REGULATED PROTEOLYSIS Flashcards
How does notch signaling contribute to development?
By amplifying the difference between cells.
What is lateral inhibition?
Its a process where a single cell in a population commits to a fate and inhibit all its neighboring cells from commiting to the same fate.
How is lat. inhibition achieved?
Ligand Delta binds notch and transmits the inhibitory signal via notch to the surrounding cells inhibiting them from differentiating.
True/False
Notch is capable of lateral activation
True: in some tissues
Describe the notch/delta interaction
- After synthesis, notch is cleaved into two domains that reassembles to a heterodimer in golgi
- Notch migrates to the plasma membrane where
delta binds notch which causes intracellular protease to cleave the cytoplasmic tail of notch
- A third cleavage releases the intracellular domain which binds CSL, converting it from a repressor to an activator
- The notch/CSL complex move to the nucleus and activate gene transcription.
How many stages are the proteolysis of notch, what happens in each stage?
There are three stages:
Stage 1: After synthesis, it is cleaved before reassembly
Stage 2: A second cleavage occurs at the binding of delta
Stage 3: A third cleavage releases the intracellular domain
In a Notch high DLL low cell, what molecules are expressed and why?
Hes1 expression is high while Atoh and DLL expression is low.
This promotes the differentiation of the cell into absorptive cells
What pathway is occuring when Atoh1 expression is high which upregulates Dll while keeping HES1 low?
This is a Notch low Dll high pathway.
It promotes the differentiation of secretory cells
What happens when Wnt is absent?
Ligand Beta-Catenin is phosphorylated by glycogen synthase kinase-3beta (GSK-3Beta) targeting it for degradation.
Adenomatous polyposis coli (APC) mediates the assoc of degradetion complex to beta-catenin
and beta-catenin is lyzed.
In the presence of Wnt, what happens?
Wnt binds Frizzled and a co-receptor protein (LRP) and this inhibits beta-catenin degradation.
Beta-catenin accumulates in the cytpoplasm and nucleus via Dishevelled and a serine/threonine kinase casein kinase 1
In the nucleaus, beta-catenin binds DNA-binding proteins LEF-1/TCF and induces genes that supports cell growth and differentiation.
In most cases of colorectal cancer, what signaling is deregulated?
Wnt signaling
Why Wnt signaling?
it is essential for stem cell maintenance in the intestine, control aspects of cell fate.
What are the transmembrane receptors of Hedgehog and their functions?
Patch: inhibits smoothened
Smoothened: Sends signal to protein complex to inhibit proteolysis & release complex from microtubules.
Describe the hedgehog signaling process.
Hedgehog binds patch
Smoothened relays signal into the cell
Unprocessed Ci protein is released from complex and enters nucleus and activates transcription of hedgehog genes.
What occurs in the absence of hedgehog?
Patch binds smoothened, inhibiting its activities
Ci is then processed to smallerproteins that accumulates in the nucleus where it acts as a transcriptional repressor
Describe the NF - KB pathway
TNF-Alpha trimer binds its receptor - TNF-alpha receptor
IKKK is activated via phosphorylation
IKKK phosphorylates and activates IKK to IKK - Beta
IKK-Beta phosphorylates and activate IKB exposing a nuclear localization signal
IKB is ubiquitinated and degraded in proteosome, NF-KB migrates to the nucleus and turns on transcription genes.
