Tyrosine-Kinase Receptors

Question 1

describe tyrosine kinase receptors and their function

Answer 1

• 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

Question 2

describe the mechanism of tyrosine kinase receptor activation

Answer 2

• 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

Question 3

what happens in the Grb-2 pathway when tyrosine kinase receptors become activated?

Answer 3

• 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

Question 4

what happens in the PI-3-kinase pathway when tyrosine kinase receptors become activated?

Answer 4

• 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

Question 5

what is an example of a PKR?

Answer 5

insulin receptors

Question 6

how are insulin receptors structurally different from normal PKRs?

Answer 6

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

Question 7

how do insulin receptors work?

Answer 7

• 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

Question 8

how are TKRs inactivated?

Answer 8

• when the receptor is activated, phosphatases are activated

- phosphatases dephosphorylate TKRs

Question 9

how is RAS inactivated?

Answer 9

-GTPase activating protein activates GTPase
-GTPase removes phosphates on GTP which leads to the inactivation of RAS
-

Question 10

what can happen if there are mutations in the TKR mechanisms?

Answer 10

• 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

Question 11

what is the JAK-STAT signalling pathways stimulated by?

Answer 11

growth hormone

Question 12

what happens in the JAK-STAT signalling pathway?

Answer 12

• 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

Question 13

what are serine-threonine kinase receptors?

Answer 13

2 single transmembrane receptors

Question 14

what binds to the type 2 serine-threonine receptor?

Answer 14

TGF-β

Question 15

what does TGF-β do?

Answer 15

• 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