FGF Signalling Networks

Question 1

What are the phases of the cell cycle?

Answer 1

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

Question 2

Which phase determines the length of the cell cycle?

Answer 2

G1

Question 3

How is the FGF signal transduced at the plasma membrane?

Answer 3

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

Question 4

How many FGFs are there?

Answer 4

22

Question 5

What is the mouse orthologue of human FGF 19?

Answer 5

FGF15

Question 6

What are FGFs?

Answer 6

Secreted glycoprotein sequestered by the extracellular matrix.

Question 7

What are FGFs released by?

Answer 7

Heparinases from the extracellular matrix.

Question 8

What are FGFs bound to?

Answer 8

Heparin sulfate proteoglycans (HSPGs).

Question 9

What do HSPGs do?

Answer 9

Stabilize the FGF-FFGFR by making a complex.

Question 10

How is ligand specificity regulated?

Answer 10

By the presence of cell-surface proteins and proteoglycans.

Question 11

What does ligand-receptor complex formation cause?

Answer 11

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

Question 12

What do autophosphorylated tyrosines recruit?

Answer 12

Intracellular signalling proteins.

Question 13

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

Answer 13

It’s phosphotyrosine binding domain.

Question 14

What does phosphorylation of FRS2 recruit?

Answer 14

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

Question 15

What activates Ras?

Answer 15

SOS

Guanine nucleotide exchange factor (GEF)

Question 16

What is mTOR?

Answer 16

Mechanistic target of rapamycin

A serine kinase.

Question 17

What does mTOR do?

Answer 17

Regulates cell proliferation, growth, survival, metabolism

Question 18

How does mTOR mediate signalling?

Answer 18

By forming the protein complexes mTORC1 and mTORC2

Question 19

What are the roles of FGFs?

Answer 19

Tissue development
Wound healing and regeneration
Homeostasis
Angiogenesis.

Question 20

What do FGFR2 and FGFR3 suppress?

Answer 20

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

Question 21

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

Answer 21

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.

Question 22

Which FGFs are upregulated in prostate cancer?

Answer 22

FGF2 & FGF6

Question 23

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

Answer 23

Breast cancer

Question 24

In which cancers is FGF19 over-expression found?

Answer 24

Liver, colonic and lung squamous carcinomas.

Question 25

In which cancers are FGFR3 mutations found?

Answer 25

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

Question 26

Which translocation is found in 15% of multiple myelomas?

Answer 26

t(4;14)

Question 27

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

Answer 27

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

Question 28

In which cancers is amplification of FGFR1 found?

Answer 28

10% of oestrogen receptor-positive breast cancers | Smoking related lung cancer

Question 29

How does mutant FGFR lead to abnormal signalling?

Answer 29

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

Question 30

Are there any clinical trials looking at FGF inhibitors?

Answer 30

Yes, 7 are currently recruiting patients.

Question 31

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

Answer 31

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.

Question 32

In which cancers is FGFR2 down regulated?

Answer 32

Bladder cancer, prostate cancer and salivary adenocarcinomas.

Question 33

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

Answer 33

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.