What is intracellular signalling?
Set of linked biochemical events that connect a specific biological stimulus with a specific cellular response
What are the four properties of intracellular signalling pathways?
Specificity Transduce signal across membrane into cell Amplify external signal within the cell Regulate cellular signals (STAR)
What are the five layers of the signalling pathway?
Signal Receptor Transduction Intracellular targets Cellular response
=(CRITTRS)
Examples of extracellular signals?
Tastants Odorants Photons Peptides Lipids Amino acids derivatives e.g. epinephrine, histamine Nucleotides e.g. ATP Gases
=(TOPPLANG)
What is a ligand?
A molecule that binds to a specific site on another molecule, usually a receptor protein
Examples of cell signalling outcomes?
Changes in gene expression Regulate translation Regulate cell cycle Cell migration Initiate angiogenesis Initiate apoptosis
What are the three important signalling pathways in cancer?
Proliferation (mitogenesis)
Survival (anti-apoptosis)
Motility (invasion and metastasis)
=(MAIM)
What is mitogenesis?
Uncontrolled, continuous cell division leading to increased cell number and thus formation of a tumour mass
What is anti-apoptosis?
Loss of a cell’s programmed ability to commit suicide after a given number of cell divisions and/or after losing contact with its substrate
What is invasion and metastasis?
The ability of a cell to move from the primary tumour mass, into the bloodstream, or the lymph system and out again at a secondary site
Three types of mitogenic agonists?
Polypeptide growth factors
Peptides and lipids
Cytokines
Example of a polypeptide growth factor?
EGF (epithelial)
VEGF (vascular endothelial)
PDGF (platelet driven)
Three types of cell surface receptors?
Ligand gated ion channel
GPCRs
Enzyme-linked receptor e.g. GF receptor
Three steps of Growth Factor receptor signalling?
Dimerisation in extracellular space
Binding of receptor to signal
Activation of receptor
=(DEBRA)
What is Ras?
Oncogene
What does Raf recognise?
Ras-GTP
Define apoptosis.
Mechanism that allows a cell to self-destruct when stimulated by the appropriate trigger, which may result when a cell is no longer needed or becomes a threat to the organism’s health
Define anoikis.
Form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding ECM
Define necrosis.
Form of cell death that results from injury, disease, or other pathological state
Types of survival factors?
Mitogens
Integrins
Survival factors
What are integrins?
Cell-ECM adhesion factors
Heterdimers of alpha and beta subunits that bind to the EC, control cell survival, proliferation and cytoskeletal structure
What is the kinase that converts PIP2 to PIP3?
PI3K
What is the phosphatase that converts PIP3 to PIP2?
PTEN
What is PTEN?
Phosphatase and tumour suppressor
What goes wrong to initiate cancer development?
Protein mutation (activating)
Protein mutation (inactivating/deleting)
Protein addition
Protein amplification
How are signals transduced from one protein to another signalling pathway?
Generation of intracellular signals
Types of intracellular signals?
Sugars Ions Gases Nucleotides Lipids
=(SIGNL)
What is required of second messengers?
Rapidly generated, diffusable, and removed
What is changed to generate intracellular signals?
Localisation of a component
Enzyme Activity of protein
Concentration of an intracellular ligand
=(LEAC)
When EGF binds to EGFR, what happens to Grb2?
Grb2 gets phosphorylated, which activates SOS to convert Ras-GDP to Ras-GTP, which in turn is recognised by Raf protein and proliferation ensues
What type of receptor is EGFR?
Receptor tyrosine kinase
Significance of HER2?
Overexpression leads to constitutive signalling
HER2 positive breast cancer shortens survival
What is Herceptin?
Humanized anti-HER2 antibody; high affinity and specificity
What is Imatinib (/Gleevec)?
Abl-specific tyrosine kinase inhibitor; it blocks the ATP binding site of Abl kinase. Has broad spectrum anti-proliferative activity against haematological and solid tumour cell lines
Side fx of Imatinib?
Hepatic toxicity
Neutropenia at high doses
How might there be resistance to Imatinib?
Mutations in kinase domain
Amplification of BCR-Abl fusion gene
Multidrug resistance
