Cell signalling and cancer Flashcards

1
Q

What kind of signalling molecules can bind to intracellular receptors?

A

Small, hydrophobic molecules that can pass through the membrane e.g. steroids / hormones

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2
Q

What kind of signalling molecules can bind to extracellular receptors?

A

Hydrophilic proteins e.g. insulin

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3
Q

What happens once a molecule has bound to an extracellular receptor?

A

It induces an intracellular signal transduction to alter target proteins for metabolism, gene expression and structure.

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4
Q

What is a receptor Tyrosine Kinase?

A

Enzyme-coupled receptor on the cell surface, that spans the membrane once.
The extracellular domain may vary
The intracellular domain is a cytoplasmic TK.

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5
Q

What does TK do?

A

TK phosphorylates tyrosine (Tyr) residues by catalysing the transfer of a terminal phosphate group from ATP onto self ser, Thr or Tyr.

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6
Q

Give 3 examples of signalling proteins that will activate RTK?

A

EGF, Insulin, PDGF

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7
Q

What pathway is used by RTK?

A

MAP kinases pathway (mitogen activated)

PI3-kinase pathway (Phosphatidylinositol)

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8
Q

What does TK activity result in?

A

Either activates or inhibits the target protein.

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9
Q

Is phosphate addition reversible?

A

Yes with phosphatases

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10
Q

What happens when a signalling molecule binds to RTK?

A

Induces receptor DIMERISATION. The TK domains then cross-phosphorylate each other at multiple points for AUTOPHOSPHORYLATION.

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11
Q

What does the phosphorylation of Tyr residues allow?

A

Creates a high affinity binding site for cytoplasmic proteins such as:
Grb-2 for MAP kinase pathway
PI3-kinase

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12
Q

What induces the MAP kinase pathway? What does the pathway result in?

A

GF

GROWTH and PROLIFERATION

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13
Q

Give the overall order of the proteins involved in MAP kinase pathway.

A

Signalling molecule —> RTK —> Grb-2 —> Ras —> Raf —> Mek —> Erk = Cell GROWTH and PROLIFERATION

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14
Q

What is Grb-2?

A

A GF receptor bound protein. It has a SH2 domain that can recognise phosphorylated Tyr residues on RTK. The SH3 domain binds to Sos through its proline rich motif.

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15
Q

What results from the formation of receptor - Grb2 - Sos complex?

A

Recruits and activates Ras.

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16
Q

What is Ras?

A

A G protein with intrinsic GTPase activity. It is an oncogene attached to the plasma membrane.

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17
Q

What is Sos?

A

GEF - guanine nucleotide exchange factor that activates Ras by stimulating it to exchange GDP for GTP.

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18
Q

What inactivates Ras?

A

GAPs - GTPase activating proteins stimulate Ras’ intrinsic activity to hydrolyse GTP to GDP.

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19
Q

What happens after Ras has been activated?

A

It activates Raf by changing its formation. Raf is a kinase that goes on to activate Mek and Erk.

20
Q

What are Raf, Mek and Erk?

A

They are serine 3 kinases also referred to as MAP kinases.

21
Q

What is the function of Erk?

A

Erk phosphorylates target proteins such as kinases, gene regulatory proteins and TF in the nucleus to induce changes in cell behaviour.

22
Q

Which gene regulatory proteins are activated by Erk?

A

c-Myc, cyclin D, c-Myb, c-fos, c-jun

23
Q

How is MAP kinase pathway switched off and why is it important to do so?

A

Removal of extracellular signal.
Protein tyrosine PHOSPHATASES switch off RTK.
GAPs inactivate Ras.
Dephosphorylation of target proteins by phosphatases.

Allows tight control to prevent constitutive activation.

24
Q

Which genes involved in this pathway are oncogenes that predispose to cancer?

A

RTKs, Ras, jun, fos, Myc

25
Q

What is the result in a cell from the activation of PI3 kinase pathway?

A

Cell SURVIVAL, GROWTH and PROLIFERATION.

26
Q

Give an overview in order of the proteins involved in the PI3 kinase pathway.

A

Signalling molecule —> RTK —> PI3 kinase —> PIP3 —> PDK1 —> Akt —> Survival or mTor —> Growth and Proliferation

27
Q

How is PI3 kinase activated and what is its function?

A

By binding to phosphorylated Tyr residues on RTKs. It catalyses the phosphorylation of PIP2 into PIP3.

28
Q

What is PIP3?

A

PI(3,4,5)P3 is a phospholipid in cell membranes. It produces a high affinity docking site for PDK1 and Akt.

29
Q

Why must both PDK1 and Akt bind to PIP3?

A

PDK1 phosphorylates Akt.

30
Q

What is the function of Akt when active?

A

It dissociates from the membrane to phosphorylate BAD = release of anti-apoptotic molecules for survival.
Targets mTOR.

31
Q

What are the two types of mTOR and their functions?

A

Complex 1 = stimulates growth by promoting ribosome production and protein synthesis. Inhibits protein degradation.
Complex 2 = Stimulates cell survival and growth by helping PDK1 and activate Akt.

32
Q

How is PI3 kinase pathway regulated?

A

Tyrosine PHOSPHATASES will switch off RTK and dephosphorylate target proteins.
pTEN is a tumour suppresspor inositol phosphatase that removes phosphate from PIP3 so it cannot act as a docking site.

33
Q

What is HER2?

A

An oncogenic protein of the EGF family. It is an orphan receptor with no known ligand and so responds to ligand of EGFR.

34
Q

What happens to EGFR1 when it recieves a GF signal?

A

Homodimerises with another EGFR1.

35
Q

What happens to HER2 when it recieves a GF signal?

A

It heterodimerises with EGFR1 for growth and survival through PI3 kinase and MAP kinase pathway.

36
Q

What happens if HER2 is overexpressed?

A

Overexpression due to gene amplification or mutation, allows HER2 to HOMOdimerise when in excess and signal in the ABSENCE of a GF. This causes constitutive signalling and abnormal growth.

37
Q

In what cancer is HER2 overexpressed?

A

Breast Cancer

38
Q

What therapy is used to target HER2 constitutive signalling in cancer?

A

Anti-HER2 antibody e.g. Transtuzumab, Herceptin.

Causes HER2 internalisation and degradation and ADCC (antibody dependent cellular cytotoxicity).

39
Q

In what kind of cancers are anti-HER2 antibodies effective?

A

In cancers that are HER2 +ve.

40
Q

How is the HER2 antibody produced to minimise immune response on administration?

A

Monoclonal Ig produced in mice but humanised by switching the sequences.

41
Q

How does the Philadelphia chromosome form?

A

Through translocation of chromosome 22 and 9. It rejoins at the sites of BCR on 22 and Abl on 9.

42
Q

What does the Philadelphia chromosome result in?

A

Creates a hybrid gene that encodes for a BCR-ABL fusion/chimeric protein.

43
Q

What is the normal function of Abl gene?

A

Cytoplasmic TK for survival and growth

44
Q

What happens to Abl when in the chimeric protein?

A

The N-terminus of Abl is substituted for BCR sequences to constitutively activate Abl TK activity. This stimulates inappropriate proliferation haematopoietic precursor cells and prevents apoptosis.

45
Q

What type of cancer is the BCR-Abl mutation associated with?

A

Chronic Myeloid Leukaemia - Uncontrolled proliferation of haematopoietic stem cells leading to excessive WBCs accumulating in the blood stream.

46
Q

What treatment is used in CML?

A

Abl Kinase inhibitor e.g. Imatinib. Blocks ATP binding pocket on the TK domain of BCR-Abl to prevent phoshorylation of proteins.

47
Q

Why do only 80% of patients respond to Imatinib?

A

Pts in acute phase CML with show an initial response but the relapse as a result of resistance and second mutations in the TK domain to prevent the drug from binding in the pocket.