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Lecture notes of 20 pages for the course Cell Biology and developmental genetics at QMUL
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Growth factor receptor signallingLearning objectives:
1. Signalling cascades
- Ras
- AKT
Must know well
Come up in exam
- JAK-STAT
- TGF-beta signalling
- Beta-catenin
- G-protein
2. Deregulations in cancer
Signal pathway
• Signal molecule (ligand) outside the cell
• Receptor intracellular signal
• Target protein
• Response
Growth factor receptor signalling – overview + plan of the lecture
1. GF binds to and activates RTK receptor
2. Assembly of RTK signalling complexes
3. Trigger RTK signalling pathway
- Immediate response (change in cytoskeleton)
- Slow response (central dogma)
4. How RTK signalling is switched off
5. What can go wrong in cancer
,Receptor tyrosine kinase: RTK
• Large family of RTK
• All have a single chain except insulin or insulin related receptor tyrosine kinase
• All are transmembrane receptors (span the membrane 7 times)
• Blue = kinase domain (enzymatic activity) for phosphorylation.
1-RTK activation (step 1: how is RTK activated)
Conformational change, dimerization
• Initially thought that the ligand binds to the monomer and then they dimerise and become activated- this is true but
not as simple. RTK in the cell can be found in different stages.
- Some can be found as monomer and some can be found as inactive dimer.
- Sometimes RTK can be found as active dimer as the monomers are close to each other and as a result can
trans autophosphorylate each other
- There is an equilibrium between these different sages
- The active dimer is not stable without ligand and therefore there are not many of these active dimers in the
cell
- However, once ligand binds to the active dimer, the active dimer becomes stable
• This mode of RTK activation is found in many RTK such as EGFR, FGFR, c-Met
1. Inactive monomers
2. Inactive dimer
3. Active dimer
, - Can have active dimer without ligand binding because both monomers can trans auto phosphorylate each
other
4. Ligand bound active dimer
5. Active dimer
- The active dimer is not stable without the ligand, therefore not highly present in the cell.
- Once a ligand binds to the active dimmer, the reaction goes from step 4,3,2,1 hence the reverse arrows.
Conformational change
• This mode of activation is found in insulin receptor (hence this mode is an exception because the insulin receptor is
already a dimmer)
1. Inactive dimer
2. Active dimer
3. Ligand active bound dimer
2-RTK signalling complexes assembly
• Once the RTK is activated, get assembly of signal complex
• Blue box = kinase domain
• For photoreceptor to be activated:
- Need Trans auto phosphorylation between each of the 2 monomers in the dimmer, which results in
Phosphorylation in the kinase domain
Also called activation loop
• Once dimmerised, there is conformational change in the receptor to enable ATP binding to get phosphorylation
• The kinase is active and is able to phosphorylate itself first
• The kinase of a receptor phosphorylates residues downstream
• Below the kinase domain is docking sites
• The docking sites have 1 specific tyrosine, once the tyrosine is phosphorylated it binds to a signalling molecules
• There are 2 different classes of molecules that will bind to the docking sites
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