Tyrosine Kinase Signalling Pathways Flashcards
What receptors do hydrophilic molecules interact with?
Hydrophilic molecules cannot pass through membranes, so have to interact with extracellular receptors.
What receptors do hydrophobic molecules interact with?
Hydrophobic molecules can pass through membranes so can interact with intracellular receptors.
What is a transmembrane receptor made up of and what does it do?
A cystine rich hydrophobic domain (head) which interacts with the ligand.
A hydrophobic tyrosine kinase domain (tail) that interacts with downstream signalling machinery.
How is information transmitted from the ligand receptor to the effector?
Dimerization.
Conformational changes to membrane receptors, which are associated with G proteins.
What is dimerization?
Each ligand binds to a receptor.
The receptor brings the ligands together and they activate each other.
What is a Drosophila eye made up of?
Each eye is made of 800 ommatidia.
What is in an ommatadia?
8 photoreceptors
4 cone cells
2 primary pigment cells
6 secondary pigment cells
3 tertiary pigment cells
What pathway is required for R (photoreceptor) cell recruitment?
Ras / Raf / MEK / ERK pathway.
What is Ras?
A small GTPase. Controlled by GEFs and GAPs.
What is a GEF?
G protein exchange factor.
What is a GAP?
GTPase activation protein.
What happens in the first stage of the Ras pathway?
PDGF ligand is dimerized.
It has a high affinity for receptors (K alpha)
What is the affinity for K alpha receptors?
10^-10 M
What happens in the second stage of the Ras pathway?
Trans membrane P-Y residues are phosphorylated in cytositic tail.
What happens in the third stage of the Ras pathway?
P-Y residues bind to SH2 domain on GRB2 adaptor protein.
What happens in the fourth stage of the Ras pathway?
SH2 binds to SOS protein which is a GEF.
What happens in the fifth stage of the Ras pathway?
SOS-GEF switches GDP to GTP, which activates Ras.
What happens in the sixth stage of the Ras pathway?
Ras-GTP is binds to inhibitory domain of MEK. MEK is switched on.
What happens in the seventh stage of the Ras pathway?
MEK activates ERK.
MEK and ERK are S/T kinases.
What happens in the eighth stage of the Ras pathway?
ERK translocate to the nucleus and interacts with TIS, triggering gene expression.
What signalling pathway is activated in 80% of melanomas?
Ras / Raf / MEK / ERK
What mutation in the Ras pathway causes melanoma?
V600.
In the kinase activation loop.
What was / is melanoma treated with.
Melanoma was treated with BRAF kinase inhibitors, which works well at first before resistance is developed.
Now, BRAF and MEK inhibitors are used.
What is the JAK / STAT signalling pathway?
Made of 4 janus kinases
and 7 signal transducer and activator transcriptions
What are the 4 janus kinases? (JAK)
JAK1
JAK2
JAK3
TYK2
What are the 7 signal transducer and activator transcription (STAT)
STAT1-4
STAT5a
STAT5b
STAT6
What mutation causes myleoproliferatice neoplasms?
JAK2 V617F
What is a type I inhibitor?
Bind to active conformation of the kinase. Aspartate residue facing the ATP binding pocket.
What is a type II inhibitor?
Bind to the inactive conformation of the kinase. Aspartate residue binds facing away from ATP binding pocket.
What is a type III inhibitor?
Occupy an allosteric pocket adjacent to ATP binding site.
What is a type IV inhibitor?
Occupy an allosteric pocket away from ATP binding pocket.
