2024 - London - Signal Transduction

Question 1

What are the different kinds of cell surface receptors that are involved in signal transduction?

4 types

Answer 1

1. ligand-gated ion channels
2. G-protein coupled receptors
3. Nuclear hormone receptors
4. Receptor tyrosine kinases

2024 - London - Signal Transduction

Question 2

Who donates the phosphate to a kinase?

Answer 2

ATP
ATP + Pr = ADP + phospho-Pr

Question 3

Where are most of the kinases?

Answer 3

In the cytoplasm.
They are serine or threonine kinases.

Question 4

How is Ras activated? Is there a direct binding of Ras throught the receptor?

Answer 4

No, Ras is activated through adaptor proteins.
A growth factor binds to RTK, and generates a binding site for the Grb2 and Shc adaptor proteins.
These adaptor proteins recruit Ras GTPase exchange factor (GEF), SOS to the inner surface of the membrane.
SOS catalyzes the exchange of GDP to GTP on Ras and makes it active.

Question 5

What is the active form of Ras?

Answer 5

Ras-GTP (active)
Ras-GDP (inactive)

Question 6

Ras mutations are common in what cancer in people?

Answer 6

pancreatic cancer

Question 7

What replaces GTP to GDP and vice versa in Ras cycle?

Answer 7

Ras GEFs(guanine nucleotide exchange factor): GDP->GTP (activation)
Ras GAPs (GTPase acivating proteins): GTP -> GDP (inactivation)

Question 8

What connects Ras activation to the nucleus?

Answer 8

MAPK pathway
Ras -> Raf -> MEK -> ERK
ERK goes into the nucleus

Question 9

What are the two main signaling pathways?

Answer 9

Ras
PI3K/AKT/mTOR pathway

These two thought to be seperate but they are interconnected.

Question 10

PI3Ks are a key component in which hormone signaling?

Answer 10

Insulin.
This is the reason for some of the side effects of PI3K inhibitors.

Question 11

What are the differnt isoforms of PI3Ks, and which ones are improtant for us?

Answer 11

4 families: Class I, II, III, IV.
class I PI3Ks are the most improtant to activate AKT and downstream signaling.

Question 12

Which PI3K isoforms regulate different aspects of immune responses?

Answer 12

PI3Kγ: regulates chemokine-mediated recruitment and activation of immune cells.
PI3Kδ: regulates B and T lymphocyte development and function

They are both class I PI3Ks.

Question 13

What is the role of PTEN in regulating signaling through PI3K?

Answer 13

PTEN is the negative regulator of PI3K pathway. (inhibits conversion of PIP2 to PIP3)
PTEN acts as a tumor suppressor gene.

Question 14

What kind of immune cell is PI3Kdelta improtant for?

Answer 14

Tregs, they are fully dependent on PI3Kdelta signaling. If you inhibit that, you can get autoimmunity.
It doesn’t effect other T cells.

Question 15

What is the role of AKT (protein kinase B) in PI3K signaling?

Answer 15

AKT is a link between PI3K and downstream signaling. It’s a **master regulator **
- activation of mTOR complex 1: promotes cell survival, and controls cell growth
- regulates nutrient uptake and metabolism, including glucose uptake in muscle and fat cells.
- inhibits cell apoptosis

Question 16

Cytokine signaling drug example

Answer 16

Apoquel

Question 17

Cytokine signaling pathway

Answer 17

Cytokine -> receptor -> JAK -> STAT -> gene expression

Question 18

TGF-ß signaling kinds

Answer 18

canonical TGF-B/SMAD signaling pathway
The non-SMAD-dependent TGF-B pathway

Question 19

Integrin signaling
active and inactive forms?

Answer 19

inactive integrin (bent)
Active integrin (extended)

there are outside-in, and inside-out signaling.

Question 20

In normal cells, signaling is terminated through multiple mechanisms. What are they? (5 mechanisms)

Answer 20

1. Limiting growth factor/chemokine/ligand
2. Receptor internalization
3. Intracellular phosphatases
4. Phosphorylation of critical residues
5. Proteasome mediated degradation terminating signal

Question 21

How cytokine signaling is regulated?

Answer 21

by SOCS = Suppressor of Cytokine Signaling
They terminate cytokine signaling. Bind to JAKs and inhibit them.
Both SOCS1 and SOCS3 contain a KIR! (kinase inhibitory region) for the suppressino of JAK tyrosine kinase activity.

Question 22

How AKT signaling is regulated?

Answer 22

1. Dephosphorylation
2. Ubiquitination

Question 23

How a RTK is regulated?

Answer 23

binding of antagonist molecules, other kinases or phosphatases, and ubiquitination

Question 24

What is the most common cancer mutation in humans?

Answer 24

P53

Question 25

Examples of RAS mutation in canine cancers?

Answer 25

BRAF mutation in bladder cancer

Question 26

Example of PI3K mutation in canine cancers?

Answer 26

Hemangiosarcoma