LECTURE 4 (Growth factor signalling and oncogenes) Flashcards
What is a ligand?
A molecule that binds to a specific site on another molecule
What are the different types of receptors?
- Intracellular receptor
- Ligand-gated ion channel receptor
- G-protein coupled receptor
- Enzyme-linked receptor
What is the Epidermal growth factor (EGF)?
A tyrosine kinase receptor
What is the function of tyrosine kinase receptors?
Tyrosine kinase receptors phosphorylate tyrosine residues on target proteins -> Phosphorylation results in a CONFORMATIONAL CHANGE of the protein target
Describe the mechanism of the Epidermal growth factor (EGF)
1) EGF binds to the Epidermal growth factor receptor (EGFR)
2) Growth factor binding causes a conformational change that unmasks a DIMERISATION DOMAIN required for receptor dimerisation
3) The close proximity of two receptors enables kinase domain of one receptor of the dimer to phosphorylate the other receptor of the dimer
Describe how phosphorylated tyrosine residues activate intracellular transducer RAS
1) Phosphorylated tyrosine residues create high-affinity binding sites for proteins that contain Src homology 2 (SH2) domains
2) Grb2 = an intracellular protein that contains SH2 and SH3 domains
3) The two SH3 domains of Grb2 interact with the exchange protein SOS (son of sevenless) which facilitates the activation of the pivotal intracellular transducer RAS
Describe how RAS activation leads to MAP kinase cascade
1) SOS stimulates the inactive RAS to replace its bound GDP by GTP which activates RAS to relay the signal downstream
2) Activated RAS propagates signalling further inside the cell via a kinase that goes from RAS to RAF KINASE to MEK KINASE and finally MAP KINASE
3) MAP KINASE dimerises and enters the nucleus phosphorylating proteins and activating immediate early genes (including G1 cyclins)
What is the function of the AP1 transcription factor?
It binds to DNA and regulates gene expression involved in growth, differentiation and death
What is one mechanism by which AP-1 induces cell cycle progression?
Binding to and activating the cyclin D gene, a critical regulator of the cell cycle
What are the mechanisms that induce AP-1?
- Direct phosphorylation of members of the Fos family by MAPK affects their DNA-binding activity
- MAPK phosphorylation and subsequent activation of other transcription factors increases the expression of both fos and jun genes
Describe the mechanism of Phosphatidylinositol 3-kinase
1) Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is an effector protein
2) Production of the second messenger (PIP3) recruits the serine/threonine kinase PDK-1 to the membrane -> AKT (another serine/threonine kinase) is also recruited to the membrane where it is phosphorylated and activated by PDK-1
3) Activated AKT is translocated into the nucleus where it phosphorylates nuclear substrates
What is an Oncogene?
A mutated gene that has the potential to cause cancer
[before an oncogene becomes mutated its called a PROTO-ONCOGENE and plays a role in regulating normal cell division]
What do Point mutations/deletions in coding sequences result in?
Structural and functional changes
What do point mutations and deletions in regulatory sequences result in?
Over-expression
What do Chromosomal translocations result in?
Fusion proteins with novel functions
