Transmembrane Signalling and Phosphorylation

Question 1

What is paracrine singalling?

Answer 1

A signal which induces a response in nearby cells

Question 2

What is autocrine signalling?

Answer 2

Signalling which acts on itself

Question 3

What is endocrine signalling?

Answer 3

Signals which are produced by endocrine cells

Can signal a long distance

Question 4

What is synaptic signalling?

Answer 4

Moves small distances across a synapse (neurotransmitters)

Question 5

What is contact dependent signalling?

Answer 5

Cell to cell junctions

Question 6

types of compounds which use matrix dependent signalling

Answer 6

• Cadherins

- Integrins

Question 7

What are cadherins?

Answer 7

Types of cell adhesion molecules - important in forming adhesion junctions

Question 8

What are integrins?

Answer 8

Any class of animal transmembrane protein which is involved in adhesion of cells to each other and their substrate

Question 9

Form of cellular dependent signalling

Answer 9

matrix dependent

Question 10

Form of cell to cell communication

Answer 10

gap junctions

Question 11

Types of compounds which use gap junctions

Answer 11

Second messengers e.g, cAMP

Ions e.g. calcium and sodium

Question 12

What are the different modes of signal transmission?

Answer 12

Conformational coupling (preformed complex)
Conformational coupling (diffusion-dependent complex formation)
Post translational modification
Protein degradation

Question 13

Explain preformed complex

Answer 13

Signal changes the shape of A, causes B to change shape, join together = signal

Question 14

Explain protein degradation

Answer 14

A and B are a preformed complex. Stimulus causes them to dissociate and degrade

Question 15

What are the classes of transmembrane receptors?

Answer 15

GPCR
Cytokine receptors 
Receptor tyrosine kinase 
TGF-beta receptors
Hedgehog receptors 
Wnt receptors 
Notch receptor

Question 16

What is different about notch receptors than others?

Answer 16

Requires cleavage and then it will become a receptor

Question 17

What are protein:protein interactions?

Answer 17

Where one protein activates another

Question 18

What are macromolecular complexes?

Answer 18

Where all of the proteins bind to a scaffold and they activate one another on there

Question 19

What is the effect of an asymmetric dimer?

Answer 19

weak EGFR dimer = sustained effect = differentiation

Question 20

What is the effect of symmetric dimer?

Answer 20

strong EGFR dimer = transient effect = proliferation

Question 21

What are the fives ways which target cells can be desensitised to a signal molecule?

Answer 21

• Receptor sequestration
• Receptor downregulation
• Receptor inactivation
• Inactivation of signalling protein
• Production of inhibitory protein

Question 22

Explain receptor sequestration

Answer 22

Where the receptor binds a ligand, moves into the cell via an endosome where the ligand is released and then reinserted on the membrane.
When the receptor is in the endosome there can be no signal detection.

Question 23

Explain receptor downregulation

Answer 23

The receptor is internalised into an endosome. The endosome fuses with a lysosome. Receptor degradation.

Question 24

Explain receptor inactivation

Answer 24

An inactivator binds to the receptor

Question 25

Explain inactivation of a signalling protein

Answer 25

An inactivator binds to the signalling protein downstream of the receptor

Question 26

Explain inhibitory protein production

Answer 26

The receptor signals to a signalling protein in the cell -> the signalling protein signals to an inhibitory protein -> inhibits the signalling protein Negative feedback

Question 27

Treatment for receptor induced cancers

Answer 27

use monoclonal antibodies which stop the ligand from binding

Question 28

Example of a EGFR lung cancer drug

Answer 28

Gefitinib

Question 29

What is TGF-beta important in?

Answer 29

During development and adult tissue homeostasis | Cancer biology

Question 30

What does TGF-beta stand for?

Answer 30

transforming growth factor-beta

Question 31

Examples of TGF-beta

Answer 31

Bone morphogenetic proteins | Growth and differentiation factor

Question 32

What are TGF-beta cytokines involved in?

Answer 32

``` Regeneration Differentiation Development Apoptosis Immunosuppression Proliferation Migration Angiogenesis ```

Question 33

What type of type II receptor does TGF-beta bind?

Answer 33

TbetaRII

Question 34

What type of type I receptor dos TGF-beta bind?

Answer 34

ALK5 and ALK1

Question 35

What R-smads does ALK5 cause?

Answer 35

Smad2 | Smad3

Question 36

What R-smads does ALK1 cause?

Answer 36

Smad1 Smad5 Smad8

Question 37

What co-smad does ALK1 and ALK5 cause

Answer 37

Smad4

Question 38

What does TGF-beta get secreted as part of?

Answer 38

A latent complex

Question 39

What are the components of the latency complex?

Answer 39

LAP - latency associated protein LTBP - Latency TGF-beta binding protein LLC - Large latent complex

Question 40

How do you activate TGF-beta?

Answer 40

Need to chop the latency component 1) Proteolysis with MMPs 2) Activation by integrins 3) Activation by: - thrombospondin-1 - ROS - Low pH - Mechanical force

Question 41

Process of TGF-beta signalling

Answer 41

1) Release from ligand traps (extracellular milleau) 2) Interaction with receptors (plasma membrane) 3) ALK5 (anaplastic lymphoma kinase) activation (plasma membrane) 4) Smad activation (plasma membrane, early endosome, cytoplasm) 5) Smad hetero-obligomerisation 6) Smad transcription factor interaction on DNA 7) Pathway termination

Question 42

Explain how release from ligand traps work

Answer 42

homodimeric ligand Interacts with the ECM domain in the type II receptors The homodimeric structure means it binds two receptors at the same time = lower affinity for the type I receptors

Question 43

What is the structure of R-SMAD?

Answer 43

MH1 and MH2 domains | The MH2 has a hydrophobic corridor, basic pocket and a site of receptor phosphorylation

Question 44

What is the function of R-SMAD MH1?

Answer 44

- DNA binding - Nuclear localisation - Binding DNA to co-factors

Question 45

What is the function of R-SMAD MH2?

Answer 45

- Receptor interaction and phosphorylation - Homo- and hetero- oligomerisation - Nuclear export - Binding to co-activators and co-repressors

Question 46

What is the structure of Co-SMAD?

Answer 46

MH1 and MH2 domains | MH2 domains - basic pocket and SAD domain

Question 47

Function of Co-Smad MH1 domain

Answer 47

DNA binding

Question 48

Function of Co-Smad MH2 domain

Answer 48

R-Smad binding | Interactions with transcriptional activators and repressors

Question 49

What is SAD?

Answer 49

Smad activation domain | transcription activator

Question 50

What does Smad7 complex with?

Answer 50

p300 and Smurf

Question 51

What is smurf?

Answer 51

E3 ubiquitin ligase - polyubiquitylate the receptor to target it for degradation

Question 52

What are the antitumour properties of TGF-beta?

Answer 52

- tumour suppressor - induces cell growth arrest - induces senescence - TGF-betaRII inactivation promotes recruitment of myeloid progenitor cells Loss of smad promotes genomic instability - induces apoptosis

Question 53

What are tumour promoter properties of TGF-beta?

Answer 53

- potent immunosuppressor - promotes invasion, intravasation, extravasation and metastatic colonisation - promotes angiogenesis - promotes tumour cell survival

Question 54

What kind of vesicles are used in receptor 1 and receptor 2 degradation?

Answer 54

Caveolin

Question 55

What homolog was discovered across animal species? And what was it called in flies?

Answer 55

Int-1 | Wingless (Wg)

Question 56

What are the names of the genes which encode the Int-1?

Answer 56

Wingless-related integration site-1 (WNT1)

Question 57

Describe WNT ligands

Answer 57

Glycoproteins Heavily glycosylated Signal in paracrine and autocrine routes

Question 58

What is the WNT signalling receptors?

Answer 58

FZD receptor

Question 59

Describe FZD receptors

Answer 59

Similar to GPCRs Bind to the N-terminal of extra-cellular Cys-rich domain Co-receptors required

Question 60

Define Groucho

Answer 60

A type of non-DNA binding corepressor for specific transcription factors

Question 61

Give two examples of transcription factors which bind to groucho

Answer 61

LEF | TCF

Question 62

What happens to beta-catenin in the presence of a WNT ligand

Answer 62

1) WNT ligand binds to FZD receptor 2) Dishevelled (DVL) becomes activated by phosphorylation 3) Destruction complex phosphorylates beta-catenin 4) Beta-catenin is targetted for ubiquitylation and degradation

Question 63

Common target genes for WNT/beta-canenin

Answer 63

c-Myc Axin2 CyclinD1

Question 64

What are the two WNT ligand signalling pathways

Answer 64

beta-catenin dependent pathway | beta-catenin independent pathway

Question 65

Where does beta-catenin exist?

Answer 65

plasma membrane - E-cadherin bound | cytoplasmic

Question 66

Name a common WNT/beta-catenin pathway in cancer

Answer 66

APC - frameshift and deletion mutations so you cannot degrade beta-catenin

Question 67

What cancers does APC effect?

Answer 67

- small intestine - smooth muscle - liver - pancreas - stomach - large intestine