enzyme or an ion channel. A trimeric GTP-binding protein (G protein) mediates the interaction between the activated receptor and this target protein (Figure 15–16B). The activation of the target protein can change the concentration of one or more small intracellular mediators (if the target protein is an enzyme), or it can change the ion permeability of the plasma membrane (if the target protein is an ion channel). The small intracellular mediators act in turn to alter the behavior of yet other signaling proteins in the cell. All of the G-protein-coupled receptors belong to a large family of homologous, multipass transmembrane proteins.
Describe Enzyme-Coupled receptors:
Enzyme-coupled receptors either function directly as enzymes or associate directly with enzymes that they activate (Figure 15–16C). They are usually single- pass transmembrane proteins that have their ligand-binding site outside the cell and their catalytic or enzyme-binding site inside. Enzyme-coupled receptors are heterogeneous in structure compared with the other two classes. The great majority, however, are either protein kinases or associate with protein kinases, which phosphorylate specific sets of proteins in the target cell when activated.
What are the functions of mTOR?
It functions as a sensor of the body environment. For example, it senses nutrients such as amino acids, oxygen availability, growth factors and hormones.
It also sets the cell up for catabolism or anabolism. Thus, when mTOR is active it leads to high cell growth and low autophagy.
On the other hand, when mTOR is inactive, it leads to HIGH autophagy.
What are the two mTOR complexes and what are their differences?
In mammalian cells, mTOR complex 1 contains the protein raptor; this complex is sensitive to rapamycin, and it stimulates cell growth—both by promoting ribosome production and protein synthesis and by inhibiting protein degradation. Complex 1 also promotes both cell growth and cell survival by stimulating nutrient uptake and metabolism.
mTOR complex 2 contains the protein rictor and is insensitive to rapamycin; it helps to activate Akt, and it regulates the actin cytoskeleton via Rho family GTPases.
What are the two factors that activate mTOR?
1- Growth factors
2- Amino acids and nutrient availability
Explain how growth factors activate Phosphoinositide 3 kinase (PI3K)?
In the presence of growth factors (Neuregulin for example), PI3K phosphorylates phosphoinositides PIP2 and PIP3, which then activate PDK1. PDK1 then phosphorylates Akt.
How can this process be inhibited at this point?
Phosphatases can be removed from phosphoinositides by phosphatases and tensin homolog (PTEN), which would prevent PDK-1 and Akt activation.
To continue, once Akt is activated, it phosphorylates Tuberous Sclerosis 1 and 2 (TSC1–>Hamartin and TSC2–> Tuberin).
What is the effect of TSC1/2 phosphorylation?
It blocks their actions, and since they act to regulate mTOR activity by phosphorylating and inhibiting Rheb1 (makign it Rheb-GDP), they inhibit mTORC1 activation. Rheb normally activates mTORC1 in its Rheb-GTP complex.
However, Akt directly phosphorylates mTORC1.
How does TSC1/2 affects mTORC1 and mTORC2?
Does rapamycin inhibits mTORC2?
TSC1/2 complex inhibits mTORC1, but increases mTORC2 activity.
It does, but at high doses or prolonguen exposures.
What are the functions of mTORC1 and mTORC2?
mTORC1 is highly involved with protein translation. It involves the activation of S6 Kinase 1, which downregulates mTOR2 activity.
mTORC2 function to regulate Akt itself and impact Cytoskeleton
Describe the highly interactive signaling of mTOR?
mTORC2 regulates Akt activity by phosphorylating it at Ser473, which is required for full Akt activation.
Activated Akt downregulates TSC1/2 activity, thereby activating mTORC1 and directly activates mTORC1 by phosphorylation of mTOR itself.
mTORC1 activates S6Kinase 1, which regulates protein synthesis.
Phosphorylated S6K1 inhibits mTORC2, thereby downregulating Akt activation.
Describe mTORC1:
- mTOR complexes with Raptor (regulatory-associated protein of mTOR).
- **Nutrient sensitive
- Also activated by insulin and other growth factors.
- Activates ribosome biogenesis and protein synthesis
- Phosphorylates and inhibits repressors of mRNA translation 4E-binding proteins (4E-BPs)***.
- Phosphorylates and activates the ribosomal S6 kinase (S6K1).
- Active mTORC1 inhibits autophagy.
•Inactivated in stress conditions
Describe mTORC2:
complexes with Rictor (rapamycin-independent companion of TOR)
Phosphorylates Akt on Ser473 which enhances likelihood of full Akt
activation by phosphorylation on Thr301.
It is mainly involved in *cytoskeletal* organization.
What happens to mTOR activity in environments with excess nutrients?
- Excess mTOR activity
- Metabolic dysfunction
- Excess adipocyte differentiation into white adipose tissue.
- mTORC2 drives excess lipid biogenesis and glycogen.
- Excess mTORC1 downregulates signaling from the insulin receptor—insulin insensitivity***. Moreover, activated mTOR inhibits insulin signaling through IRS1.
Describe how mTORC1 is regulated by amino acids:
- mTORC1 activity is regulated by amino acid availability/energy status.
- This regulation is independent of but integrates with PI3K/Akt activity driven by growth factors
- Rags (Ras-related GTP-binding protein) does the following:
–They are small GTPases
–Activated in the presence of amino acids
–Bind to lysosomes via Ragulator
–Bind mTORC1, moving it to lysosome membrane.
–Activate Rheb1 at lysosome (activates mTORC1)
–Autophagy inhibition requires active Rags***
