#L3 Burdette AMPK, mTOR, and more

mTOR is a type of —/— kinase that is the central regulator of cellular —, —, and —

serine, threonine, metabolism, growth, proliferation

mTOR responds to —, —, — levels

energy, amino acids, oxygen

mTOR forms two complexes:

mTORC1 - mTOR and ?

mTORC2 - mTOR and ?

raptor, rictor

mTOR1 is the central integrator of —

growth factor signaling

Insulin — mTOR1 signaling

activates

mTOR is — (what kind of kinase?)

PIIK (phosphatidylinositol 3-kinase)

The c-terminus of mTOR has a — and — kinase domain that is conserved and required for function.

serine, threonine

When mTOR is activated, it has 3 key effects:

• S6K —

• Translation inhibitor —

• Catabolism —

activation, turned off (no new protein; protein synthesis is used instead (using existing materials), turned off (favors anabolism)

Is protein synthesis catabolism or anabolism?

anabolism (build protein with existing materials)

mRNA translation is blocked by —

4E BPs binding tightly to eIF4E

mTORC1 — 4E-BP which releases

phosphorylates, eIF4E

Effect of free eIF4E? Initiates

translation of growth promoting proteins (anabolism)

mTOR favors anabolism or catabolism?

anabolism (promotes growth)

mTOR is activated when nutrients are sufficient, promoting anabolism and energy storage.

A. True

B. False

True

What is rapamycin?

mTOR inhibitor

3 Effects of Rapamycin to mTOR:

Immunosuppression (blocks proliferation of T-cells), helps prevent of restenosis (re-narrowing of artery by inhibiting smooth muscle cell proliferation), prevent proliferation of cancer cells

In normal conditions, mTOR helps the body use insulin effectively by promoting — and promoting — in response to nutrients.

energy storage, cell growth

When someone has insulin resistance, mTOR signaling can become dysregulated in 2 ways:

• mTORC1 signaling interference with —

• — → impair insulin signaling

insulin receptor, excessive mTOR1 activation

How does RapaLink-1 work? It combines —, which targets — with —, which targets — to effectively target — mTOR

rapamycin, mTORC1, MLN0128, both mTORC1 and mTORC2, mutant

RapaLink1 may be useful in patients…

A. With a mutation causing loss of PTEN

B. With a mutation in mTOR causing activation

C. That have lost sensitivity to rapamycin

D. All of the above

All of the above

When ATP levels are low, AMP levels —

rise

Increased AMP indicates the — ATP

need for more

AMP acts as an — activator of AMPK.

— can also activate AMPK by adding a phosphate group to it, further triggering AMPK’s activity

allosteric, LKB1

When is AMPK activated? When ATP is — and AMP is —

low, high

Does AMPK favor anabolism or catabolism?

catabolism

AMPK activation switches on — pathway to restore —.

For example, it can stimulate processes like — and —

catabolic, energy, fatty acid oxidation, glucose uptake

AMPK — mTOR when energy levels are low

inhibits (opposite)

AMPK inhibits mTOR by —

phosphorylating TSC

AMPK is activated by — on —, primarily by — or —

phosphorylation, Thr 172, LKB1, CAMKK2

LKB1 plays a central role in both — activation and promoting — by phosphorylating —

AMPK, autophagy, ULK1

LKB1 activates AMPK, leading to — of mTOR1

inactivation

AMP inhibits the — of AMPK, keeping it active when energy is —

dephosphorylation, low

— signals via CaMKK2 can activate AMPK — of AMP levels

Calcium, independently

— inactivates AMPK by binding to its — subunit and promoting its —

CIDEA, beta, ubiquitin dependent degradation

AMPK — glucose production in liver

decrease

AMPK — lipid synthesis in liver

decrease

AMPK — lipid oxidation in liver and skeletal muscle

increase

AMPK — glucose uptake in skeletal muscle

increase

AMPK — mitochondrial biogenesis in skeletal muscle

increase

AMPK — lipolysis in adipose tissues

decrease

AMPK — lipogenesis in adipose tissue

decrease

AMPK — insulin sensitivity in adipose, liver, skeletal muscle

increase

AMPK — insulin secretion in pancreas

decrease

AMPK — insulin levels in pancreas

decrease

AMPK can phosphorylate a variety of substrates. Which ones would impact gene expression?

A. Histones

B. Transcription factors

C. Cytoskeletal proteins

D. All of the above

All of the above

What pathway sense low ATP levels?

AMPK

What pathway restore ATP levels?

AMPK

What pathway stimulate catabolic pathway that generates ATP

AMPK

What pathway inhibit anabolic pathway that consumes ATP

AMPK

What pathway sense amino acid availability

mTOR

What pathway regulate cell growth and cell proliferation

mTOR

What pathway regulate tissue and organ growth

mTOR

What pathway stimulate protein synthesis

mTOR

What pathway stimulates ribosomal biogenesis

mTOR

What pathway inhibit autophagy

mTOR

What pathway regulates glucose metabolism

insulin

What pathway protects from oxidative stress

insulin

What pathway promote cell growth and proliferation?

insulin

What pathway promotes cell survival (antiapoptosis)?

Insulin

What pathway controls enzymes and regulatory proteins by phosphorylation?

Insulin

What pathway regulates gene transcription

insulin