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CAN > Cell Signalling and Cancer > Flashcards

Cell Signalling and Cancer Flashcards

1
Q

How many times do tyrosine kinase receptors span the membrane?

A

Once.

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2
Q

What is the function of the tyrosine-kinase (intracellular) domain of a tyrosine kinase receptor?

A

To phosphorylate target proteins in the cell.

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3
Q

List 9 tyrosine kinase receptors.

A

1 - Epidermal growth factor receptor (EGF).

2 - Insulin receptor.

3 - Insulin-like growth factor receptor (IGF).

4 - Tropomyosin receptor kinase A (Trk A).

5 - Platelet-derived growth factor receptors (PDGF).

6 - Macrophage colony-stimulating factor receptors (MCSF).

7 - Fibroblast growth factor receptors (FGF).

8 - Vascular endothelial growth factor receptors (VEGF).

9 - Ephrin receptors.

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4
Q

Which class of receptors trigger the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways?

A

Tyrosine kinase receptors.

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5
Q

Which class of signalling molecules trigger the MAP pathway?

A

Growth factors.

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6
Q

What is the outcome of the MAPK pathway?

A

Cell proliferation.

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7
Q

Describe the action of kinases.

A

Kinases catalyse the transfer of the terminal phosphate group of ATP to specific serine, threonine or tyrosine residues on target molecules.

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8
Q

What is the effect of phosphorylation on target molecules?

A

Usually activation, but sometimes inhibition.

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9
Q

Describe the action of phosphatases.

A

Phosphatases cleave a phosphate group from the serine, threonine or tyrosine residues on target molecules.

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10
Q

Give an overview of the MAPK pathway.

A

1 - Signalling molecule.

2 - Tyrosine kinase receptor.

3 - GRB2.

4 - Sos.

5 - Ras.

6 - Raf.

7 - Mek.

8 - Erk.

9 - Cell growth.

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11
Q

Upon binding to a ligand, what conformational change occurs in a tyrosine kinase receptor?

Why is this important?

A
  • Dimerisation of the two receptor molecules, known as homodimerisation.
  • This enables kinase domains of the neighbouring receptor molecules to cross-phosphorylate each other on tyrosine molecules.
  • This creates high affinity binding sites for many proteins.
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12
Q

In the MAPK pathway, what is the function of GRB2?

Which domains are important for its function?

A
  • It acts as an adaptor protein using the SH2 and SH3 domains:
  • SH2 recognises specific phosphorylated tyrosine residues and binds to the high affinity binding site of a dimerised tyrosine kinase receptor.
  • SH3 binds to a motif in sos proteins. Binding to SH3 enables sos to recruit and activate ras protein.
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13
Q

What is ras protein?

How does sos activate ras?

A
  • A small G-protein with GTPase activity bound to the plasma membrane by a covalently attached lipid group.
  • Sos exchanges GDP for GTP in ras to activate ras.
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14
Q

To which class of proteins does sos belong?

A

Guanine nucleotide exchange factors (GEFs).

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15
Q

What is the effect of GTPase-activating proteins (GAPs) on activated ras?

A
  • They inactivate ras by stimulating its GTPase activity, which cleaves a phosphate group from GTP to form GDP.
  • This terminates the signalling event.
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16
Q

What is the role of ras in the MAPK pathway?

A

It activates raf by inducing a conformational change.

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17
Q

What type of molecule is raf?

What is its target?

A
  • A kinase.

- It phosphorylates mek.

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18
Q

What type of molecule is mek?

What is its target?

A
  • A kinase.

- It phosphorylates erk.

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19
Q

What type of molecule is erk?

What is its target?

A
  • A kinase.
  • It phosphorylates transcription factors in the nucleus such as:

1 - C-jun.

2 - C-fos.

3 - C-mys.

4 - C-myb.

5 - Cyclin D.

20
Q

What is the function of erk?

A

To induce changes in gene expression that increase cell proliferation.

21
Q

List 4 ways by which the MAPK pathway can be turned off.

A

1 - Removal of the extracellular signal.

2 - Switching off activated tyrosine kinase receptors by way of protein tyrosine phosphatases such as SHP-1 and SHP-2.

3 - Ras GAPs such as p120 and neurofibromin.

4 - Dephosphorylation of target proteins by phosphatases.

22
Q

List the outcomes of the PI3K pathway.

A

1 - Cell survival.

2 - Cell growth.

23
Q

Give an overview of the PI3K pathway.

A

1 - Signalling molecule.

2 - Tyrosine kinase receptor.

3 - PI3 kinase.

4 - PIP3.

5 - PDK1.

6 - Akt (PKB).

7 - Bad.

8 - mTOR.

24
Q

What is PI3 kinase?

What is its function?

A
  • A lipid kinase in the PI3K pathway that mirrors the function of GRB2:
  • It becomes active upon binding to high affinity binding sites of tyrosine kinase receptors.
  • Activation of PI3 kinase enables PI3 kinase to phosphorylate PIP2 into PIP3.
25
Q

What is the source of PIP2?

A

It is derived from phosphatidylinositol (PI), which is a membrane lipid.

26
Q

Describe the structure of phosphatidylinositol.

A

In order:

1 - Fatty acid chain.

2 - Glycerol.

3 - Phosphate.

4 - Inositol (a sugar).

27
Q

How is phosphatidylinositol used to produce PIP2?

A
  • It is phosphorylated at the 4 position on inositol to produce PIP.
  • PIP is phosphorylated at the 5 position on inositol to form PIP2.
28
Q

What is the function of PIP3?

A

It acts as a docking site for PDK1 and Akt.

29
Q

Describe the interaction between PDK1 and akt.

Which other molecule is involved in this interaction?

A
  • Upon binding to PIP3, PDK1 phosphorylates, and therefore activates, akt.
  • Activated Akt moves away from the plasma membrane.
  • mTOR assists in the activation of Akt.
30
Q

What is bad protein?

How is it activated?

What is the outcome of bad activation?

A
  • A protein that binds with apoptosis inhibitory proteins, rendering them inactive.
  • It is activated by Akt.
  • Bad activation promotes cell survival.
31
Q

What is the function of 14-3-3 protein?

A

It binds, and therefore sequesters, inactive bad protein in the cytoplasm.

32
Q

How is mTOR activated?

A

mTOR is activated by Akt.

*NB mTOR also assists in the activation of Akt as previously mentioned.

33
Q

List the two functionally distinct protein complexes of mTOR.

A

1 - mTOR complex 1.

2 - mTOR complex 2.

34
Q

What is the function of mTOR complex 1?

How does it do this?

A
  • To stimulate cell growth.

1 - By promoting ribosome production, and therefore protein synthesis.

2 - By inhibiting protein degranulation.

35
Q

What is the function of mTOR complex 2?

A
  • To stimulate cell survival and cell growth.
  • It does this by activating Akt, which results in more active mTOR complex 1 (increases cell growth) and bad protein (increases cell survival).
36
Q

List 4 ways by which the PI3K pathway can be turned off.

A

1 - Removal of the extracellular signal.

2 - Switching off activated tyrosine kinase receptors by way of protein tyrosine phosphatases such as SHP-1 and SHP-2.

3 - PTEN, an inositol lipid phosphatase which removes phosphate from PIP3 so that it no longer acts as a docking site for PDK1 and Akt.

4 - Dephosphorylation of target proteins by phosphatases.

37
Q

Define stratified medicine.

A

A more effective way of treating cancer by grouping patients according to the specific genetic lesion.

38
Q

What is HER?

A
  • A gene that encodes EGF receptors:

- HER1 encodes EGFR1 and HER2 encodes EGFR2.

39
Q

How does the function of EGFR1 differ from that of EGFR2?

A
  • EGFR1 works like a normal tyrosine kinase receptor.
  • However there is no known ligand for EGFR2.
  • EGFR2 heterodimerises with EGFR1.
  • It can then respond to the EGFR1 ligand, EGF.
40
Q

In what proportion of breast cancers is HER2 overexpressed?

A

HER2 is overexpressed in 30% of breast cancers.

41
Q

How is EGFR2 alone able to produce cancer?

A
  • EGFR2 is able to homodimerise when overexpressed.

- It is able to do this despite the lack of a ligand for EGFR2.

42
Q

What is the treatment for HER2 overexpression?

A
  • Trastuzumab (herceptin) is an anti-HER2 antibody.
  • It causes internalisation and degradation of EGFR2.
  • It also causes an antibody-dependent cellular cytotoxicity (ADCC) response, where the antibody triggers an immune response to destroy the cancer cell.
43
Q

What causes chronic myelogenous leukaemia?

A
  • Presence of the philadelphia chromosome, which forms as a result of a translocation between chromosomes 22 and 9.
  • The breakage and rejoining occurs at the sites of the BCR and ABL genes creating a hybrid BCR-ABL fusion gene.
  • BCR isnt B cell receptor. Both BCR and ABL encode kinase proteins.
44
Q

Where is ABL kinase located?

A

In the cytoplasm (compared to the tyrosine kinase receptors which are membrane-bound).

45
Q

How does the BCR-ABL fusion gene cause chronic myelogenous leukaemia?

A
  • The BCR gene translocates with the regulatory sequences of ABL.
  • The kinase encoded by BCR-ABL is therefore constitutively active.
  • This stimulates inappropriate proliferation of haematopoietic precursor cells, preventing them from dying by apoptosis.
46
Q

What is the treatment for ABL-BCR fusion gene expression?

A
  • Imatinib (gleevec) is a synthetic ABL inhibitor that blocks the nucleotide binding pocket (where GTP binds) of the tyrosine kinase domain of the BCR-ABL protein.
  • This inhibits phosphorylating capability of the BCR-ABL protein.
47
Q

Why do patients show relapse to imatinib (gleevec)?

A

Because they eventually develop resistance due to secondary mutations to the tyrosine kinase domain.

CAN (24 decks)

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