12.1 Signaling IV Flashcards
Which pathways require regulated proteolysis?
1) Notch and Delta
2) Wnt / b-catenin
3) Hedgehog
4) NFk-B
Signal pathways that use degradation of signaling components or inhibitors of signaling components are involved in what type of functions?
many of these of involved in early development where rapid changes in gene expression are produced by the degradation of proteins that inhibit the function of key transcription factors. q
The notch receptor and its ligand Delta play a major role in what processes?
in development processes of most tissues.
Delta signaling is an example of what type of signaling event?
contact dependent as it is used by one cell to tell its neighboring cell what to do.
How do drosophila maintain the correct proportion of neuronal and epithelial cells?
-using the notch/delta signaling system
- As individual nerve cells begins to develop, it expresses delta on its surface.
- neighboring cells are signaled through the notch receptor that their neighbor has become a neuron and this prevents them from also becoming neurons.
What happens if there is a mutation in either delta or notch?
too many cells will become neurons and not enough will become epithelial cells.
In the notch/delta signaling, which protein undergoes proteolysis?
The notch receptor undergoes proteolysis in the signaling system.
-in undergoes proteolysis in three different places and only two are dependent on delta signaling.
What are the stages of the notch receptor undergoing proteolysis?
1) Interaction between notch and delta causes cleavage of the protein by an extracellular protease followed by an intracellular one.
2) the cleavage event on the inside of the cell membrane is accomplished by a proteolytic enzyme complex called gamma secretase. . One the regulatory subunits, called presensilin, is mutated in some forms of
early Alzheimer’s disease
3) Notch tail moves into nucleus to activate Notch-responsive genes by converting a transcriptional repressor to an activator transcription factor (CSL).
4) CSL is converted from an inactivator of transcription factor to an activator of transcription.
What is unique about the notch receptor?
Unlike most receptors, notch cannot be recycled. Once it is activated by proteolysis you can’t rejoin the pieces back together to form the inactive form.
What is Wnt? And what type of events/processes is it involved in?
a signaling protein that is secreted by cells and detected by other cells having an appropriate receptor and regulates proteolysis of beta catenin
INVOLVED in different developmentally regulated events
What is the basic mechanism of Wnt signaling?
to stabilize a transcription enhancer called beta catenin
In the absence of Wnt signals, what happens to beta catenin?
beta catenin is phosphorylated by a degradation complex and the phosphorylated beta catenin is target for proteolytic degradation by the general machinery for protein degradation and recycling in cells.
How do the receptors for Wnt look in drosophila?
they are frizzeld and the LDL receptor related protein or LRP which binds to a fatty acid linked to Wnt signaling peptide.
What is frizzled in drosophila?
a seven pass transmembrane protein that is not an actual G protein. instead the binding of Wnt to frizzled and LRP causes the recruitment of an intermediate called disheveled and the kinase that are part of the degradation complex. In turn this causes phosphorylation of the protein.
What is Axin in the Wnt signaling?
Axin is a scaffolding component of the degradation compex and after its phosphorylated the degradation complex falls apart. As a consequence, beta catenin is no longer phsophorylated which allows beta catenin to be present long enough to enter the nucleus and regulate the transcription of Wnt responsive genes.
What is unique about the Wnt signaling pathway?
the active signaling component, beta catenin, is always being produced but then it is inactivated by destroying it (unless an appropriate activation signal is present. This allows the cell to respond rapidly to signaling events.
In Wnt signaling pathway what regulates the transcription factor of Wnt responsive genes?
axin is phosphorylated and this causes the degradation complex to fall apart, which means beta catenin is no longer phosphorylated and this allows beta catenin to be present long enough to enter the nucleus and regulate the transcription of Wnt responsive gene
what regulates proteolysis of beta catenin?
Wnt
In drosophila Wnt signaling regulates what?
the orientation and distribution of epidermal hair forming cells in drosophila.
What is the difference in appearance between a drosophila with a normal hedgehog protein and a mutant hedgehog protein?
Normal drosophila have a long body and mutant have a short body and prickly appearance aka mutant alters the morphology of the embryo
What happens when the hedgehog ligand binds to iHog (receptor)?
1) Smoothened becomes localized to the plasma membrane.
2) it then recruits the degradation complex and inactivates it. (this looks like Wnt signal)
3) inactivation of the degradation compex allows unprocessed Ci to be produced which enters the nucleus and now activates gene expression of hedgehog dependent genes.
EXAMPLE OF an active regulator of transcription that is constitutively degraded
What is a unique feature of the hedgehog pathway?
the inactive intermediate found on the intracellular vesicles and the linkage of the degradation complex to the microtubules
What does NFkB stand for?
Nuclear factor kappa light chain enhancer of activated B cells
this basically means that it is a factor that enhances antibody production by B cells
NFkB is a latent regulator of gene expression, what does this mean?
this means NFkB is always around waiting to be activated in cells.
In the absence of an activating signal, what is the behavior of NFkB?
NFkB is bound to an inhibitor called ikB, which stands for inhibitor of NFkB.
What can phosphorylate iKB? What is one of the most important examples?
a number of signaling elements can activate a regulator complex that phosphorylates ikB. It is called the inhibitor of NFkV kinase or IKK.
One of the most important examples of receptors that can active IKK is the tumor necrosis factor alpha ligand binding receptor aka TNF alpha.
What happens when IKK is activated?
IKK complex will phosphorylate ikB, targeting it for degradation. This then liberates NFkB
What follows after ikB is phosphorylated and frees NFkB?
NFkB is free to enter the nucleus and alters gene expression in combination with cofactors that are already present.
How is the NFkB system unique?
in that the protein that gets degraded is not a transcription factor itself, but instead is a protein that is inactivating the active transcription factor.
Major Points of the Notch and Delta Signaling Systems
Delta is the signal. Common in epithelial cells and neurons.
Intracellular domain of Notch is degraded by gamma secretase
Cleavage product is active regulator of gene expression
Major Points of the Wnt/Beta-catenin Signaling Systems
Wnt is the signal, LRp and frizzled are the receptor
Receptor activation activates disheveled, which inhibits a degradation complex
Beta-catenin is no longer degraded, enters the nucleus and initiates gene
Major points of the Hedgehog signaling system
Hedge is the signaling ligand
iHog and patched are the receptor
Binding of hedgehog deactivates repressor activity of patched
Smoothened arrives at membrane and deactivates a complex that normally binds
to microtubules and degrades Ci. (The degradation product is a functional inhibitor of gene expression)
Full length Ci enters the nucleus and activates gene expression
Major points in the NFk-B signaling system
Many inflammation and stress signals and receptors, one important one is
TNF alpha
NFkB is normally inhibited by binding to ikB
Receptor activation leads to activation of a complex that phosphorylates ikB and
causes it to be degraded. The complex is ikB kinase (IKK)
Degradation of the inhibitor (ikB) frees NFkB and allows it be up regulate
expression of target genes.
What occurs in the hedgehog signaling pathway in the absence of an active signal? aka in its inactivating stte?
in the absences of an activating signal, a protein called cubitus interruptus (CI) is targeted for degradation. however, the degradation is only partial and results in a small negative regulator of gene expression being produced.
This negative regulator enters the nucleus of cells and inhibits the production of hedgehog dependent genes.
How is the processing of CI (cubitus interruptus) accomplished?
much like the Wnt signaling and the degradation complex is linked to microtubules by one of its components called Costal.
What does Costal do to Ci cubitus interruptus?
Costal appears to help keep unprocessed CI from accidentally entering the nucleus and initiating transcription
What are the three trans membrane proteins involved in The Hedgehog signaling system?
1) iHog - the receptor for the hedgehog signal
2) Patched
3) Smoothened
mutation in patched or smoothened create what ?
produce mutant flies that have odd looking bristles
Where is smoothened present?
on intracellular vesicles instead of the plasma membrane and it is maintained there by the function of inactivated patched
What is presensilin?
a regulatory subunit in the delta/notch system that when mutated is it present in some forms of early Alzheimer’s disease
