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CAN > L04 - Cell Signalling & Cancer > Flashcards

L04 - Cell Signalling & Cancer Flashcards

1
Q

How many times do receptor tyrosine kinases 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 tyrosine residues on target proteins

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3
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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4
Q

Describe the action of kinases.

A

Kinases catalyse the transfer of the terminal phosphate group of ATP to specific serine (Ser), threonine (Thr) or tyrosine (Tyr) residues on target proteins

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5
Q

What is the effect of phosphorylation on target molecules?

A

Usually activation, but sometimes inhibition

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6
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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7
Q

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

Why is this important?

A
  • Dimerisation of two receptor molecules, known as homodimerisation
  • This enables kinase domains of the neighbouring receptor molecules to cross-phosphorylate each other on multiple tyrosine residues (autophosphorylation)
  • This creates high affinity binding sites for many proteins e.g. Grb-2 & PI 3-kinase
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8
Q

What is the outcome of the MAPK pathway?

A

Cell proliferation

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9
Q

Give a brief overview of the MAPK pathway.

A

1 - Signalling molecule

2 - Tyrosine kinase receptor

3 - Grb-2

4 - Sos

5 - Ras

6 - Raf

7 - Mek

8 - Erk

9 - Cell growth/proliferation

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10
Q

In the MAPK pathway, what is the function of Grb-2?

Which domains are important for its function?

A
  • It acts as an adaptor protein using its SH2 and SH3 domains:
  • SH2 recognises specific phosphorylated tyrosine residues on RTKs 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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11
Q

What is Ras protein and how is it activated?

A
  • A small G-protein with GTPase activity bound to the plasma membrane by a covalently attached lipid group
  • Sos stimulates the exchange of GDP for GTP in Ras to activate Ras
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12
Q

To which class of proteins does Sos belong?

A

Guanine nucleotide exchange factors (GEFs)

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13
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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14
Q

What is the role of Ras in the MAPK pathway?

A

It activates Raf by inducing a conformational change, localised at the cell membrane

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15
Q

What is Raf and what is its function?

A
  • A serine threonine kinase

- It phosphorylates Mek

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16
Q

What is Mek and what is its function?

A
  • A serine threonine kinase

- It phosphorylates Erk

17
Q

What is Erk and what is its function?

A
  • A serine threonine kinase
  • It phosphorylates transcription factors in the nucleus and regulates gene expression such as:

1 - C-jun

2 - C-fos

3 - C-myc

4 - C-myb

5 - Cyclin D

=> cell growth/proliferation

18
Q

In what 4 ways can the MAPK pathway can be turned off?

A

1 - Removal of the extracellular signal

2 - Switching off activated RTKs by protein tyrosine phosphatases (PTPs) e.g. SHP-1 & -2

3 - Ras GAPs e.g. p120GAP, neurofibromin

4 - Dephosphorylation of target proteins by serine/threonine phosphatases

19
Q

What are the outcomes of the PI3K pathway?

A

1 - Cell survival

2 - Cell growth/proliferation

20
Q

Give a brief overview of the PI3K pathway.

A

1 - Signalling molecule

2 - Tyrosine kinase receptor

3 - PI 3-kinase enzyme activation

4 - PI(4,5)P2 to PI(3,4,5)P3

5 - PDK1 & Akt

6a - Protein BAD

6b - Kinase mTOR

7a - Prevention of apoptosis

7b - ↑ ribosome production & protein synthesis, ↓ protein degradation, Akt activation

21
Q

What is PI3 kinase and what is its function?

A
  • A lipid kinase
  • It is activated by binding to phosphorylated Tyr residues on RTKs and catalyses the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3
22
Q

What is the source of PIP2?

A
  • PI is a phospholipid in cell membranes
  • It is phosphorylated to PI(4)P
  • This is phosphorylated to PI(4,5)P2
23
Q

Describe the structure of phosphatidylinositol.

A

Phosphatidylinositol is classified as a glycerophospholipid that contains a glycerol backbone, two non-polar fatty acid tails, a phosphate group substituted with an inositol polar head group

24
Q

What is the function of PIP3?

A
  • PIP3 acts as a docking site for PDK1 & Akt

- PDK1 = phosphatidylinositol dependent kinase & Akt = protein kinase B

25
Q

Describe the interaction between PDK1 and Akt.

A

Upon binding to PIP3, PDK1 phosphorylates & activates Akt

26
Q

What is Bad protein and what are its functions?

A
  • Bad is a cytoplasmic protein that complexes with apoptosis inhibitory proteins, inactivating them
  • Akt phosphorylates BAD, which causes the release of death inhibitory proteins & the prevention of apoptosis
27
Q

How is mTOR activated and what are its functions?

A
  • Akt phosphorylates kinase mTOR
  • mTOR complex 1 stimulates cell growth by:

1 - Promoting ribosome production & protein synthesis

2 - Inhibiting protein degradation

  • mTOR complex 2 stimulates cell survival by helping activate Akt
28
Q

In what 4 ways can the PI3K pathway can be turned off?

A

1 - Removal of the extracellular signal

2 - Switching off activated RTKs by protein tyrosine phosphatases (PTPs)

3 - Dephosphorylation of target proteins by serine/threonine phosphatases

4 - PTEN = inositol lipid phosphatase which removes phosphate from PIP3 (forming PIP2), so it can no longer act as docking site for PDK1 & Akt

29
Q

What is HER2?

A
  • An oncoprotein with an orphan receptor (no known ligand)

- Activated by heterodimerisation with other EGFR family members

30
Q

What is the treatment for HER2 overexpression?

A

Trastuzumab (Herceptin) – humanised anti-HER2 antibody, which causes HER2 internalisation/ degradation & ADCC

31
Q

What causes chronic myelogenous leukaemia?

A
  • Chronic myelogenous leukaemia (CML) is usually associated with the Philadelphia chromosome, which forms from translocation between chromosomes 22 & 9
  • Breakage & re-joining occurs at the sites of BCR & ABL genes, creating a hybrid gene encoding hybrid BCR-ABL fusion protein
  • BCR-ABL stimulates inappropriate proliferation of haematopoietic precursors & prevents apoptosis, leading to an accumulation of excessive WBCs in the blood
32
Q

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

A

Imatinib (Gleevec) – a synthetic ABL kinase inhibitor that blocks the ATP binding site of Tyr kinase domain of BCR-ABL

33
Q

Why do patients show response then relapse with imatinib (Gleevec)?

A

Patients show response then relapse due to resistance via secondary mutations in Tyr kinase domain (preventing the drug binding)

CAN (20 decks)

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