Cell proliferation Flashcards
what is cell proliferation
increase in cell number
what is cell proliferation essential for
tissue homeostasis
what else is tissue homeostasis dependent on
the apoptotic pathway operating correctly
what can deregulation in cell proliferation or apoptosis result in
diseases such as cancers and neurodegeneration
what are mitogens
growth factors or cytokines with the potential to active cell cycle
what does the mitogenic signal cause
the cell to synthesise proteins in order to overcome the restriction point (“R” point)
what is the restriction point
acts as a cellular brake to block cells from advancing from G1 phase to S phase
what regulates cell proliferation
MAPK signalling
Mitogen Activated Protein Kinase
the cascade have 3 component structures
ERK signalling pathway
caused by growth factors
Raf, MEK, ERK
leads to cell growth and cell division
p38 signalling pathway
caused by cytokines, osmotic stress and DNA damage
TAK, MKK3, p38
leads to inflammation apoptosis
JNK signalling pathway
caused by cytokines, osmotic stress and DNA damage
ASK,MKK4, JNK
leads to inflammation apoptosis
what do mitogens signal to
cell surface receptors such as members of the receptor tyrosine kinase family
what do tyrosine kinases do
phosphorylate tyrosine residues on target proteins
how many receptor tyrosine kinases and how many classes
50 RTK into 20 different classes each with multiple members
activation of receptor tyrosine kinase signalling
signalling molecules bind to the receptor
receptor dimerise and kinase activity is stimulated
auto phosphorylation and trans-phosphorylation of tyrosines
phosphorylated sites allow other proteins to dock to which in turn activates them
which receptor tyrosine kinases are part of the ErbB family
HER1, HER2, HER3 and HER4
erbB1
known as HER1 or EGFR (epidermal growth factor receptor)
has a tyrosine kinase domain which is intracellular
membrane between
then extracellular receptor domain
associated with EGF, TGF alpha and amphiregulin ligands
erbB2
known as HER2 or neu
has an intracellular tyrosine kinase domain
membrane between
not associated with any specific ligands
erbB3
known as HER3
same structure as others except no tyrosine kinase domain
associated with heregulins ligand
erbB4
known as HER4
has a tyrosine kinase domain
same structure as others
associated with NRG2, NRG3 and heregulins ligands
what is dimerisation critical for
signal specificity
signal activity (HER2:HER3)
redundancy
homodimers of ErbB receptors
HER1:HER1
HER2:HER2
HER3:HER3
HER4:HER4
problem with HER2:HER2 homodimerisation
no specific ligands
lack of specific homodimer function
problem with HER3:HER3 homodimerisation
no tyrosine kinase domain
lack of specific homodimer function
what does the activation of EGFR cause
downstream Ras signalling
process of EGFR activation
causes adaptor protein like Grb2 to bind first
enables other proteins to bind to GRb2 to come closer to p-EGFR
SOS can bind to GRb2 and allows it to be activated by p-EGFR
SOS activation allows Ras activation and ERK signalling is activated
in how many cancers is Ras mutated
30%
what is Ras
G-protein similar to G alpha subunit of heterotrimeric G-protein coupled receptor
small GTPase
SOS functions as a guanine exchange factor (GEF)
when is Ras inactive
when bound to GDP
GTP-ase activating proteins stimulate Ras to hydrolyse GTP thereby inactivating itself
when is Ras active
when bound to GTP
GEF stimulates Ras to replace the bound GDP in exchange of GTP
process of activated Ras
binds to Raf which is a serine/threonine kinase and is activated by autophosphorylation
Raf phosphorylates MEK
MEK is activated
MEK phosphorylates ERK (MEK very specific to ERK to ensure signal specificity)
ERK is activated
what is the significance of ERK activation
ERKs phosphorylate many nuclear and cytoplasmic proteins such as transcription factors c-Jun and c-fos
allows ERKs to regulate cell proliferation, differentiation, migration, inhibition of apoptosis
in cell proliferation what can ERKs induce
Myc
is a transcription factor
activates transcription of necessary genes to allow cells to pass the R-point
how can cells regulate proliferation
turn off proliferative signalling
get destroyed when signalling becomes excessive (induce apoptosis)
two ways that ERK signalling can be turned off
prevent release of EGF
inactivate EGFR
preventing the release of EGF
target metalloproteinases
EGF is normally synthesised as a transmembrane protein which is leaved by metalloproteinaes during cell proliferation
inactivating EGFR
remove the receptor
EGFR is internalised via endocytosis and sent to lysosomes for destruction
what causes constant proliferation signalling to ERK
deregulation of endoscope -> increased EGFR levels
over activation of metalloproteinase -> increase EGF levels
over expression of EGFR -> increased signalling
mutation in kinase domain -> always active
deletion of ligands binding domain EGFR variant III -> always active
what are the three mechanisms to target EGFR
- EGFR receptor inhibitors
- EGFR dimerisation inhibitors
- Tyrosine kinase inhibitors
name the EGFR receptor inhibitors
cetuximab
matuzumab
nimotuzumab
panitumumab
name EGFR dimerisation inhibitors
trastuzumab
pertuzuzmab
both HER2 inhibitors
tyrosine kinase inhibitors
gefitinib
erlotinib
lapatinib
mechanisms for resistance to EGFR inhibitors in non small cell lung carcinomas
bypass mechanisms
EGFR alterations
bypass mechanism examples
HER2 amplification
B-RAF mutations
met amplification
PI3K signalling
small cell lung carcinoma
EGFR alteration examples
T790M mutation (largest cause for resistance)
EGFR T790M amplification
Ras cancer mutations
mutated Ras can’t be inactivated by GTPase-activating proteins GAPs
Ras remains bound to GTP
B-Raf in cancer
mutated in 7% of all cancers
frequently mutation is V600E (valine to glutamic acid)
mutation increases the kinase activity by 500-fold
