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Cell Proliferation and Underlying diseases > Transmembrane Signalling and Phosphorylation > Flashcards

Transmembrane Signalling and Phosphorylation Flashcards

1
Q

What is paracrine singalling?

A

A signal which induces a response in nearby cells

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2
Q

What is autocrine signalling?

A

Signalling which acts on itself

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3
Q

What is endocrine signalling?

A

Signals which are produced by endocrine cells

Can signal a long distance

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4
Q

What is synaptic signalling?

A

Moves small distances across a synapse (neurotransmitters)

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5
Q

What is contact dependent signalling?

A

Cell to cell junctions

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6
Q

types of compounds which use matrix dependent signalling

A
  • Cadherins

- Integrins

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7
Q

What are cadherins?

A

Types of cell adhesion molecules - important in forming adhesion junctions

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8
Q

What are integrins?

A

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

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9
Q

Form of cellular dependent signalling

A

matrix dependent

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10
Q

Form of cell to cell communication

A

gap junctions

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11
Q

Types of compounds which use gap junctions

A

Second messengers e.g, cAMP

Ions e.g. calcium and sodium

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12
Q

What are the different modes of signal transmission?

A

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

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13
Q

Explain preformed complex

A

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

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14
Q

Explain protein degradation

A

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

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15
Q

What are the classes of transmembrane receptors?

A 
GPCR
Cytokine receptors 
Receptor tyrosine kinase 
TGF-beta receptors
Hedgehog receptors 
Wnt receptors 
Notch receptor
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16
Q

What is different about notch receptors than others?

A

Requires cleavage and then it will become a receptor

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17
Q

What are protein:protein interactions?

A

Where one protein activates another

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18
Q

What are macromolecular complexes?

A

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

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19
Q

What is the effect of an asymmetric dimer?

A

weak EGFR dimer = sustained effect = differentiation

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20
Q

What is the effect of symmetric dimer?

A

strong EGFR dimer = transient effect = proliferation

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21
Q

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

A
  • Receptor sequestration
  • Receptor downregulation
  • Receptor inactivation
  • Inactivation of signalling protein
  • Production of inhibitory protein
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22
Q

Explain receptor sequestration

A

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.

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23
Q

Explain receptor downregulation

A

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

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24
Q

Explain receptor inactivation

A

An inactivator binds to the receptor

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25
Q

Explain inactivation of a signalling protein

A

An inactivator binds to the signalling protein downstream of the receptor

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26
Q

Explain inhibitory protein production

A

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

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27
Q

Treatment for receptor induced cancers

A

use monoclonal antibodies which stop the ligand from binding

28
Q

Example of a EGFR lung cancer drug

A

Gefitinib

29
Q

What is TGF-beta important in?

A

During development and adult tissue homeostasis

Cancer biology

30
Q

What does TGF-beta stand for?

A

transforming growth factor-beta

31
Q

Examples of TGF-beta

A

Bone morphogenetic proteins

Growth and differentiation factor

32
Q

What are TGF-beta cytokines involved in?

A 
Regeneration
Differentiation 
Development 
Apoptosis 
Immunosuppression 
Proliferation
Migration 
Angiogenesis
33
Q

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

A

TbetaRII

34
Q

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

A

ALK5 and ALK1

35
Q

What R-smads does ALK5 cause?

A

Smad2

Smad3

36
Q

What R-smads does ALK1 cause?

A

Smad1
Smad5
Smad8

37
Q

What co-smad does ALK1 and ALK5 cause

A

Smad4

38
Q

What does TGF-beta get secreted as part of?

A

A latent complex

39
Q

What are the components of the latency complex?

A

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

40
Q

How do you activate TGF-beta?

A

Need to chop the latency component

1) Proteolysis with MMPs
2) Activation by integrins
3) Activation by:
- thrombospondin-1
- ROS
- Low pH
- Mechanical force

41
Q

Process of TGF-beta signalling

A

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

42
Q

Explain how release from ligand traps work

A

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

43
Q

What is the structure of R-SMAD?

A

MH1 and MH2 domains

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

44
Q

What is the function of R-SMAD MH1?

A
  • DNA binding
  • Nuclear localisation
  • Binding DNA to co-factors
45
Q

What is the function of R-SMAD MH2?

A
  • Receptor interaction and phosphorylation
  • Homo- and hetero- oligomerisation
  • Nuclear export
  • Binding to co-activators and co-repressors
46
Q

What is the structure of Co-SMAD?

A

MH1 and MH2 domains

MH2 domains - basic pocket and SAD domain

47
Q

Function of Co-Smad MH1 domain

A

DNA binding

48
Q

Function of Co-Smad MH2 domain

A

R-Smad binding

Interactions with transcriptional activators and repressors

49
Q

What is SAD?

A

Smad activation domain

transcription activator

50
Q

What does Smad7 complex with?

A

p300 and Smurf

51
Q

What is smurf?

A

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

52
Q

What are the antitumour properties of TGF-beta?

A
  • 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
53
Q

What are tumour promoter properties of TGF-beta?

A
  • potent immunosuppressor
  • promotes invasion, intravasation, extravasation and metastatic colonisation
  • promotes angiogenesis
  • promotes tumour cell survival
54
Q

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

A

Caveolin

55
Q

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

A

Int-1

Wingless (Wg)

56
Q

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

A

Wingless-related integration site-1 (WNT1)

57
Q

Describe WNT ligands

A

Glycoproteins
Heavily glycosylated
Signal in paracrine and autocrine routes

58
Q

What is the WNT signalling receptors?

A

FZD receptor

59
Q

Describe FZD receptors

A

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

60
Q

Define Groucho

A

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

61
Q

Give two examples of transcription factors which bind to groucho

A

LEF

TCF

62
Q

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

A

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

63
Q

Common target genes for WNT/beta-canenin

A

c-Myc
Axin2
CyclinD1

64
Q

What are the two WNT ligand signalling pathways

A

beta-catenin dependent pathway

beta-catenin independent pathway

65
Q

Where does beta-catenin exist?

A

plasma membrane - E-cadherin bound

cytoplasmic

66
Q

Name a common WNT/beta-catenin pathway in cancer

A

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

67
Q

What cancers does APC effect?

A
  • small intestine
  • smooth muscle
  • liver
  • pancreas
  • stomach
  • large intestine

Cell Proliferation and Underlying diseases (12 decks)

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