mTOR

Question 1

What are the functions of mTOR?

Answer 1

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

Question 2

What does active mTOR result in?

Answer 2

high cell growth and low autophagy

Question 3

What does inactive mTOR result in?

Answer 3

high autophagy

Question 4

Which mTOR is more sensitive to rapamycin?

Answer 4

mTORC1

Question 5

By what two processes is mTOR activated?

Answer 5

• growths factor activation

- amino acid/nutrient availability

Question 6

How do growth factors activate Akt in the mTOR pathway?

Answer 6

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

Question 7

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

Answer 7

phosphatase and tennis homolog (PTEN)

Question 8

What does Akt do the mTORC1?

Answer 8

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

Question 9

What does TSC1/2 do to mTORC1?

Answer 9

• inhibits mTORC1

- inactivated by Akt phosphorylation

Question 10

What does TSC1/2 do to mTORC2?

Answer 10

TSC1/2 increases mTORC2 activity

Question 11

What does mTORC1 do?

Answer 11

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

Question 12

What does mTORC2 do?

Answer 12

• lipid breakdown and synthesis
• regulates Akt
• cytoskeletal organization

Question 13

How does mTORC2 regulate Akt activity?

Answer 13

by phosphorylating it, which is required for full Akt activation

Question 14

How does mTORC1 downregulate Akt?

Answer 14

• mTORC1 activates S6Kinase1 (regulates protein synthesis

- phosphorylated S6K1 inhibits mTORC2, downregulating Akt activation

Question 15

What is the regulatory associated protein of mTORC1?

Answer 15

Raptor

Question 16

What is the regulatory associated protein of mTORC2?

Answer 16

Rictor

Question 17

How do mTORC1 and mTORC2 enhance cell growth?

Answer 17

mTORC1 - increases eIF4E (global translation factor)

mTORC2 - increases Akt and IGF (growth factor)

Question 18

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

Answer 18

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

Question 19

What is the result of excess mTORC2 activity?

Answer 19

excess lipid biogenesis and glycogen

Question 20

What is the result of excess mTORC1 activity?

Answer 20

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

Question 21

How is mTORC1 regulated by amino acids?

Answer 21

• 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

Question 22

How does mTORC1 inhibit autophagy?

Answer 22

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

Question 23

What occurs when PTEN is mutated?

Answer 23

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

Question 24

How do TSC1/2 mutations result in cancer?

Answer 24

regulates Akt -> activates mTOR

Question 25

How do PI3K mutations result in cancer?

Answer 25

usually activates Akt

Question 26

How may mTOR drive tumorigenesis?

Answer 26

- 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

Question 27

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

Answer 27

- increase mTORC1 (insulin resistance) | - reduce mTORC2 (altered lipid metabolism)

Question 28

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

Answer 28

increase Rheb1 activity

Question 29

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

Answer 29

mTORC1 increased in immune cells

Question 30

How do mutations Tsc1/2 result in tuberous sclerosis?

Answer 30

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

Question 31

What happens with loss of PTEN?

Answer 31

drives Akt signaling to mTOR

Question 32

What happens with loss of Tsc1/2?

Answer 32

drives mTOR1 activation and reduces mTORC2 signaling

Question 33

How does rapamycin/rapalogs inhibit mTOR?

Answer 33

- blocks mTORC1 activity | - at high dose/long exposure also block mTORC2 (likely pulling mTOR out of system)

Question 34

How do ATP-competitive mTOR kinase inhibitors work?

Answer 34

- competitive binding to mTOR catalytic site | - blocks both mTORC1 and mTORC2

Question 35

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

Answer 35

- pathways very complicated - only effective for a subset of cancers - different tissues have different responses

Question 36

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

Answer 36

- 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

Question 37

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

Answer 37

possibility of inducing specific tumors or diabetes

Question 38

What do newer inhibitors of the mTOR pathway target?

Answer 38

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