Receptor Tyrosine Kinases Lecture PDF

PUBLIC / CYHOEDDUS Kinase-linked receptors  PUBLIC / CYHOEDDUS Learning Outcomes Describe receptor tyrosine kinases structure Explain the activation and signal transduction of RTKs Explain insulin/insulin receptor signal...

PUBLIC / CYHOEDDUS Kinase-linked receptors  PUBLIC / CYHOEDDUS Learning Outcomes Describe receptor tyrosine kinases structure Explain the activation and signal transduction of RTKs Explain insulin/insulin receptor signalling pathway and the key role it plays in metabolism  PUBLIC / CYHOEDDUS GPCRs v RTKs G Protein Coupled Receptors Receptor Tyrosine Kinases Definition A type of cell surface receptors that have a 7 A type of enzyme-linked cell transmembrane domains surface receptors that have two monomers Structure 7 transmembrane domains Dimer From a single ligand Triggers only one cell response Trigger multiple cell responses binding Energy molecule involved GTP ATP Linked enzymes No Enzyme kinases Time scale Seconds Hours  PUBLIC / CYHOEDDUS Enzyme linked receptors Discovered through investigation of growth factors Nerve growth factor Platelet-derived growth factor Fibroblast growth factor Epidermal growth factor Once activated, this enzyme acts like an enzyme or forms a complex with another protein that acts as an enzyme Can trigger multiple signal transduction pathways at once Involved in a range of disease pathologies including diabetes and cancer  PUBLIC / CYHOEDDUS Structure Consist of:- Extracellular domain which binds the ligand Transmembrane domain Intracellular or cytoplasmic domain which contains the tyrosine kinase site Tyrosine kinase adds phosphate groups from ATP to tyrosine residues on target proteins  PUBLIC / CYHOEDDUS Receptor tyrosine kinase MOA Many variants Structure the same but MOA varies MOA Protein phosphorylation leads to an increase in gene transcription Main types Receptor tyrosine kinases Serine/threonine kinases Cytokine receptors Have no intrinsic kinase activity Activate cytosolic tyrosine kinase activity  PUBLIC / CYHOEDDUS Activation of a receptor tyrosine kinase Ligand binding to RTK monomers results in dimer formation Within the dimer the conformation is changed, locking the kinase into an active state Kinase of one receptor then phosphorylates a tyrosine residue contained in the “activation lip” of the second receptor  PUBLIC / CYHOEDDUS Signal transmission Forces the activation lip out of the kinase active site, allowing ATP binding and resulting in enhanced kinase activity. This induces phosphorylation at further tyrosine residues Phosphotyrosine is a conserved “docking site” for many intracellular signal transduction proteins that contain SH2 domains  PUBLIC / CYHOEDDUS Signal transduction Signalling protein, bound and now active, relays a signal into the cell’s interior Facilitation of signalling cascades by adaptor proteins Including a message for cell proliferation Gene mutations, that cause this pathway to be consistently turned on, are a causative factor in many types of cancer Activated receptor tyrosine kinases are only turned off when they are brought into the cell and digested by lysosomes  PUBLIC / CYHOEDDUS Insulin signalling….simple version Insulin is made and stored until required Via other cell signalling pathways, is released and travels to target cell (endocrine signalling) Insulin binds to receptor and via signal transduction results in glucose transporters moving to the plasma membrane Glucose uptake is increased.  PUBLIC / CYHOEDDUS Insulin signalling…..the reality  PUBLIC / CYHOEDDUS Members of the type II receptor tyrosine kinase (RTK) family Function as heterotetramers 2 extracellular ligand binding α subunits and two β subunits, comprising the transmembrane and tyrosine kinase domains Family consists of:- Insulin-like growth factor-1 receptor (IGF-1R) Cancer physiology Insulin receptor isoform A (InsR-A) Foetal tissue and reappears in cancer physiology Insulin receptor isoform B (InsR-B) Adult tissue metabolism  PUBLIC / CYHOEDDUS Multiple ligands can bind different receptors Binding specificity and affinity Multiple ligands exist which can bind to more than one receptor, however preferential binding does occur IGF-II is a very important mitogen which drives growth and is linked to cancer InsR-A linked to diabetes Receptors are activated when the ligand binds https://www.researchgate.net/publication/240311807_Insulin_Receptor_and_its_Relationship_with_Different_Forms_of_Insulin_Resi stance  PUBLIC / CYHOEDDUS Regulation of glucose uptake in muscle and fat cells Glucose transporters are stored in walls of cytoplasmic vesicles Insulin induced IRS-1/PI-3 kinase/PKB signalling triggers vesicle translocation to the plasma membrane Vesicle fuse with membrane where they take up glucose and pass in to the cell  PUBLIC / CYHOEDDUS Mitogen effects Grb activates Ras, Raf, MAPK pathway Phosphorylates and activates transcription factors Alters gene expression Some genes have insulin responsive elements which regulate their expression  PUBLIC / CYHOEDDUS Summary With some exceptions, RTKs usually dimerise following ligand binding Dimerisation activates intrinsic cytoplasmic tyrosine kinase which auto-phosphorylates the cytoplasmic domain of the receptor Adaptor proteins are recruited by the activated/phosphorylated cytoplasmic domain of the receptor Adaptor proteins recognise, bind and can activate other adaptor/signalling proteins Signal is propagated  PUBLIC / CYHOEDDUS Insulin example summary Insulin binds to already dimerised tetrameric insulin receptor Ligand binding induces autophosphorylation of the cytoplasmic domain of the receptor Insulin recruits the adaptor protein IRS-1 which signals through the PI3-kinase/PKB signalling pathway Insulin-induced signal transduction causes glycogen uptake and glycogen synthesis