11. Receptor Tyrosine Kinases Flashcards
give two examples of receptor tyrosine kinases
platelet derived growth factor receptor
insulin receptor
what are platelet derived growth factor receptors involved in
embryonic development
cell proliferation & migration
on epidermal growth factor receptors, what is the ligand
epidermal growth factor
what is epidermal growth factor involved in
cell growth
proliferation
differentiation
what does the cytosolic domain of a RTK contain
a c-terminal tyrosine rich tail
what happens when the ligand binds
binding of the ligand creates a conformational change
which exposes the dimerisation arm
dimerisation arms interact and dimerisation occurs
which region of the RTK contains the dimerisation arm, when is It available
region 2
- only visible when the receptor is stimulated
what does dimerisation induce
autophosphorylation on tyrosine residues on the activation lip of tyrosine kinase
what are the phosphorylated residues often used as?
docking sites between proteins to allow interactions and for the signal to be transducer from the receptor down through the signalling cascade
how do kinases interact
asymmetrically
explain the roles of acceptor and donor kinases
acceptor kinase is activated by donor kinase which moves out from the active site
= phosphorylation
what does MAPK stand for
mitogen activated protein kinease
what is GRB
an adaptor protein
what domains does GRB contain
SH2 and SH3
what does the SH2 domain in GRB interact with
phospho-tyrosine residues
what can GRB2 do that GRB cannot
bind to phospho-tyrosine residues on other proteins
what can GRB2’s SH3 domain bind
Sos
how does GRB2 bind to RTKs
via its SH2 domain
what does SOS bind to
Ras
what must be activated to recruit downstream signalling proteins
monomeric G-protein Ras
what allows Ras to bind GTP or GDP
a guanyl nucleotide binding site
what enzyme converts GTP into GDP as soon as GTP binds
intrinsic GTPase activity
what molecule promotes GDP exchange for GTP
guanine nucleotide- exchange factor (GEF)
what molecule accelerates GTP hydrolysis
GTPase-activating protein
what is the function of Sos
pries Ras open - allowing GDP to diffuse out
- promoting GTP binding
what displaces Sos
switch I & II interacting with GTP
what happens when Sos dissociates from Ras
Ras is then free to activate downstream signalling components
what is responsible for 50% of colorectal tumours
a single activating point mutation in the K-ras oncogene
- interferes with GTPase activity
now that Ras is activated, what does it next bind to
the N-terminal of Raf
what activates Raf
dephosphorylation of a serine that binds Raf to regulatory proteins
what causes Raf to dissociate from the 14-3-3 regulatory protein
hydrolysis of GTP
= Ras-GDP
what does Raf kinase phosphorylate
MEK
what is the name of the regulatory protein Raf is bound to
14-3-3
once activated, what does MEK next activate>
another kinase called MAPK
what is MAPK called in humans
ERK
what does MEK use to activate the MAPK
MAP kinase kinase
what is Raf
a MAP kinase kinase kinase
what does active MAPK do
dimerises and phosphorylates protein kinase
p90
where do active MAPK and p90 migrate to
the nucleus
what does MAPK and p90 do in the nucleus
phosphorylates TCF and SRF
what does TCF stand for
ternary complex factor
what does SRF stand fro
serum response factor
what does phosphorylated SRF and TCF bind to?
serum response element
SRE
