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Lecture 23: "Receptor Tyrosine Kinases"

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Western University
Biology 2382B
Robert Cumming

Cell Biology Lecture No. 23: Receptor Tyrosine Kinases Wednesday April 3 , 2013 LECTURE 22 CONT’D IP3/DAG Signalling Pathway & Ca : 2+ -This pathway can be triggered by a ligand binding to a GPCR that activates either the G or G sαounit αq leading to the activation of phospholipase C. Cleavage of PlP2 by phospholipase C yields IP and DAG. 2+ 3 After diffusing through the cytosol, IP i3teracts with and opens Ca channels in the membrane of the 2+ endoplasmic reticulum, causing the release of stored Ca ions into the cytosol. One of several cellular responses induced by a rise in cytosolic Ca is the recruitment of protein kinase C (PKC) to the plasma membrane, where it is activated by DAG. The activated membrane-associated kinase can then phosphorylate various cellular enzymes and receptors, thereby altering their activity (step 6). Nitric Oxide, cGMP & PKG: 2+ -The Ca nitric oxide (NO)-cGMP pathway is important for the relaxation of arterial smooth muscle. Nitric oxide is synthesized in endothelial cells in response to the activation of acetylcholine GPCR, 2+ phospholipase C, and the subsequent elevation in cytosolic Ca . NO diffuses locally through tissues and activates an intracellular NO receptor with guanylyl cyclase activity in nearby smooth muscle cells. The resulting rise in cGMP activates protein kinase G (PKG), leading to the relaxation of the muscle and thus vasodilation. Nitroglycerin is often used to treat angina (a severe chest pain due to isochemia – lack of oxygen supply of the heart muscle) because it decomposes into NO. Viagra Vs. Levitra & Its Mode Of Action: -Viagra acts as an inhibitor of phosphodiesterase-5 (PDE-5). PDE-5 usually converts cGMP to GMP, however when inhibited, cGMP is present longer (leading to increased activation of PKG) which results in longer periods of muscle relaxation in the penis (blood more likely to flow in). Side effects include maintenance of erection, elevated blood pressure and blood circulation issues in other parts of the body. Another interesting side effect of Viagra includes the stimulation of cyanopsia (vision that is tinted blue) due to diminished enzyme activity sensitising the retinal rod cells, which are most sensitive to wavelengths of light that appear blue-green. LECTURE 23 Introduction To Receptor Tyrosine Kinases: -Receptor tyrosine kinases (RTKs) are membrane bound receptors (have a single transmembrane α-helix) with intrinsic kinase activity in their cytoplasmic domain. Binding of a ligand (e.g. growth factors or insulin) to an RTK’s extracellular ligand-binding domain activates tyrosine kinase activity due to receptor dimerization. Phosphorylated tyrosines bind to adapter proteins, which eventually activate Ras (acts as a GTPase switch protein to signal further “downstream” kinases). Aberrant signalling is at the root of many human cancers. Activation Of Receptor Tyrosine Kinases: -The cytosolic domain of RTK contains an intrinsic protein tyrosine kinase catalytic site. In the absence of a ligand, RTKs generally exist as monomers with poorly-active kinases. Ligand binding causes a conformational change that promotes the formation of a functional dimeric receptor, bringing together two poorly-active kinases that then phosphorylate each other on a tyrosine residue in the activation lip. Phosphorylation causes the lip to move out of the kinase catalytic site, thus increasing the ability of ATP and the protein substrate to bind. The activated kinase then phosphorylates several tyrosine residues in the receptor's cytosolic domain. The resulting phosphotyrosines function as docking sites for various downstream signal transduction proteins. Adaptor Proteins: -The recruitment of intracellular signal transduction proteins to the cell membrane occurs by binding to phosphotyrosine residues in receptors or receptor-associated proteins. Cytosolic proteins with Src homology 2 (SH2) or Phosphostyrosine-binding (PTB) domains can bind to specific phosphotyrosine residues in activated RTKs or cytokine receptors. In some cases, these signal transduction proteins then are phosphorylated by the receptor's intrinsic or associated protein tyrosine kinase, enhancing their activity. Certain RTKs and cytokine receptors utilize multidocking proteins such as Insulin receptor substrate protein (IRS-1) to increase the number of signalling proteins that are recruited and activated. Subsequent phosphorylation of a receptor-bound IRS-1 by the receptor kinase creates additional docking sites for SH2-containing signalling proteins. Discovery Of The First O
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