STAT
survival, proliferation and oncogenesis
Akt
angiogenesis, tumorigenesis and inhibition of apoptosis
ERK
gene expression and cell-cycle progression
PKC
transformation, differentiation and apoptosis
What is unique about HER receptors?
Some don’t show any ligand - activated on nearby receptor activation
DNA rearrangement mutations in HGF-R and c-Met HGF-R heterodimer
localized on cellular membranes.
The unmutated receptor makes cell motile for them to be able to move. It has two ligand binding domains bound by disulfide bonds. The mutated receptor has a translocation, the c-Met fragment of the cytoplasmic domain is fused to another cytosolic protein, and ligand binding is not able to regulate the receptor activity anymore.
Result of HGF-R and c-Met HGFR mutation
This re-arrangement results in aberrant localisation and activation of Met tyrosine kinase activity, and it was identified in sarcomas.
HGF-mediated signaling
- > regulates diverse cellular processes
- Prosurvival signaling and motility are regulated, as well as proliferation.
- Chromosomal translocation 9-22 produces an oncogene that constantly signals downstream without the need for a receptor or a ligand, nevertheless.
Small GTPases are _______ in cancer, and they are really important in _______ due to their role in ____________
deregulated
cell structure
actin cable formation inside the cell.
E-cadherin
keeps cell together in normal cells.
Mutations in small GTPases
weaken the cell-cell junctions and allow metastasis by decreasing E-cadherin expression. Polarity is messed up so cells grow on top of each other in 3D .
Matrix metalloproteases
provide cells enough motility to move around the body and they have a distinct role in metastatic growth.
-> digest the basal membrane and connective tissue, allowing them more freedom of movement and proliferation.
5 main effects of Matrix metalloproteases
- Release of growth factors
- Degradation of matrix barriers
- Degradation to reveal cryptic sites (laminin 5 and angiotensin)
- Disruption of cell-matrix adhesion
- Disruption of cell-cell adhesion
Which MMP’s are overexpressed in malignant growth
2 and 9
The most important domain in MMP’s are
the furin cleavage site, which acts as the autoinhibitory region for the enzyme’s catalytic activity.
Why is the furin cleavage site important?
- It folds and binds to the catalytic domain, it would only be activated when there is another protease called furin.
- If there is no furin, the protein would remain inactive.
Combination of events is necessary for activity.
Angiogenesis
new blood vessels form from preexisting blood vessels
VEGF expression leads to
Neovascularization of the tumor
What are 2 mechanisms by which cancer cells maintain a lower rate of apoptosis?
- Bcl-2 is a proto-oncogene, which inhibits the protease cascade that leads to cell death.
- PI3K / Akt signalling regulates cell survival pathway
- Overexpression or activating mutations in Bcl2, PI3K, and PKB / Akt are found in many types of human cancer.
What is used instead of pyruvate in glycolysis of cancer cells?
Pyruvate Kinase M2
mTOR stands for
mammalian target of tropomyosin
- serine/threonine kinase that lacks the substrate binding sequence
- key regulator for anabolic and catabolic biological events uses small GTPases to sense amount of ATP and monomers present and the level of growth factor signalling.
How do AMP kinase phosphorylate tumor suppressors?
G1/S checkpoint is controlled by phosphorylation of Rb by cyclin-dependent kinases, and deregulation of this checkpoint (cyclin D1 overexpression or inactivation of CDK inhibitors) would contribute to malignant growth.
Properties of Transformed Cells
- Reduced requirement for growth supplements (serum, growth factors, hormones).
- Loss of capacity to go into quiescent arrest (growth arrest)
- Altered morphology (look different from precursors)
- Loss of contact inhibition (tumor cells grow on top of each other)
- Loss of anchorage dependence (tumor cells grow in soft agar)
- Form tumor in “nude” mice.
- > Many cancer cell lines, derived from naturally occurring tumors have these properties in culture.
