Receptor Tyrosine Kinase signaling Flashcards
What are receptor tyrosine kinases?
- an enzyme coupled receptor
- have intrinsic kinase activity
- phosphorylate substrates on tyrosine residues
- ligand binding outside the cell activates the kinase inside the cell
What is the structure of the tyrosine kinase domain?
- have 2 domains linked together by a flexible region
- N terminal domain contains an ATP binding site
- C terminal domain contains substrate binding site and 2 alpha helices that determine specificity by the exposed amino acids in the helix
- activation loop in the C terminal domain
- contains one or more Tyr molecules
- binds to catalytic cleft
What 2 conformations is the activation loop in for tyrosine kinase domain?
unphosphorylated form - sits in the substrate binding site
phosphorylated form - the loop flips away from the binding site
How do drugs inhibit RTKs?
bind to the ATP binding site on the N terminal domain
How does the RTK become activated?
- receptor dimerisation and inter-molecular phosphorylation
- forced dimerisation activates RTK signalling in the absence of ligand
- ligand acts to dimerise receptors
What is achondoplasia?
- commonly known as dwarfism
- premature stopping of long bone elongation
- mutations in FGFR3
- causes transmembrane domain to dimerise in the absence of ligand
What is crozoun syndrome?
- genetic disease resulting in premature fusion of skull bones
- mutations in the extracellular domain of FGFR2 which produces cysteine residues
- leading to covalent dimerisation and activation of signalling in the absence of ligand
What happens during ‘dominant negative’ receptor mutants?
- a receptor is mutated to lack kinase domain
- unable to signal even though they do bind the ligand as usual
- can block a wild type receptor from signalling due to dimerisation
What does activation of kinase lead to in RTK?
- inter receptor phosphorylation of the tyrosine residues seen in C terminal tail of receptor
- auto phosphorylation
- recruitment of substrates
- this causes binding sites for signalling proteins
- activated signalling proteins relay signals downstream
How does RTK recruits its substrates?
- by specific recognition of pTYR by SH2 and PTB domains
- these domains have tyrosine phosphate specific binding functions
- binding site for phosphotyrosine and amino acid side chain
How does the signal start from when the RTK is activated?
- The SH2 domain of the adaptor protein (Grb2) is recruited to the activated RTK tails
- Recognition domain SH3 in Grb2, recruits a protein called Sos (Ras-GEF)
- When Sos is recruited, it interacts with inactive Ras protein (which is a G-protein) and displaces GDP with GTP and activates Ras
- Can interact with downstream pathways
What downstream pathway is activated by Ras GTPase?
- MAP kinase cascade
- sequence of kinases that phosphorylate each other
- terminal phosphorylase (Erk) phosphorylates and initiates a range of changes of behaviour
What are cytokine receptors?
- family of structurally related ligands and receptors
- ligand recognition mechanism
- act via receptor dimerisation
- signal via activation of JAK (just another kinase lol) family through phosphorylation of the STAT family
Why are cytokines medically important?
erythropoetin: - induces proliferation of erythroblasts - treatment for anemia G-CSF: - induces the proliferation of neutrophils - treatment with chemo
What is the structure of the receptor that growth hormones (and cytokines) bind to?
- has cytokine homology domain where 2 modules are at right angle to each other
