SPECIFICITY
TRANSDUCTION
AMPLICATION
REPLICATION
Ligands can be any small molecule; peptides, amino acids, steroids, prostaglandins.
The response of the cell might be altered motility, altered activation, survival, division, angiogenesis or death.
Mitogenesis
Apoptosis
Invasion
Metastasis
Mitogenesis is the EGF, PDGF or VEGF which cause growth and proliferation. The receptors have tyrosine kinase activity- more activation leads to a cascade of growth signals. This is carcinogenic. Peptides and lipids can act of G-PCRs. Cytokines can bind to adaptor proteins and lipid protein kinases.
PDGF is to do with platelets- it promotes the proliferation of connective tissue.
EGF is from the submaxillary glands and it is particularly vital in the proliferation of epithelial cells.
TGFA is related to EGF.
TGFB is from activated T-helper cells and is involved in the anti-inflammatory response.
VEGF is involved in angiogenesis.
Kinases catalyses the removal of phosphate from ATP and its placed onto another molecule. Phosphorylation might turn a protein on or off.
Hallmarks of cancer:
Evades apoptosis
Self sufficient in growth signals
Limitless replicative potential
Invade and Metastasises
Insensitive to anti-growth signals
Sustains angiogenesis
Mitogenic signalling:
SHC + Grb2 + Sos --> phosphorylate RAS-GDP to RAS-GTP --> Raf --> Mek --> Mapk --> Erk activates gene expression
Survival factors prevent the normal apoptosis of cells. Survival can be triggered by cytokines and growth factors. Integrins also provide anti-apoptotic signals. IGF plays a role in telling the cell not to apoptose. Upregulation causes too much signal and there is growth.
EGF --> PI3K --> PIP3 is usually converted back to PIP2 by PTEN which causes apoptosis by preventing signalling. PIP3 --> PDK --> ATK --> PKV --> INHIBITION OF APOPTOSIS
There is a lot of redundancy in cell signalling as many pathways can cause the same thing. The cancer generates the ability to generate its own survival signals by constitutively active receptors. This can occur by protein mutation or removing an inhibitory signal, or adding a complementary pathway; or just amplifying the signal.
Intracellular signals usually use protein interactions or lipid alterations. Second messengers are usually rapidly generated, diffusible and removed. It is a quick process and fulfills the amplification requirements. Conformational changes usually occur that cause the 2nd messenger. There is increased localisation or concentration of something downstream.
Chemotherapy acts to stop the cell division from occurring. However, this causes side effects because it acts on all rapidly dividing cells.
HER2 in breast cancer signals through the RAS pathway. This leads to mitogenesis and survival. This is a normal signalling pathway but in HER2 positive breast cancer there are a lot more of these receptors available so an increased signal. Women who have this have a shorter survival overall due to this mechanism. Herceptin is a drug that has been used to target these receptors and reduce this problem.