mTOR Flashcards
What are the functions of mTOR?
- senses the environment (nutrients, oxygen availability, growth factors, hormones)
- sets the cell up for anabolism or catabolism
What does active mTOR result in?
high cell growth and low autophagy
What does inactive mTOR result in?
high autophagy
Which mTOR is more sensitive to rapamycin?
mTORC1
By what two processes is mTOR activated?
- growths factor activation
- amino acid/nutrient availability
How do growth factors activate Akt in the mTOR pathway?
- bind to a receptor tyrosine kinase
- PIP3 is activated
- PIP3 activates PDK-1
- PDK-1 phosphorylates Akt
What can prevent the activation of PDK-1 and Act in the mTOR pathway?
phosphatase and tennis homolog (PTEN)
What does Akt do the mTORC1?
- Akt phosphorylates TSC1/2 and inhibits it (TSC1/2 usually inhibits mTORC1)
- phosphorylates mTORC1 to activate it
What does TSC1/2 do to mTORC1?
- inhibits mTORC1
- inactivated by Akt phosphorylation
What does TSC1/2 do to mTORC2?
TSC1/2 increases mTORC2 activity
What does mTORC1 do?
- lipid biosynthesis
- ribosome biosynthesis
- protein translation
- inhibits repressors of mRNA translation 4E-binding proteins (4E-BPs)
What does mTORC2 do?
- lipid breakdown and synthesis
- regulates Akt
- cytoskeletal organization
How does mTORC2 regulate Akt activity?
by phosphorylating it, which is required for full Akt activation
How does mTORC1 downregulate Akt?
- mTORC1 activates S6Kinase1 (regulates protein synthesis
- phosphorylated S6K1 inhibits mTORC2, downregulating Akt activation
What is the regulatory associated protein of mTORC1?
Raptor
What is the regulatory associated protein of mTORC2?
Rictor
How do mTORC1 and mTORC2 enhance cell growth?
mTORC1 - increases eIF4E (global translation factor)
mTORC2 - increases Akt and IGF (growth factor)
What happens to mTOR when there is an excess of nutrients?
- excess mTOR activity
- metabolic dysfunction
- excess adiposity differentiation into white adipose tissue
What is the result of excess mTORC2 activity?
excess lipid biogenesis and glycogen
What is the result of excess mTORC1 activity?
downregulates signaling from the insulin receptor -> insulin insensitivity
- through IRS1
How is mTORC1 regulated by amino acids?
- 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
How does mTORC1 inhibit autophagy?
- Rags activated by amino acids -> localize mTORC1 to lysosome
- activated mTORC1 phosphorylates and inactivates crucial proteins for autophagy (ULK1/2)
What occurs when PTEN is mutated?
- normally a tumor suppressor that down regulates Akt activation
- mutations result in uncontrolled cell growth
How do TSC1/2 mutations result in cancer?
regulates Akt -> activates mTOR
How do PI3K mutations result in cancer?
usually activates Akt
How may mTOR drive tumorigenesis?
- 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
What is the role of the PI3-kinase/Akt/mTOR pathway in diabetes?
- increase mTORC1 (insulin resistance)
- reduce mTORC2 (altered lipid metabolism)
What is the role of the PI3-kinase/Akt/mTOR pathway in polycystic kidney disease?
increase Rheb1 activity
What is the role of the PI3-kinase/Akt/mTOR pathway in systemic erythemia lupus?
mTORC1 increased in immune cells
How do mutations Tsc1/2 result in tuberous sclerosis?
- Tsc1 and Tsc2 are tumor suppressors that normally downregulate mTOR activity
- mutations cause uncontrolled cell growth resulting in hamartomas benign tumors
What happens with loss of PTEN?
drives Akt signaling to mTOR
What happens with loss of Tsc1/2?
drives mTOR1 activation and reduces mTORC2 signaling
How does rapamycin/rapalogs inhibit mTOR?
- blocks mTORC1 activity
- at high dose/long exposure also block mTORC2 (likely pulling mTOR out of system)
How do ATP-competitive mTOR kinase inhibitors work?
- competitive binding to mTOR catalytic site
- blocks both mTORC1 and mTORC2
Why don’t mTOR inhibitors reduce mTOR hyper activation in cancer therapy?
- pathways very complicated
- only effective for a subset of cancers
- different tissues have different responses
Why don’t rapalogs work well to reduce mTOR hyperactivation?
- 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
Why does mTOR inhibition not work well to reduce immune responses (tissue rejection)?
possibility of inducing specific tumors or diabetes
What do newer inhibitors of the mTOR pathway target?
- kinase inhibitors
- directly inhibit kinases of both mTORC1 and mTORC2 (ATP competitive)
