Lecture 4 - cancer signaling Flashcards
what is signal transduction
the conversion of information into a chemical change, a universal property of living cells
how is specificity of signal transduction achieved?
by molecular complementarity between the signal and receptor molecules mediated by weak noncovalent forces
what type of receptors are theunder this category and give eg
single-pass transmembrane proteins.
ANF receptors (atrial natriuretic factor receptors): NPR1,2,3 in kidney, guanylate cyclase-coupled receptors (NO-activated guanylate cyclase
what types of receptors are involved in cancer signalling?
- GPCR
- RTKs
- Receptor guanylyl cyclase
- gated ion channel
- adhesion receptor (integrin)
- nuclear receptor
5 features of signal transduction system
- specificity
- amplification
- modularity
- desentilizaiton/adaptation
- integration
meaning of modularity
- various parts coming together
- proteins w multivariant affinities from diverse signalling complexes from interchangeable parts
- phosphorylation provides reversible points of interaction
reversible, interchangeable
meaning of desentilizaiton/adaptation
feedback control: receptor activation triggers a feedback loop that shuts off the receptor / removes it from CSM
meaning of integration
combine outputs from multiple signals:
- when 2 signals have opposing effects
- result is the integrated input of from both receptors
examples of mutations changing signalling molecules
GOF: PI3K (enzyme) - hyperactivation
LOF: PTEN - eliminate negative regulation for proiferation
PI3K-Akt pathway
- activation of RTK by ligand binding
- PIP2 is phophorylated into PIP3
- AKT is activated by PIP3 to promote cell growth, proliferation & survival (inhibiting apoptosis)
- PTEN dephosphorylates PIP3 back into PIP2
RAS-ERK pathway
- Ras activates Raf (protein kinase)
- Raf eventually activates ERK (act as TF) to stimulate a number of pro-oncogenic pathways
- This pathway could be integrated with the PI3K/AKT pathway and others
how does Ras-ERK pathway impact cell metabolism?
- via MYC: regulates glucose uptake, glycolysis, the pentose phosphate pathway, synthesis of glutamine transporters and glutaminase (GLS)
- the pathway stimulates glucose transporters (GLUTs), activates mTORC pathway and inhibition of FoxO TFs
glutaminase converts glutamine into glutamate to be metabolised in the mitochondria
mTORC pathway: regulates cell growth, prolif, suvival
FoxO TFs: induce cell cycle arrest
Background of RAS
could we cure cancer
- a type of GTPase
- active when bound to GTP, inactive when bound to GDP
- has intrinsic GTPase activity to ceave GTP into GDP
- regulated by: guanine nucleotide exchange factors (GEF) (GDP –> GTP)
- regulated by: GTPase (GTP –> GDP)
Mutation in Ras
mutation into:
- Ras always “on”
- G12, G13, Q61, A146, etc.
mechanism of Ras (KRAS)
KRAS -(GEF)-> activated KRAS –> activate ERK (stimulates a number of pro-oncogenic pathways
G12D mutation in KRAS
- this mutation leads to projection of a bulkier and negatively charged side group into the active site
- cause steric hindrance in GTP hydrolysis
- impair GTPase function, KRAS becomes constitutively active due to bound GTP
what if we tried to target RAS for cancer treatment?
- block membrane recruitment of Ras
- Ras membrane localization depends on FTASE (farnesyltransferase) which catalyse addition of farnesyl moiety to cysteine residue on C-terminus CAAX motif on RAS - FTASE inhibitor
- still have alternative modification by geranylgeranyl transferase 1 (GGTASE-1) can also target RAS to membrane
other proteins that have to undergo farnesylation may also be affected
