12 - Second Messenger Signaling in Neuronal Development II Flashcards
True or false: a protein localized all over the cell cannot act as a polarizing signal
False: the activation of this protein can be a polarizing signal
How can a protein that is localized all over the cell act as a polarizing signal?
In its specific activation by an activator in a specific location
Besides physical localization, how can a signal be localized?
Through its activation
How does LKB1 lead to axonal development?
Localized in the axon, and activated by PKA (from cAMP) in the axon
True or false: PAR-1 is localized within the neurite that will become the axon
False: PAR-1 is found everywhere in the neuron
How can PAR-1 lead to axon formation if it is not localized in the axon?
Its activation by LKB1 is localized within the axon
Which protein(s) are localized in a neurite to predict axon fate?
LKB1, phosphorylated LKB1, phosphorylated PAR-1
Which protein(s) are not localized in a neurite to predict axon fate?
PAR-1
What type of localization is seen with LKB1?
Physical and activation localization
What type of localization is seen with PAR-1?
Activation localization (not physical)
True or false: signaling pathways can interact with each other
True: they can converge or antagonize with each other to determine a biological function
True or false: neuronal development is an easy task
False: it is a fairly difficult and coordinated process
Why is neuronal development a hard task?
Hard to prolong a signal (as opposed to an on/off signal)
How long does axonal development take?
24-48 hours
What determines the output a signal will generate?
- The nature of the signal
- The strength / duration of the signal
- The signaling determinants a cell has
True or false: signals can be activating or inhibitory
True: the cell needs to integrate these signals to generate a response
Complete the sentence: signaling is ______, and it matters _____
Signaling is a well ordered set of instructions, and it matters how the instructions are arranged
What types of links are possible in signaling pathways?
Positive and negative
What is a positive link?
A activates B (A –> B)
What is a negative link?
A inhibits B (A –| B)
What is the schematic for a positive link?
A –> B
What is the schematic for a negative link?
A –| B
What does a double negative link result in?
A positive link
A –| B –| C = A –> C
What is fan in?
Multiple upstream regulators converge on one downstream target
What is fan out?
One upstream regulator diverges into many downstream targets
What is the consequence of a linear signaling arrangement?
One spark will end the signal (no feedback)
What is the consequence of a circular signaling arrangement?
Can continuously activate itself (positive feedback)
What is a self regenerative pathway?
A pathway where a downstream effector can activate itself through a specific pathway
What needs to be coupled to a positive feedback loop?
Negative feedback
What is the significance of negative feedback in a positive feedback loop?
After some delay, can stop the signal and prevent it from continuing indefinitely
Why is there a time consideration between the positive and negative feedback of a system?
Want the positive feedback to run for some time, but also to turn off eventually
What is a feedback?
When the output from a given protein follows a path of links that return to regulate the proteins of origin
True or false: there are different arrangements of positive and negative feedback
True: there are different ways the pathway can be set up
True or false: you can get negative feedback through only positive links
False: there is no way to inhibit with only activation
True or false: you can get positive feedback through only negative links
True: a double negative is equivalent to a positive
How can kinases be used in positive feedback?
One kinase can phosphorylate other kinases, which can also activate the original kinase
How can a ligand lead to positive feedback?
Promotion of more cell surface receptors (insertion or translation), or increased secretion of the ligand
How can a ligand lead to negative feedback?
Internalization of the receptors
How is positive feedback used in axonal development?
Persistent signal of polarization
What is the PDZ domain?
A protein binding domain (PSD-95, Dlg-1, ZO-1)
What do scaffold proteins do?
Bring signaling determinants to specific locations in the cell
How can PKA be controlled?
By making it bind to a scaffold protein and localizing it within the cell
How does the cell decide where to sequester PKA?
By where it wants PKA to be active
How do scaffold proteins help PKA be active in a specific part of the cell?
By having all the upstream and downstream regulators of PKA also bound to the scaffold proteins
What are the two specific roles of scaffolds?
- Sequester signaling determinants into specific locations of the cell
- Sequester signaling determinants needed for that particular protein to function
What are the scaffold proteins studied in this positive feedback loop (polarization)?
PAR-3 and PAR-6
What kinase binds to PAR-6?
aPKC
What does aPKC bind to?
PAR-6
What does aPKC stand for?
Atypical protein kinase C
How are PKCs grouped?
By their mode of activation
What is PKC?
A broad family of serine/threonine kinases
What are the 3 major families of PKC?
Classical, novel, and atypical
How is classical PKC activated?
Through calcium, DAG, and a phospholipid (PS)
How is novel PKC activated?
Through DAG
How is atypical PKC activated?
Through lipid second messengers (phosphatidylinositols) (not calcium or DAG)
Which PKC is activated through calcium and DAG?
Classical
Which PKC is activated through DAG?
Novel
Which PKC is activated through phosphatidylinositol?
Atypical
What is the structure of PKC?
A regulatory domain that inhibits the catalytic domain
In cell polarization, what activated aPKC?
Binding of PAR-6 to the regulatory domain of aPKC
What proteins bind to PAR-6?
PAR-3, aPKC, and Cdc42-GTP
True or false: PAR-3 and PAR-6 associate together in the positive feedback loop
True: these two scaffold proteins join together many signaling determinants, and they are associated together
How is PAR-6 an adaptor molecule?
It links Cdc42 and aPKC to PAR-3
Where do PAR-3 and PAR-6 localize in epithelial cells?
At the apical domain
What is the function of PAR-3 and PAR-6 in epithelial cells?
Determine the boundary of the apical and basolateral domain, recruit apical determinants, and exclude basolateral determinants
Which PAR protein forms oligomers?
PAR-3
What is the significance of PAR-3 forming oligomers?
It leads to robust recruitment of scaffold proteins (and therefore signaling determinants)
