signalling through proteolysis Flashcards
signalling pathways that involve regulated proteolysis
development + cancer:
Notch
WNT/beta-catenin
Hedgehog
immune response:
NFkB
regulated proteolysis involved in…
which steps of cell signalling?
activation of membrane receptor when ligand binds
relay of signal
regulating activity of regulatory proteins
stem cells
self-renewing
generate transit-amplifying progeny
-> differentiate into functional cell types
persist for long time
regulated by immediate envrio
= niche
Notch signalling
- no. of receptors and ligands
4 receptors
(NOTCH1 - NOTCH4)
5 ligands
(DSL, JAG1, DLL1, DLL3, DLL4)
Notch signalling
- 1st of 3 proteolytic cleavage events
- cleavage at site 1 occurs in golgi
by furin protease
during maturation of receptor + transport to cell surface
Notch signalling
- 2nd of 3 proteolytic cleavage events
- receptor-ligand binding
-> cleavage at S2
mediated by ADAM10 + ADAM17 metalloproteinases
Notch signalling
- 3rd of 3 proteolytic cleavage events
- S3 cleavage by gamma-secretase
- > releases NICD (notch intracellular domain) from PM
Notch signalling
- final step
NICD translocates to nucleus
- > binds to CSL (transcriptional repressor)
- > becomes an activator
Notch signalling controls cell fate decisions
lineage specification
maintains SCs by inhibiting differentiation
induces differentiation
lineage specification:
lateral inhibition controls neural cell fate in Drosophila neuroectoderm
- basic principle
unspecified epithelial cells
-> eventually become neuronal cells
lineage specification controlled by differential delta expression
delta = inhibitory signal protein
lateral inhibition controls neural cell fate in Drosophila neuroectoderm
- mechanism
2 neighbouring cells:
- low levels of delta, weak notch signalling
if 1 expresses higher level of delta
- > sends strong notch signal
- > if doesn’t receive strong signal back
= can differentiate
induction of differentiation:
terminal differentiation in epidermis
- basic principle
SCs give rise to transiently-amplifying cells
- > proliferate couple times before they differentiate
- > pushed up towards spinous layer
- > express proteins making them distinct from basal cell layer
induction of differentiation:
terminal differentiation in epidermis
- mouse experiment
RBP-K knockout
(mouse ortholog of CLS)
Hes1 = one of the Notch signalling target genes in the epidermis
lower levels of Hes1 in epidermis of those with knockout
.:. Notch signalling inactivated
mice died immediately + v thin skin
do different Notch receptors have different functions?
-e.g. in human epidermis
supra-basal terminally differentiating cells express higher levels of Notch3
basal cells express higher levels of Notch1
all epidermal cells express similar Notch2 levels
why is Notch1 expressed highly in basal cells?
important for suppressing high levels of proliferation in trans-amplifying progenitor cells
Notch signalling in a tumour suppressive pathway
- oncogenic mutation in normal stem cell
- loss of function mutations in Notch
- impaired differentiation + expansion of mutant stem cells
- additional oncogenic hits
- tumour initiation from mutant clones
Wnt signalling
- Wnt proteins
Wnt proteins
= secreted signal molecules
- regulate proteolysis of B-catenin
Wnt signalling
- B-catenin
multifunctional protein
2 cellular pools:
> cell-cell junctions
> cytoplasm
Wnt signalling
- absence of Wnt signal
cytoplasmic B-catenin rapidly degraded by B-catenin destruction complex
- > phosphorylates
- > targets for degradation in proteasome
Wnt signalling
- presence of Wnt signal
blocks proteolytic processing of B-catenin
- > enters nucelus
- > binds to TFs in LEF1/TCF family
- > displaces transcriptional repressor Groucho
= acts as co-activator to drive gene expression
Wnt signalling
- cancer
hyper activation of Wnt signalling
e.g. colon cancer due to mutation in B-catenin
Hedgehog signalling
- absence of HH signal
Cubitus interruptus (latent transcriptional repressor) ubiquitylated + proteolytically cleaved
CI not completely degraded
-> processed into a smaller garment
-> accumulates into nucleus
= transcriptional repressor
Hedgehog signalling
- presence of HH signal
blocks proteolytic processing of CI
-> transcriptional activator
Hedgehog signalling
- cancer
hyper activation of HH signalling
-> BCC (basal cell carcinoma)
