Week 3 - Receptor Tyrosine Kinase

Question 1

How is RTK activated?

Answer 1

• inactive receptor monomers
• closed tyrosine incorporated within
• ligand binds
• monomers move closer together
• dimerisation
• tyrosine open
• autophosphorylation
• receptors phosphorylate each other
• further phosphorylation occurs

Question 2

How are the RTK signalling complexes assembled?

Answer 2

• docking sites bind to the receptor
• they are amino acids, which recruit and activate signalling molecules
• RTKs contain protein recognition domains
• recognise molecules required for cell signal transduction
• e.g phosphorylated tyrosine, phospholipids, proline rich proteins
• signalling molecules phosphorylate ( enzymatic activity from kinase or GTPase) and get phosphorylated
• adaptors only get phosphorylated

Question 3

What is the Ras signalling pathway?

Answer 3

• Grb-2 (*Growth factor Receptor-Bound protein-2) binding
• protein contains Sos
• Sos contains GEF
• GEF phosphorylates GDP to GTP
• Ras is activated
• Raf activates MEK
• MEK activates Erk1/2
• promotes protein synthesis and transcription for proliferation, differentiation, and migration
• deactivated by GAP (GTP hydrolysis)
• deactivation can be blocked by oncogenic mutation

Question 4

What is the PI3K signalling pathway?

Answer 4

• Protein Inositol 3 Kinase
• a lipid kinase
• P110 subunit phosphorylates PIP₂ to form PIP₃
• PIP₃ recruits PH domains that contain AKT and PDK1 proteins
• PH with AKT can bind to PIP₂ but it has a higher affinity to PIP₃
• binding of PH domain is not enough to activate AKT protein, so PDK1 and mTOR phosphorylate AKT to fully activate
• promotes metabolism, survival, and proliferation

Question 5

How is RTK signalling regulated?

Answer 5

• phosphotases (e.g. GAP)
• endocytosis
• ubiquitination
• degradation
• lipid phosphatase (e.g. PTEN) inhibits formation of PIP₃
• protein phosphatases (e.g. PP2A) inactivates Akt

Question 6

How can RTKs cause cancer?

Answer 6

• they are proto-oncogene
• its over expression/ gene amplification/ modification will cause it to become an oncogene
• mutation can cause ligand-independent firing
• autocrine signalling