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M2M > mTOR > Flashcards

mTOR Flashcards

1
Q

What are the functions of mTOR?

A
  • senses the environment (nutrients, oxygen availability, growth factors, hormones)
  • sets the cell up for anabolism or catabolism
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2
Q

What does active mTOR result in?

A

high cell growth and low autophagy

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3
Q

What does inactive mTOR result in?

A

high autophagy

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4
Q

Which mTOR is more sensitive to rapamycin?

A

mTORC1

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5
Q

By what two processes is mTOR activated?

A
  • growths factor activation

- amino acid/nutrient availability

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6
Q

How do growth factors activate Akt in the mTOR pathway?

A
  • bind to a receptor tyrosine kinase
  • PIP3 is activated
  • PIP3 activates PDK-1
  • PDK-1 phosphorylates Akt
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7
Q

What can prevent the activation of PDK-1 and Act in the mTOR pathway?

A

phosphatase and tennis homolog (PTEN)

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8
Q

What does Akt do the mTORC1?

A
  • Akt phosphorylates TSC1/2 and inhibits it (TSC1/2 usually inhibits mTORC1)
  • phosphorylates mTORC1 to activate it
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9
Q

What does TSC1/2 do to mTORC1?

A
  • inhibits mTORC1

- inactivated by Akt phosphorylation

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10
Q

What does TSC1/2 do to mTORC2?

A

TSC1/2 increases mTORC2 activity

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11
Q

What does mTORC1 do?

A
  • lipid biosynthesis
  • ribosome biosynthesis
  • protein translation
  • inhibits repressors of mRNA translation 4E-binding proteins (4E-BPs)
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12
Q

What does mTORC2 do?

A
  • lipid breakdown and synthesis
  • regulates Akt
  • cytoskeletal organization
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13
Q

How does mTORC2 regulate Akt activity?

A

by phosphorylating it, which is required for full Akt activation

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14
Q

How does mTORC1 downregulate Akt?

A
  • mTORC1 activates S6Kinase1 (regulates protein synthesis

- phosphorylated S6K1 inhibits mTORC2, downregulating Akt activation

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15
Q

What is the regulatory associated protein of mTORC1?

A

Raptor

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16
Q

What is the regulatory associated protein of mTORC2?

A

Rictor

17
Q

How do mTORC1 and mTORC2 enhance cell growth?

A

mTORC1 - increases eIF4E (global translation factor)

mTORC2 - increases Akt and IGF (growth factor)

18
Q

What happens to mTOR when there is an excess of nutrients?

A
  • excess mTOR activity
  • metabolic dysfunction
  • excess adiposity differentiation into white adipose tissue
19
Q

What is the result of excess mTORC2 activity?

A

excess lipid biogenesis and glycogen

20
Q

What is the result of excess mTORC1 activity?

A

downregulates signaling from the insulin receptor -> insulin insensitivity
- through IRS1

21
Q

How is mTORC1 regulated by amino acids?

A
  • Rags/RHEB complex not fully activated until Rags is activated by amino acids (RHEB activated by growth factors)
  • activated Rheb1 at lysosome activates mTORC1 and anchors to lysosome
22
Q

How does mTORC1 inhibit autophagy?

A
  • Rags activated by amino acids -> localize mTORC1 to lysosome
  • activated mTORC1 phosphorylates and inactivates crucial proteins for autophagy (ULK1/2)
23
Q

What occurs when PTEN is mutated?

A
  • normally a tumor suppressor that down regulates Akt activation
  • mutations result in uncontrolled cell growth
24
Q

How do TSC1/2 mutations result in cancer?

A

regulates Akt -> activates mTOR

25
Q

How do PI3K mutations result in cancer?

A

usually activates Akt

26
Q

How may mTOR drive tumorigenesis?

A
  • activating mutations may drive cell growth
  • mTORC1 suppressing autophagy may enhance tumorigenicity
  • autophagy may be a tumor suppressor (limiting growth)
  • mTORC2 directly activates Akt, increasing cell proliferation
27
Q

What is the role of the PI3-kinase/Akt/mTOR pathway in diabetes?

A
  • increase mTORC1 (insulin resistance)

- reduce mTORC2 (altered lipid metabolism)

28
Q

What is the role of the PI3-kinase/Akt/mTOR pathway in polycystic kidney disease?

A

increase Rheb1 activity

29
Q

What is the role of the PI3-kinase/Akt/mTOR pathway in systemic erythemia lupus?

A

mTORC1 increased in immune cells

30
Q

How do mutations Tsc1/2 result in tuberous sclerosis?

A
  • Tsc1 and Tsc2 are tumor suppressors that normally downregulate mTOR activity
  • mutations cause uncontrolled cell growth resulting in hamartomas benign tumors
31
Q

What happens with loss of PTEN?

A

drives Akt signaling to mTOR

32
Q

What happens with loss of Tsc1/2?

A

drives mTOR1 activation and reduces mTORC2 signaling

33
Q

How does rapamycin/rapalogs inhibit mTOR?

A
  • blocks mTORC1 activity

- at high dose/long exposure also block mTORC2 (likely pulling mTOR out of system)

34
Q

How do ATP-competitive mTOR kinase inhibitors work?

A
  • competitive binding to mTOR catalytic site

- blocks both mTORC1 and mTORC2

35
Q

Why don’t mTOR inhibitors reduce mTOR hyper activation in cancer therapy?

A
  • pathways very complicated
  • only effective for a subset of cancers
  • different tissues have different responses
36
Q

Why don’t rapalogs work well to reduce mTOR hyperactivation?

A
  • they don’t inhibit all mTORC1 substrate phosphorylation equally (e.g. S6Kinase inhibited but not 4E-BPs)
  • inhibiting mTORC1 feeds back to activate mTORC2 or longterm may block mTORC2
37
Q

Why does mTOR inhibition not work well to reduce immune responses (tissue rejection)?

A

possibility of inducing specific tumors or diabetes

38
Q

What do newer inhibitors of the mTOR pathway target?

A
  • kinase inhibitors

- directly inhibit kinases of both mTORC1 and mTORC2 (ATP competitive)

M2M (41 decks)

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