FGF Signalling Networks Flashcards
What are the phases of the cell cycle?
G1: Gap - time for growth M: Mitosis G2: Gap - time for growth (G0 : non-dividing phase, terminally differentiated) S: DNA synthesis
Which phase determines the length of the cell cycle?
G1
How is the FGF signal transduced at the plasma membrane?
Formation of the ternary FGF2/heparin/FGFR1 complex initiates the FGF signalling at the cell membrane.
How many FGFs are there?
22
What is the mouse orthologue of human FGF 19?
FGF15
What are FGFs?
Secreted glycoprotein sequestered by the extracellular matrix.
What are FGFs released by?
Heparinases from the extracellular matrix.
What are FGFs bound to?
Heparin sulfate proteoglycans (HSPGs).
What do HSPGs do?
Stabilize the FGF-FFGFR by making a complex.
How is ligand specificity regulated?
By the presence of cell-surface proteins and proteoglycans.
What does ligand-receptor complex formation cause?
Conformational change of the kinase domain, leading to cross-phosphorylation of FGFR (autophosphorylation).
What do autophosphorylated tyrosines recruit?
Intracellular signalling proteins.
At which domain does FGFR substrate 2 (Frs2) bind FGFR?
It’s phosphotyrosine binding domain.
What does phosphorylation of FRS2 recruit?
Adaptor proteins, such as son of sevenless (SOS) and growth factor receptor bound 2 (GRB2).
What activates Ras?
SOS
Guanine nucleotide exchange factor (GEF)
What is mTOR?
Mechanistic target of rapamycin
A serine kinase.
What does mTOR do?
Regulates cell proliferation, growth, survival, metabolism
How does mTOR mediate signalling?
By forming the protein complexes mTORC1 and mTORC2
What are the roles of FGFs?
Tissue development
Wound healing and regeneration
Homeostasis
Angiogenesis.
What do FGFR2 and FGFR3 suppress?
Bone growth, by inhibiting cell proliferation and promoting premature differentiation.
What is the evidence for the involvement of FGF signalling in cancer?
- FGF promotes angiogenesis.
- FGFR3 mutations in bladder cancer.
- Amplifications of FGFR1 in smoking-related squamous cell lung carcinoma, FGFR2 in gastric cancer.
Which FGFs are upregulated in prostate cancer?
FGF2 & FGF6
There are higher expression levels of FGF1, FGF2, and FGF7 in which cancer?
Breast cancer
In which cancers is FGF19 over-expression found?
Liver, colonic and lung squamous carcinomas.
In which cancers are FGFR3 mutations found?
Cervical cancer, multiple myeloma, prostate cancer, spermatocytic seminomas, skin cancer (benign).
Which translocation is found in 15% of multiple myelomas?
t(4;14)
What happens in the t(4;14) translocation?
The promoter region of immunoglobulin heavy chain is linked to FGFR3 leading to over-expression of FGFR3.
In which cancers is amplification of FGFR1 found?
10% of oestrogen receptor-positive breast cancers
Smoking related lung cancer
How does mutant FGFR lead to abnormal signalling?
Lack of ligand-binding domain leads to ligand-independent activation.
Mutations in transmembrane domain lead to activation.
Are there any clinical trials looking at FGF inhibitors?
Yes, 7 are currently recruiting patients.
What is the evidence that FGFR activation act as a tumour suppressor in some cases?
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.
In which cancers is FGFR2 down regulated?
Bladder cancer, prostate cancer and salivary adenocarcinomas.
What are the problems that have been encountered with FGF therapy?
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.
