9. Examples of cancer pathways Flashcards
What is the result of mutations in proteins involved in key signalling pathways?
Cells acquire characteristic traits, e.g independence from cell cycle, growth regulation of apoptosis
This leads to uncontrolled proliferation and spatial restriction –> metastasis
What is the RAS/MAPK pathway and what is its role?
Mitogen activated protein kinase
Links extracellular signals to cellular process, e.g proliferation, migration, differentiation, apoptosis
What are the 4 major MAPK cascades, and what are they activated by?
- ERK - growth factors
- JNK - stress
- P38 - stress
- ERK5 - stress
Which MAPK pathways are stress-activated, and what is their function?
JNK, P38, ERK5
Regulate inflammation, DNA damage response, apoptosis
Generally the response is anti-proliferative & pro-apoptotic
What is a protein kinase?
Enzyme that phosphorylates a protein by transferring a phosphoryl group (-PO32-) from ATP to a serine, threonine, or tyrosine residue.
This activates the protein’s function
How is the action of protein kinases antagonised?
By protein phosphatases - control the level of target protein phosphorylation
What are the two main groups of protein kinases?
- Tyrosine kinases
- Serine/threonine kinases
What is the consequence of feedback in the ERK cascade?
Overactivation of ERK –> upregulation of EGFR ligands e.g. TGF alpha
Promotes feedback loop that is critical for tumourigenesis
What genes are commonly mutated in the ERK cascade?
EGFR
RAS (h, k, n)
BRAF
What is the consequence of EGFR mutations?
How are they treated?
De-regulated in 30% of cancers (lung, breast, glioblastoma)
Affect ATP binding pocket –> enhanced signalling
Treated with TKIs - T790M found in patients with acquired resistance to TKIs
What type of protein is EGFR?
Receptor tyrosine kinase
What type of protein is RAS?
What is its role?
GTPase
Mediates mitogenic signalling by receptor tyrosine kinases, e.g. EGFR
Mutated in 17% of cancers
What type of protein is BRAF?
What is the common mutation?
Tyrosine kinase
V600E
What cancers is BRAF commonly mutated in?
Melanoma, CRC, NSCLC
What is the role of the PI3K/AKT/mTOR pathway?
Transduces signals from growth factors/cytokines into intracellular signals by generating phospholipids
