receptor tyrosine kinase Flashcards
receptor tyrosine kinase function
- cell growth
- motility
- metabolism
- cell survival
- differentiation
RTKs are activated by _____;
dimerization
when two nearby RTKs in the membrane are bound by their ligands, they undergo a
conformational change, bind to each other, and co-activate by phosphorylating each other.
for these RTKs, their substrates (PO4 targets) are .
other RTKs
Once activated, RTKs can also act as
catalysts for other reactions.
two different kinds of RTKs can dimerize to
generate a different signal than a dimer formed of two of either kind.
it doesn’t have to be a homodimerization
RTKs generally trigger complex kinase cascades that result in changes in
gene expression.
All RTKs activate:
ras signaling
Ras proteins:
membrane-bound switches regulated by GAPs and GEFs (see below). Involved with cell proliferation.
In the “off” state:
it’s bound to GDP
In GTP-bound (active) form, Ras proteins sets ______
off proliferative cascade.
Generally, Ras proteins can:
switch themselves off (intrinsic GTP->GDP activity)
GAP:
(increases its ability to switch itself off).
GTP activating protein
Inactivating mutations in GAPs can cause cancer since ras proliferation is unchecked.
in the active state:
it’s bound to GTP.
GEF:
Guanine nucleotide exchange factors:
helps exchange “spent” GDP for fresh GTP (thus activating Ras proteins).
Increase-of-function mutations in GEFs can lead to
cancer since Ras protein is constantly being activated again after it inactivates itself.
GEFs: turn Ras proteins ____
on
oncogenes
GAP: turn Ras proteins____
off (tumor suppressor genes).
mechanism of stim of ras GTPase by RTKs
- Dimerized RTKs bind to and activate Grb2, an adaptor protein; this has a SH3 binding
domain which binds to Sos, which is a GEF (Ras activator). - Sos being bound, it’s brought into proximity with Ras proteins, which are located in the cell membrane like the RTKs.
- Essentially RTKs activate Ras proteins by changing the location of GEFs, not by catalytic activity. (Movement of proteins into proximity causes proliferation).
Dimerized RTKs bind to and activate________; this has a SH3 binding domain which binds to____,
Grb2, an adaptor protein
SOS
SOS is a
a GEF (Ras activator).
Sos being bound, it’s brought into proximity with _____, which are located ______
Ras proteins
in the cell membrane like the RTKs
Essentially RTKs activate Ras proteins by
changing the location of GEFs, not by catalytic activity. (Movement of proteins into proximity causes proliferation).
Epidermal growth factor receptor (EGFR): is overexpressed in
a variety of tumors; good drug target for cancer treatment.
two main classes of RTK-targeted anti-cancer agents
- antibodies and
2. TKI’s
Antibodies: recognize
Recognize extracellular domain of RTKs.
antibodies act as
competitive antagonists: prevent ligand from being able to bind to the extracellular receptor domain.
TKIs (tyrosine kinase inhibitors): inhibit
tyrosine kinase activity of RTKs.
TKIs (tyrosine kinase inhibitors): works by
competitively binding to the ATP binding pockets of specific RTKs. No ATP, no phosphorylation, no activation of RTK dimers.
Recall that the “closed” or un-ATP-bound TK has a specific conformation that allows
more specific drug targeting– however, there’s still enough similarity that TKIs will inevitably have multiple TK targets.
Patients with non-small-cell lung cancer show only a 20% response to TKIs.
The 20%: usually

non-smokers, women, Asian descent.
When you’ve had a mutation in EGFR to make the activation domain much more active, the response to TKIs tends to get ____
better.
why does a EGFR mutation make TKI better response?
it’s thought that with an improved or more efficient EGFR proliferation pathway, the cell may be “addicted” to that pathway– which would make the cell much more vulnerable to TKIs, which target that pathway.
Notice this also applies to patients with abnormally high levels of EGFR in their tumor cells: again, may be “addicted” to this pathway.
mechanism of resistance to TKI’s caused by EGFR somatic mutations.
- There are secondary (after first treatment) mutations in EGFR that cause decreased response after an initial improvement when treated with the TKI.
- Essentially, seem to be selecting for EGFR proteins that have mutations that block TKI binding.
there are drugs that can inhibit these mutant EGFR proteins– since we know what the mutations are, we can use the sequence to target ____
inhibitory drugs.
Describe mechanism of receptor tyrosine kinase activation.
- Ligand binding drives dimerization, which activates catalytic activity of the kinase resulting in Tyrosine autophosphorylation at specific sites.
Explain molecular mechanism of stimulation of ras GTPase by RTKs
- Tyrosine Phosphorylation of receptor causes binding by SH2-domain-containing proteins including the adaptor protein Grb2, which binds a Ras GEF called Sos.
Proximity of Sos with membrane-bound Ras results in guanine nucleotide exchange.
Describe mechanism of action of two main classes of RTK-targeted anti-cancer agents (antibodies and TKI’s)
- primary role of antibodies is to block ligand binding to the receptor. TKIs inhibit catalytic activity (usually) by binding in substrate-binding site of the kinase.
List tumor cell characteristics that predict clinical response to EGFR-targeted therapeutics
-response to EGFR TKI correlated with receptor mutations that may “activate” the receptor, EGFR amplification or overexpression as determined by FISH or immunohistochemistry.
Describe mechanism of resistance to TKI’s.
Acquired resistance- second site mutations in EGFR arising or selected in patients who initially benefit from therapy but then acquire resistance and disease progression.
These mutations block inhibitor binding to the kinase active site.
May be able to design new inhibitors to avoid this problem.
Activation of other receptors like Met or ErbB2.
Combine inhibitors or make dual specificity inhibitors?
Primary resistance- if the tumor has a Ras mutation inhibiting the receptor further up the pathway will not be effective
