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Cancer > FGF Signalling Networks > Flashcards

FGF Signalling Networks Flashcards

1
Q

What are the phases of the cell cycle?

A 
G1: Gap - time for growth
M: Mitosis
G2: Gap - time for growth
(G0 : non-dividing phase, terminally differentiated)
S: DNA synthesis
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2
Q

Which phase determines the length of the cell cycle?

A

G1

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3
Q

How is the FGF signal transduced at the plasma membrane?

A

Formation of the ternary FGF2/heparin/FGFR1 complex initiates the FGF signalling at the cell membrane.

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4
Q

How many FGFs are there?

A

22

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5
Q

What is the mouse orthologue of human FGF 19?

A

FGF15

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6
Q

What are FGFs?

A

Secreted glycoprotein sequestered by the extracellular matrix.

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7
Q

What are FGFs released by?

A

Heparinases from the extracellular matrix.

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8
Q

What are FGFs bound to?

A

Heparin sulfate proteoglycans (HSPGs).

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9
Q

What do HSPGs do?

A

Stabilize the FGF-FFGFR by making a complex.

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10
Q

How is ligand specificity regulated?

A

By the presence of cell-surface proteins and proteoglycans.

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11
Q

What does ligand-receptor complex formation cause?

A

Conformational change of the kinase domain, leading to cross-phosphorylation of FGFR (autophosphorylation).

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12
Q

What do autophosphorylated tyrosines recruit?

A

Intracellular signalling proteins.

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13
Q

At which domain does FGFR substrate 2 (Frs2) bind FGFR?

A

It’s phosphotyrosine binding domain.

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14
Q

What does phosphorylation of FRS2 recruit?

A

Adaptor proteins, such as son of sevenless (SOS) and growth factor receptor bound 2 (GRB2).

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15
Q

What activates Ras?

A

SOS

Guanine nucleotide exchange factor (GEF)

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16
Q

What is mTOR?

A

Mechanistic target of rapamycin

A serine kinase.

17
Q

What does mTOR do?

A

Regulates cell proliferation, growth, survival, metabolism

18
Q

How does mTOR mediate signalling?

A

By forming the protein complexes mTORC1 and mTORC2

19
Q

What are the roles of FGFs?

A

Tissue development
Wound healing and regeneration
Homeostasis
Angiogenesis.

20
Q

What do FGFR2 and FGFR3 suppress?

A

Bone growth, by inhibiting cell proliferation and promoting premature differentiation.

21
Q

What is the evidence for the involvement of FGF signalling in cancer?

A
  1. FGF promotes angiogenesis.
  2. FGFR3 mutations in bladder cancer.
  3. Amplifications of FGFR1 in smoking-related squamous cell lung carcinoma, FGFR2 in gastric cancer.
22
Q

Which FGFs are upregulated in prostate cancer?

A

FGF2 & FGF6

23
Q

There are higher expression levels of FGF1, FGF2, and FGF7 in which cancer?

A

Breast cancer

24
Q

In which cancers is FGF19 over-expression found?

A

Liver, colonic and lung squamous carcinomas.

25
Q

In which cancers are FGFR3 mutations found?

A

Cervical cancer, multiple myeloma, prostate cancer, spermatocytic seminomas, skin cancer (benign).

26
Q

Which translocation is found in 15% of multiple myelomas?

A

t(4;14)

27
Q

What happens in the t(4;14) translocation?

A

The promoter region of immunoglobulin heavy chain is linked to FGFR3 leading to over-expression of FGFR3.

28
Q

In which cancers is amplification of FGFR1 found?

A

10% of oestrogen receptor-positive breast cancers

Smoking related lung cancer

29
Q

How does mutant FGFR lead to abnormal signalling?

A

Lack of ligand-binding domain leads to ligand-independent activation.
Mutations in transmembrane domain lead to activation.

30
Q

Are there any clinical trials looking at FGF inhibitors?

A

Yes, 7 are currently recruiting patients.

31
Q

What is the evidence that FGFR activation act as a tumour suppressor in some cases?

A

Inactivating mutations of FGF2 is found in melanoma.
Mice tha tlack FGFR2IIIb in keratinocytes develop skin cancer more easily.
Expression of FGFRIIIb blocks proliferation in bladder cancer line.

32
Q

In which cancers is FGFR2 down regulated?

A

Bladder cancer, prostate cancer and salivary adenocarcinomas.

33
Q

What are the problems that have been encountered with FGF therapy?

A

Inhibition of normal function of FGF23 in phosphate homeostasis (leading to abnormal calcification).
Inhibition of FGFR1-IIIc in hypothalamus leading to severe anorexia in animal models.

Cancer (11 decks)

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