Transcript 160823_PLY_lung_mole..

The origin of cancer
What is cancer?
Cancer Research UK defines it as: “… when abnormal cells divide in an uncontrolled way.
The Cell Cycle
The Cell Cycle
Go is modulated by:
Mitogens, stimulate cell
division, mostly by removing
intracellular negative feedback
controls that block progress
through the cell cycle.
Growth factors, which
stimulate cell growth by
promoting the synthesis of
proteins and other
macromolecules and by
inhibiting their degradation.
Survival factors, which
promote cell survival by
suppressing apoptosis.
Resting phase or cell
quiescence (heart/neuron)
The Cell Cycle
Go is modulated by:
ALK -1
EGFR
KRAS
These are tyrosine kinases
Regulation of The Cell Cycle
Most receptors for growth factors are tyrosine kinases
Al Pacino says:
A tyrosine kinase?
WHAT THE &%$* IS A
TYROSINE KINASE ?!
Regulation of The Cell Cycle
Most receptors for growth factors are tyrosine kinases
• Discovered in 1982
• Receptor for epidermal growth factor (EGF)
• When activated, transfers a phosphate group from
ATP to selected intracellular tyrosine side chains.
• These phosphorylated domains are recognised by
intracellular proteins and start a signal cascade.
Phase 1: Extracellular signal
Phase 2: Intracellular signal cascade
Phase 3: Profit.
EGFR: Epidermal Growth Factor Receptor
Involved in growth; cell proliferation; differentiation and survival
Family of four tyrosine kinase receptors
• HER-1 (ErbB-1)
• HER-2/neu (ErbB-2)
• HER-3 (ErbB-3)
• HER-4 (ErbB-4)
EGFR: Epidermal Growth Factor Receptor
A transmembrane cell signalling receptor with four distinct domains:
EGF binding site
Plasma membrane
Tyr
Tyr
Tyr
Tyrosine kinase
Tyr
Tyr
Cytoplasmic tail
EGFR: Epidermal Growth Factor Receptor
How does it function?
Epidermal growth factor (EGF)
binds to its receptor (EGFR) on
the cell membrane
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
EGFR: Epidermal Growth Factor Receptor
How does it function?
Homo- and hetero-dimerization of the
transmembrane region and
autophosphorylation of tyrosine kinase
molecules.
Signal cascade pathway activated (e.g.MAPK)
leading to DNA synthesis and cell replication
ATP
ADP
P
P
P
P
P
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
P
P
P
P
P
EGFR: Epidermal Growth Factor Receptor
EGFR
RAS
GDP
Transcription
Grb
SOS
RAS
GTP
MYC
RAF
MEK
MNK
CREB
MAPKKK
MAPKK
MAPK
Kirsten rat sarcoma viral oncogene homolog
KRAS = Kirsten rat sarcoma viral oncogene homolog
KRAS is a molecular switch.
KRAS recruits and activates the proteins required
in growth factor receptors, e.g.: B-RAF (a member
of the MAPK pathway)
All this preparation is ignored
BRAF initiates the whole signalling cascade at this point
Also known to play a role in the Warburg effect of
malignant tumours.
BRAF was here..
ALK-1: Anaplastic lymphoma kinase
Adenocarcinoma of the lung responsible for 3-5% of non-small cell lung cancer
ALK-1 is:
• the result of a inversion fusion gene mutation on 2q
• ALK and EML1 change position
• ALK fuses to EML4
• Produces a chimeric fusion protein with constitutive ALK1 action.
• Promotes and maintains malignant behaviour.
• Almost mutually exclusive with EGFR or KRAS
TYROSINE KINASE TAKE HOME MESSAGE
• Cell signalling is a complicated process involving many
interlocking parts
• One solitary change can upset the whole cascade.
• Molecular biology is never as simple as it appears!