Lecture 2- abhorrent growth Flashcards
what is the role of fibroblast growth factor receptors
TM receptors on cell surfaced used for communication between cells and extracellular environment
how are the 4 isoforms of FGFRs generated
alternative splicing of IgIII domain of the invariant exon. epithelial cells predominantly express IIIb and mesenchymal cells predominantly express IIIc
how many FGFs are there
22
how many phylogenic FGF sub families are there
7
how many mechanistic FGF sub families are there
3 (paracrine, endocrine and autocrine)
describe the structure of FGFRs
comprise 2 receptor molecules which contain 3 extracellular Ig domains with one heparin sulphate proteoglycan chain followed by an acid box as well as 1 TM helix and an intracellular TK domain
where on FGFRs do FGFs bind
they bind to the HSPG polysaccharide chain between IGII and IgIII
what is the result of FGF binding to FGFRs
upon binding of an FGF molecule to each FGFR monomer they dimerise which results in transphosphorylation on tyrosine residues, activation of intracellular substrates via phosphorylation and ultimately the activation of downstream signalling pathways generating diverse cellular responses
describe how FGFR instigates MAPK signalling
Activated FGFR binds the intracellular substrate FRS@a which binds GRB2, an adaptor protein. Grb2 recruits SOS which activates RAS GTPase, which activates RAF which activates MAPK and the MAPK cascade ultimately activating the FOS transcription factor which results in cell proliferation
describe how FGFR instigates PI3K signalling
Activated FGFR binds the intracellular substrate FRS@a which binds GRB2, an adaptor protein. Garb binds GAB1 which leads to PI3K mediated AKT activation. AKT kinase inhibits proapoptotic effectors such as Caspase-9 and FOXO to promote cell survival
describe how FGFR instigates PLCg1 pathway
FGFR recruits and phosphorylates the lipase PLCg1, activating it which then catalyses the hydrolysis of PIP2 into IP3 and DAG. DAg activates the PKC pathway to regulate cell motility by cytoskeletal rearrangement and IP3 stimulates the release of calcium from intracellular storage compartments which triggers the activation of calcium dependent proteins including calineurin leading to cell motility.
what are the possible results of genomic alterations to FGFR such as mutations, chromosomal translocations and gene amplification
can lead to ligand-independent signalling particularly in the case of gene amplification. it may also lead to a paracrine loop on a cancer cell as a result of splicing and amplification out of context or the establishment of an autocrine loop as a result of FGFR expression out of context or increased expression of FGF
what is the result of FGF release from stromal cells
can act on endothelial cells to promote angiogenesis. abhorrent regulation occurs in many tumours
how do selective FGFR tyrosine kinase inhibitors target cancer cells
they strongly bind to FGFRs and inhibit their phosphorylation resulting in the inhibition of proliferation and induction of cell death
how can therapeutic antibodies be used in targeting cancer
minimise the side effects as more specific for cancers which rely on just one type of FGFR
