Frailty Pathways

Question 1

IGF

Answer 1

insulin like growth factor

Question 2

was does IGF mediate

Answer 2

cell proliferation, apoptosis, differentiation, survival, metabolism, migration

Question 3

IGF and angeing

Answer 3

this pathway has be implicated in ageing since it has important unctions in growth, metabolism and fertility
- also implicated i neurodegeneration, diabetes and cancer progression

Question 4

IGF is an

Answer 4

extracellular survival signal e.g. insulin, ECF, VEGF

Question 5

IGF receptors

Answer 5

dimerised tyrosine kinases

- GF leads to conformational change leading to autophosphorylation

Question 6

IGF pathway

Answer 6

1) IGF binds to TK and causes conformational change which leads to autophosphorylation
2) once IGF is bound phosphotyrosine becomes ‘sticky’due to SH2 domain
3) PI3K (recruits via PH domain)binds and activates to PIP2 which it is bound to
4) PIP2 phosphorylates PIP3
5) and PIP3 phosphorylates PDK1
6) PDK1 and mTORC2 phosphorylate Akt to activate it

Question 7

what phosphorylates Akt in the IGF pathway and how many times must it be phosphorylated

Answer 7

PDK1 and mTORC2

• once by each enzyme
• twice in total

Question 8

once Akt has been phosphorylated twice, which processes are turned on by numerous cascades

Answer 8

1) proliferation
2) survival
3) angiogenesis

Question 9

For Akt to activated..

Answer 9

a growth factor e.g. IGF has to bind to its tyrosine kinase receptor and mTORC2 must phosphorylate

Question 10

mTOR

Answer 10

known as mammalian target rapamycin

Question 11

mTOR exists in complex with other proteins

Answer 11

mTORC1 raptor

mTORC2 rictor

Question 12

mTORC1

Answer 12

raptor

Question 13

mTORC2

Answer 13

rictor

Question 14

mTORC2 directly activates

Answer 14

Akt

Question 15

mTORC2 indirectly activates

Answer 15

mTORC1

- cell growth: ribosome production, protein synthesis, inhibits proteolysis, stimulates nutrient uptake

Question 16

mTORC1

Answer 16

when activated - cell growth

Question 17

what else has to activate mTORC1

Answer 17

Amino acids

Question 18

mTOR pathway and cancer

Answer 18

activating during: angiogenesis, tumour formation, insulin resistance, adopogenesis and T lymphocyte activation
- disregulated when cancer and type 2 diabetes occur

Question 19

How does Ak activate mTORC1

Answer 19

Akt phosphorylates and inactivates Rheb-GAP (TCS2).

Inhibited Tcs2 prevents Rheb GTPase activity.
Active Rheb- GTP bound activates mTORC1

Question 20

mTORC1 produces

Answer 20

S6 kinase which is phosphorylated to become S6 ribosome protein

Question 21

how is Akt stop cell death

Answer 21

inhibits apoptosis and autophages and UPS proteolysis

Question 22

Akt and Apoptosis

Answer 22

1) Akt inactivates Bad via phosphorylation
2) meaning Bad leases Apoptosis inhibitory protein
3) apoptosis inhibitory protein habits apoptosis

Question 23

Akt and autophagy and UPS proteolysis

Answer 23

1) AKT inhibits FOXO in the myofibril nucleus
2) preventing the transcription of Atrogen-1 and MURF
3) these genes cause autophagy and UPS proteolysis

Question 24

atrogen-1 AND MURF-1

Answer 24

• genes which promote autophagy and UPS proteolysis
• Akt inhibts transcription of these
• stopping autophagy

Question 25

IRS-1

Answer 25

insulin receptor substrate -1

Question 26

function of IRS-1

Answer 26

transits signals from IGF-1 to P13K/AKt and MAPK cascade

Question 27

how IRS-1 works

Answer 27

when IGF-1 binds IRS-1 is phosphorylated by the tyrosine kinase receptor and it recruits P13K (Akt cascade) and also Grb2/SOS (MAPK cascade)

Question 28

tyrosine phosphorylation of IRS-1 by insulin receptors introduces multiple binding site for proteins bearing…

Answer 28

SH2 domains

Question 29

proteins which contain SH2 domains

Answer 29

P13K, Grb2/SOS complex and SHP2