Week 11: Signalling, Cross Talk And Cancer

Question 1

What are receptor protein tyrosine kinase (RTK)?

Answer 1

Integral membrane proteins
Single transmembrane helix extracellular ligand binding domain
Cytoplasmic protein trypsine kinase

Question 2

What are RTK activated directly by?

Answer 2

Epidermal growth factor (EGG)
Platelet derived growth factor (PDGF)
Insulin

Question 3

What is the crucial step in RTK?

Answer 3

Dimerisation of the receptor

Question 4

Step 1 - ligand mediated dimerisation

Answer 4

Inactivated: the tyrosine kinase receptors will exist as inactive monomers where a membrane is fluid
Some RTK have two binding sites for one ligand molecule
Bivalent ligand molecules are required to bind to inactive monomers of tyrosine

Question 5

What are examples of ligand of TRK?

Answer 5

Insulin
Growth factors
Epidermal growth factor (EGF)
Platelet derives growth factor (PDGF)

Question 6

What are Ligands for RTK?

Answer 6

Hormone
Specifically peptides
Large molecules

Question 7

Where do hormonal messages circulate?

Answer 7

In bloodstream

Control proliferation of cells

Question 8

Step 2 - ligand mediated dimerisation

Answer 8

Dimerisation of the receptor
Doesn’t fully activate receptor molecules
Need phosphorylation

Question 9

Step 3: ligand mediated dimerisation

Answer 9

Following dimerisation, phosphorylation occurs
Activation of kinase activity causes kinase to catalyse the addition of phosphate groups to tyrosine on the cytoplasmic domain of receptor subunits

Question 10

What is the consequence of bringing two kinase domains in close contact?

Answer 10

Allows for trans autophosphorylation
Protein kinase activity of one receptor of diner phosphorylates the tyrosine residues in the cytoplasmic domain of the other receptor of diner

Question 11

What does kinase activity of receptor cause?

Answer 11

Phosphorylation

Question 12

Step 4 - ligand mediated dimerisation

Answer 12

Newly formed phosphotyrosine kinase
recognised by proteins within the cell
Each protein binds to a specific tyrosine kinase
Inside cell there is inactive relay proteins which are regulated by activated RTK
RTK changes shape and activates relay protein
Each activated protein triggers transduction pathway leading to cellular response

Question 13

What do residues of receptor serve as?

Answer 13

Binding sites for either SH2 or PTB domains

Question 14

Receptor mediated dimerisation

Answer 14

Ligand is monovalent
Separate ligand molecules bind to each of the inactivated monomer
Binding of each ligand induces a conformational change in the extracellular domain of receptor (creates dimerisation interface)
The ligand bound monomer interact through this interface and become active dimer

Question 15

What is present in the cytoplasm?

Answer 15

Signalling proteins with SH2 domain and PTB domains

Question 16

What does receptor activation result in?

Answer 16

Formation of signalling complexes in which SH2/PTB containing signalling proteins Bind to specific autophosphorylation sites on the receptor

Question 17

What do adaptor proteins contain?

Answer 17

SH2 domain
Additional protein-protein interaction domain
E.g. GRB2 contains one SH2 and two SH3 domains

Question 18

What do SH3 domain of GRB2 bind to?

Answer 18

sos and GAB

Question 19

What does SH2 domain bind to?

Answer 19

Phosphorylated residues of receptor tyrosine kinase within a tyr-x-asn motif a

Question 20

What does tyrosine phosphorylation of tyr-x-asn motif on RTK result in?

Answer 20

Translocation of GRB2-sos or grb2-gab from cytosol to receptor which is present at the plasma membrane

Question 21

What does PI3K (phosphoinositide-3-kinase) phosphorylate?

Answer 21

Phosphatidylinositol

Question 22

How can phosphorylating phosphatidylinositol be regulated?

Answer 22

Activating the phosphorylation of PI through another hormone signal

Question 23

What does phospholipase enzyme cleave?

Answer 23

Phosphorylated IP2

Question 24

What are the two ways in which to activate PLC?

Answer 24

GPCR action

Activated by RTK

Question 25

Ligand

Answer 25

Pathway that activates RAS

Question 26

What is RAS?

Answer 26

G protein

Monomeric GTPase

Question 27

RAS

Answer 27

Peripheral membrane protein
Covalently bound hydrocarbon tail and an acyl group which keeps fail at surface of membrane
Active when it has GTP bound
GDP bound - inactive RAS

Question 28

What is the mode of activation of RAS?

Answer 28

In active form it will drift around on the inner surface of membrane with a GDP in its jaw so when it encounters - bind and undergo conformational change
GDP will dissociate and GTP will bind
Activated RAS protein

Question 29

What does RAS hydrolyse?

Answer 29

GTP —> GDP

Question 30

How does desensitisation occur in RTK?

Answer 30

Internalisation of the receptor

Question 31

What happens after RTK are activated and dimerized?

Answer 31

RTK become internalised into cell via endocytosis

Question 32

What does it mean when a cell has fewer RTK?

Answer 32

Less sensitive to hormone

Question 33

What is Grb2-Sos?

Answer 33

An adaptor complex that binds to phosphorylated RTK

Question 34

Define convergence

Answer 34

Different signals, same response

Question 35

What is convergence?

Answer 35

Different signals perceived by different receptors but same response at end

Question 36

Define cross-talk?

Answer 36

One signal transduction pathway influences the operation of a second signal transduction pathway

Question 37

What is PLC beta activated by?

Answer 37

GPCR

Question 38

What is PLC gamma activated by?

Answer 38

TRK

Question 39

What does phosphatidylinositol molecule in membrane release?

Answer 39

diacylglycerol and IP3

Question 40

What does IP3 cause the release of?

Answer 40

Ca2+ in RER

Ca2+ released into cytoplasm can bind to other proteins and activate them