Frailty Pathways Flashcards
IGF
insulin like growth factor
was does IGF mediate
cell proliferation, apoptosis, differentiation, survival, metabolism, migration
IGF and angeing
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
IGF is an
extracellular survival signal e.g. insulin, ECF, VEGF
IGF receptors
dimerised tyrosine kinases
- GF leads to conformational change leading to autophosphorylation
IGF pathway
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
what phosphorylates Akt in the IGF pathway and how many times must it be phosphorylated
PDK1 and mTORC2
- once by each enzyme
- twice in total
once Akt has been phosphorylated twice, which processes are turned on by numerous cascades
1) proliferation
2) survival
3) angiogenesis
For Akt to activated..
a growth factor e.g. IGF has to bind to its tyrosine kinase receptor and mTORC2 must phosphorylate
mTOR
known as mammalian target rapamycin
mTOR exists in complex with other proteins
mTORC1 raptor
mTORC2 rictor
mTORC1
raptor
mTORC2
rictor
mTORC2 directly activates
Akt
mTORC2 indirectly activates
mTORC1
- cell growth: ribosome production, protein synthesis, inhibits proteolysis, stimulates nutrient uptake
mTORC1
when activated - cell growth
what else has to activate mTORC1
Amino acids
mTOR pathway and cancer
activating during: angiogenesis, tumour formation, insulin resistance, adopogenesis and T lymphocyte activation
- disregulated when cancer and type 2 diabetes occur
How does Ak activate mTORC1
Akt phosphorylates and inactivates Rheb-GAP (TCS2).
Inhibited Tcs2 prevents Rheb GTPase activity.
Active Rheb- GTP bound activates mTORC1
mTORC1 produces
S6 kinase which is phosphorylated to become S6 ribosome protein
how is Akt stop cell death
inhibits apoptosis and autophages and UPS proteolysis
Akt and Apoptosis
1) Akt inactivates Bad via phosphorylation
2) meaning Bad leases Apoptosis inhibitory protein
3) apoptosis inhibitory protein habits apoptosis
Akt and autophagy and UPS proteolysis
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
atrogen-1 AND MURF-1
- genes which promote autophagy and UPS proteolysis
- Akt inhibts transcription of these
- stopping autophagy
IRS-1
insulin receptor substrate -1
function of IRS-1
transits signals from IGF-1 to P13K/AKt and MAPK cascade
how IRS-1 works
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)
tyrosine phosphorylation of IRS-1 by insulin receptors introduces multiple binding site for proteins bearing…
SH2 domains
proteins which contain SH2 domains
P13K, Grb2/SOS complex and SHP2