Tyrosine-Kinase Receptors Flashcards
describe tyrosine kinase receptors and their function
- predominantly single transmembrane domain receptors
- activation leads to the activation of receptor kinases and activation of multiple signalling pathways
- involved in the regulation of growth, division, differentiation, survival, migration
describe the mechanism of tyrosine kinase receptor activation
- phosphorylation forms docking domains
- two signalling molecules bind to 2 separate receptors
- the two molecules form a dimer, causing the 2 receptors to join together
- this leads to autophosphorylation of specific tyrosine residues
- the formation of phosphotyrosine means the SH2 domain is recognised by other proteins to allow them to bind and undergo activation
what happens in the Grb-2 pathway when tyrosine kinase receptors become activated?
- the Grb-2 protein binds to the SH2 domain on the receptor and Grb-2 undergoes conformational change
- Grb-2 interacts w GEF protein at SH3 domain
- GEF undergoes conformation and activates RAS protein which has a GDP molecule attached
- when activated, RAS exchanges GDP for GTP
- activated RAS and GTP goes on to activate other intracellular pathways
what happens in the PI-3-kinase pathway when tyrosine kinase receptors become activated?
- PI-3-kiase is activated when it binds to specific residue on TKR
- PI-3-kinase goes and phosphorylates PIP2 to PIP3
- PIP3 binds to activating protein PDK1 and protein kinase B
- PDK1 phosphorylates and dissociates from PIP3
- PDK1 then activates other proteins
what is an example of a PKR?
insulin receptors
how are insulin receptors structurally different from normal PKRs?
insulin receptors have 2 α chains and 2 β chains which are linked together by disulfide bonds whereas normal PKRs do not have any chains
how do insulin receptors work?
- when insulin is absent, the receptor is unable to phosphorylate
- when insulin binds, the receptor phosphorylates and binds to insulin receptor sublates (IRS)
- IRS binds to PI-3-kinase and activates it
- PI-3-kinase binds to PKB
- the dissociated PKB activates glycogen synthesis + protein synthesis and increases expression of glucose receptors on cells
- this increase glucose intake of cells
how are TKRs inactivated?
- when the receptor is activated, phosphatases are activated
- phosphatases dephosphorylate TKRs
how is RAS inactivated?
-GTPase activating protein activates GTPase
-GTPase removes phosphates on GTP which leads to the inactivation of RAS
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what can happen if there are mutations in the TKR mechanisms?
- can lead to cancer:
- receptor expression: can increase or decrease in different diseases
- loss of phosphatase activity: increases PDK1 activity
- loss of GTPase activity: RAS activated for longer time
- loss of phosphatase activity on receptor: inhibit inactivation process
what is the JAK-STAT signalling pathways stimulated by?
growth hormone
what happens in the JAK-STAT signalling pathway?
- when GH binds to the receptor, causes a conformational change
- this allows one GH molecule to bind to 2 receptors
- JAK is cross-phosphorylate each other on tyrosine
- activated JAKs phosphorylate receptors on tyrosine residue
- the phosphorylated receptors act as a binding site for STAT
- JAK phosphorylates STAT which causes STAT to dissociate and form a homodimer at the SH2 domain
- the STAT dimer enters the nucleus and has a high affinity to a specific DNA binding site and regulates gene expression
what are serine-threonine kinase receptors?
2 single transmembrane receptors
what binds to the type 2 serine-threonine receptor?
TGF-β
what does TGF-β do?
- forms a dimer with the type 1 receptor which activates T1
- the activated T1 receptor binds to a specific smad protein that phosphorylates on the serine residue
- phosphorylated smad dissociates and forms a complex w smad4
- the complex translocates to the nucleus and regulates genes
