6 - Signal Transduction Pathways Flashcards
Signal transduction
- The process by which a cell converts an extracellular signal into a cellular response
- LEads to alterations in cellular activity (proliferation, apoptosis, metabolism etc)
What is signal transduction involved in
- Cell response to environment
- Cell to cell communication
- Intracellular homeostasis
Essential Signal Transduction Pathway Components
- Ligand (extracellular signal)
- Receptor (what the ligand binds)
- 2nd messengers (relay message from signal to target)
- Targets
Ligands
- Growth factors (e.g. TGF-α/β)
- Neurotransmitters (e.g. epinephrine)
- Hormones (e.g. androgens)
- Cytokines (e.g. chemokines)
Receptors
- Cell surface receptors (tyrosine kinase receptors)
- Intracellular receptor (hormone receptors e.g. ER)
2nd messengers
cAMP, kinases
Targets
Transcription factors, translation factors, chaperones, actin/myosin filaments, enzymes
JAK-STAT signalling
- Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called STATs
- The recruited STAT is activated by JAK phosphorylation, dimerizes, enters the nucleus, and turns on the expression of cytokine target genes
The EGF-Receptor (HER2) Family
- Family members are over-expressed of have activating mutations in breast, gastric and lung cancer.
- Two prominent pathways activated by the EGF/Her2 family of GF are the ras-raf-Erk and the PI3K/Akt
pathways. - Inhibitors of the signalling have been developed as either antibodies or tyrosine kinase inhibitors
One common pathway activated by many cell activators that promote cell proliferation (a hallmark
of cancer)
The ras-raf-Erk pathway
True or False, Ref is only activated by Ras
FALSE
The ras-raf-Erk pathway
- Different components of the pathway are mutated in different cancers
- i.e. in most lung cancers there are high levels of EGFR (right at the top of the pathway), while in melanoma there is a common activation of raf (specifically B-raf).
- So targeting down-stream of raf would potentially be widely applicable to many cancers
Ras mutation
Pancreatic cancer
full ras raf Erk pathway
- Ras –> RAFs –> MEK1/2 –> ERK1/2 –> ETS
- Most successful drug targets MEK1/2
Targeting ras-raf-Erk pathway in melanoma
- Activated RAS –> BRAF –> MEK –> ERK –> Normal cell proliferation and survival
- BRAFV600 –> MEK –> ERK –> increased cell proliferation and survival
- Vemurafenib targets BRAFV600
How does resistance to therapies (e.g. vemurafenib) targeting the BRAFV600 in melanoma arise
- Due to amplification of BRAF so much that the drug is insufficient to get into quantities able to inhibit all of it
- Truncation of BRAF so the drug will no longer bind
- Mutations downstream (in MEC), independent of BRAF
- Activation of other systems
- Reactivation of CRAF
Specific functions of signalling circuits
- Motility circuits
- Cytostasis and differentiation circuits
- Viability circuits
- Proliferation circuits
Central Player in the Viability Pathway of Cancer Cells.
Akt
Akt
- Elevated survival signalling (Hallmark of cancer)
- Activated by many different upstream receptor systems and feeds into multiple downstream pathways.
- Also controls protein synthesis which is also a
pathway targeted in cancer as the increased growth rate of cancer cells means they have to produce more protein.
Akt inhibitor
Perifosine
EGFR inhibitor
Erlotinib
BCR-Abl inhibitors for CML
- The BCR-Abl fusion protein is a constitutively active kinase.
- A novel drug STI571/imatinib has been able to interfere with the kinase activity of BCR-Abl, inducing apoptosis in BCR-Abl+ cells by down regulating Bcl-X.
- The specificity of the drug is highest for the abnormal BCR-Abl kinase, and much less effective against normal
kinases in the cell. - The drug, therefore, targets the cause of the leukaemia
Resistance to STI571/Imatinib
- Imatinib fits into the ATP binding pocket of wild-type BCR-Abl but when Threonine 315 is mutated to Isoleucine it can no longer fit as the Isoleucine protrudes into the space that part of the Imatinib would fit.
- Mg-ATP can still bind into the pocket so the T315I BCR-Abl is still active
