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BioMedChem Midterm 1 > 4 - AMPK, mTOR, and more... > Flashcards

4 - AMPK, mTOR, and more... Flashcards

1
Q

mTOR

A
  • PIKK (ser/thr kinase)
    • that is expressed in ALL EUKARYOTIC organisms
  • Mechanistic target of RAPAMYCIN
    • responds to energy / AA / Oxygen levels
  • INSULIN induces mTOR signaling
    • Regulates the regulation of energy
  • Forms two complexes:
    • mTORC1 = mtor + RAPTOR
    • mTORC2 = mTOR + rictor
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2
Q

mTORC1 3 Major Functions

A
  1. Activates Ribosomal Proteins
    1. S6K -> actively translating more proteins
  2. Induces the dissocation of 4E-BP1 from elF4E
    1. ​4E-BP1 normally is inhibiting elF4E
      1. –> Initiates mRNA Translation
        1. Stimulates Protein Synthesis
  3. ​​Inhibits Catabolic process of _AUTOPHAGY_

Ultimately increases

Cell mass / size / proliferation

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3
Q

mTORC1 Activation pathway

A
  • Insulin Binding starts Signaling Cascade
    • IRS-1 activates P13K
    • Pip2-Pip3
      • Activates PDK1
        • Phosphoralates Ser/Thr AKT
          • ​Inhibits TSC1/2
            • ​AMPK activates TSC
          • Inhibits RHEB conversion
            • ​Activates mTORC1
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4
Q

mTORC1 initiation of cap-dependent mRNA Translation

A
  • mTORC1 activation causes dissociation of 4E-BP1 from elF4E
    • allows elF4FE complex to form
      • binds to 7-mg CAP on 5’ end of mRNA
        • -> Initiate cap dependent mRNA Translation
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5
Q

Pathologies Associated With mTORC2

A
  • Normally, PTEN** inhibits conversion of **P13K -> mTORC2
    • Cowden / Prostate CA / Endometrial CA / Giloblastoma
      • ​All stop PTEN from inhibiting mTORC
        • -> Turn ON TRANSLATION
          • ​= Uncontrolled Growth
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6
Q

PTEN / LKB1 / NF1 / VHL

A
  • Proteins that are signaled by Oxygen/energy/hormones
    • to INHIBIT mTORC1​
      • to CONTROL translation & Protein synthesis
  • ​Various pathologies cause the Loss of the proteins
    • ​–> Activation of mTORC1
      • ​-> Uncontrolled Growth / Cancer
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7
Q

Rapamycin

A
  • pharmacological Inhibitor of mTOR
    • ​Macrocyclic Lactone
  • Induces Dimerization of mTOR / FKB12
    • ​-> loss of signaling from interacting proteins
  • ​Immunosuppresive Functions
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8
Q

Rapamycin Uses

A
  • Immunosuppresive Function
    • blocks IL2 mediated T-cell proliferation
  • Prevent Restenosis in Coronary Stents
    • potent inhibitor of vascular smooth muscle proliferation
      • keeps vascular smooth muscle from growing around the stent
  • INHIBITS proliferation of many CANCER cells
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9
Q

Immunosuppressive Function of

Rapamycin = mTOR Inhibitor

A
  • Normally mTOR allows for T-cell proliferation
    • –> cell-cycle progression of IL-2 production
      • -> Cascade of immunogenic events
  • Inhibiting mTOR
    • ​-> blocks IL-2 activation of T / B Cells
      • ​reduces the Immune Response
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10
Q

Prevention of Restenosis

Rapamycin = mTOR Inhibitor

A
  • Restenosis = Inflammation of the area around the STENT
    • Caused by the Proliferation of smooth muscle cells
  • mTOR Inhibition -> BLOCKS cell replication
    • ​blocks muscle cell migration & proliferation​ of smooth muscle cells
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11
Q

Dual Effect of Rapalogs in Type 1 Diabetes

A
  • Type 1 diabetes is treated by transplanting a pancreas or islet cells
  • Inhibiting mTOR results in:
    • Preventing the rejection of beta islet cells
      • ​but hinder islet health
        • ​b/c mTOR normally signals islet growth through S6K
    • Stopping the positive regulation of islet proliferation
      • ​mTOR normally promotes islet proliferation
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12
Q

Rapalog

A

Rapamycin + its analogs

Alter PK/PD of Rapamycin

INHIBITS mTOR

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13
Q

Rapalogs in Type 2 Diabetes

A
  • Rapamycin -> blocks S6K
    • can help restore sensitivity
      • S6K negatively inhibits Insulin receptors
  • Sustained mTOR activation is one mechanism of INSULIN RESISTANCE
    • ​from a reduction of downstream signaling of insulin receptor changes in phosphorylation
    • can also degrade IRS2
      • ​-> beta cell apoptosis
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14
Q

How does mTOR cause insulin resistance?

A
  • Normally, Insulin or Glucose Binding
    • Activates mTORC1 -> S6K
      • S6K inhibits IRS insulin receptor
        • ​= Normal Negative feedback
  • In T2DM,
    • Glucose + Obesity + Cytokines are constantly activating mTORC1
      • ​-> S6K is constantly inhibiting the insulin receptor
        • ​-> INSULIN RESISTANCE
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15
Q

AMPK-5’

A
  • Heterotrimeric Ser-Thr Kinase
    • Senses DEPLETION of intracellular energy
      • -> stimulates ATP GENERATION
        • = Catabolic
  • Allosterically activated by AMP
  • Covalently modified by phosphorylation by LEPTIN
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16
Q

AMPK is activated by?

A
  • Phosphorylation of Thr172 of the alpha subunit
    • Catalyzed by:
      • LKB1 or CaMKK2 (calcium)
      • TAK1
      • KSR2
        • ​directly acts on alpha, not Thr
  • ​Directly activated @ Gamma subunit by:
    • High AMP/ATP ratio (low energy)
      • -> also blocks inhibition of AMPK thru PP2C-alpha
  • EXERCISE
17
Q

LKB1

A

Catayzes the phosphorylation on Thr172 on the alpha subunit

Activates AMPK

LKB1 is also a tumor suppresor

18
Q

CaMKK2

CALCIUM

A

Catayzes the phosphorylation on Thr172 on the alpha subunit

Activates AMPK

Calcium dependent activation increases calcium

–> Increases activation of CaMKK2

19
Q

TAK1

A

Catayzes the phosphorylation on Thr172 on the alpha subunit

-> Activates AMPK

TAK1 is always active

20
Q

KSR2

A

Directly interacts with the alpha subunit

-> Activates AMPK

21
Q

PP2C-Alpha

A
  • INHIBITS AMPK
    • ​through inhibition of Thr172 phosporlation @ alpha
  • PP2C-alpha is Inhibited by:
    • Increase in AMP/ATP ratio
22
Q

AMPK is inhibited by?

A
  • CIDEA -> beta subunit
    • Cell-death-inducing-like-effector-A
  • PP2C-alpha -> Thr phosphorylation
23
Q

CIDEA

A

INACTIVATES AMPK

  • Forms complex w/ beta subunit of AMPK
  • Mediates ubiquitin-dependent degradation
24
Q

Metformin

A

INHIBITS mTOR

–> promising effects on cancer prevention

is a diabetes drug

25
Q

AMPK on Lipid Metabolism

A
  • Active AMPK -> Activates Catabolic Processes
    • ​fatty acid oxidation -> ATP
      • Restore AMP/ATP ratio
26
Q

mTORC1 vs mTORC2

A
  • mTORC1
    • ​RAPTOR
    • Most used in signal transduction
  • mTORC2
    • rictor
    • MAIN DIFFERENCE IS THE PROTEIN COMPLEX
27
Q

How does AMPK inhibit mTOR?

A
  • AMPK phosphorylates TSC2
    • ​Activation of TSC leads to RHEB conversion
      • -> Inhibition of mTOR signaling
    • TSC normally inhibits RHEB​ conversion
      * ​which activates mTOR signaling
28
Q

What activates mTOR?

A
  • Insulin / IGF
    • -PTEN
  • AMINO ACIDS
  • Mitogens
    • -NF1
  • High Energy
    • ​-LKB1
  • Oxygen
    • -VHL
  • P13K activation

BioMedChem Midterm 1 (9 decks)

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