1st December 2016 Endocrinology Signal Transduction: The JAK-STAT PATHWAY Cytokines Cytokines are small-secreted proteins that by binding to transmembrane receptors regulate cell · Survival · Proliferation · Differentiation · Activation All kinds of cellular activities Where the research is concentrated: Cytokines play especially key roles in immune, hematopoietic and neuronal cell lineages. Receptor Families So many functions, as there are so many tissues that use them Cytokines signal through transmembrane receptors that can be grouped according to their extracellular and cytoplasmic domains. · Tyrosine kinase receptors · Serine-threonine kinase receptors · Class 1 cytokine receptors · Class 2 cytokine receptors · Tumour necrosis factor-related · Immunoglobulin superfamily (non-RTK) · G-protein coupled receptors Examples of Class 1 Cytokine Receptors Homomeric (both subunits encoded by the same gene) receptors: · Leptin - satiety · Growth hormone · Prolactin · Erythropoietin - involved in RBC production · Thrombopoietin - makes platelets · GCSF - kills of cancer cells (mobilises neutrophils) Multimeric (more than two subunits) receptors: · Shared b: IL-3, IL-5, GMCSF · Shared gp130: IL-6, IL-11, IL-27, IL-31, CNTF, CT-1, LIF, OSM, Osteopontin · Shared g: IL-2 (T cell proliferation), IL-4, IL-7, IL-9, IL-15, IL-21 Examples of Class 2 Cytokine Receptors Multimeric Receptors: · Interferon-a, interferon-b, interferon-g, (important anti-viral compounds) · IL-10 (superfamily)
1st December 2016 Endocrinology 4-Helix Bundle Cytokines All Class 1 Cytokine Receptors bind ligands that have a common four-alpha helical structure. (Bind those that look a like) Class 2 Cytokine Receptors bind ligands with a variety of structures Structure of Growth Hormone Human Growth Hormone (long-chain 4-helix bundle) Gene duplication that replicates the ligand, and the receptors start changing due to gene duplication. Wep helices/monomeric) The genes are duplicated and put together to form different structures - the amino acids on top are changed to form different ligands. Crystal structures are not what it is exactly; need to consider that the structure doesn't look like that all the time. Murine Interferon- beta (5 IL-10 is a homodimer Interferon-gamma is a homodimer Receptor Features Cytokine Class 1 Receptor Extracellular: Hematopoietin domains: · WSXWS motif (tryptophan, serine, any amino acid, tryptophan, serine) gives a structural role in the structure · 4 conserved cysteine residues Intracellular: NO INTRINSIC KINASE ACTIVITY - not kinases Conserved membrane-proximal a-helical segment that binds JAKs Cytokine Class 2 Receptors Extracellular:
1st December 2016 Endocrinology Hematopoietin domains: · 4 conserved cysteines but doesn't have the WSXWS domain Intracellular: NO INTRINSIC KINASE ACTIVITY Conserved membrane-proximal a-helical segment that binds JAKs JAK-STAT PATHWAYS JAK: cytoplasmic tyrosine kinases (110-140 kDa) have an active kinase and pseudo kinase domain and a receptor binding domain Receptor association FERM 1 JAKs associate with the receptor in the cytoplasm NH2 PKD JH7 JH6 JH5 JH4 JH3 JH2 KD COOH JH1 STATS are used by JAKs to get the signal to the nucleus STAT: signal transducer and activator of transcription 1. Transcriptional Activation domain - help recruit RNA polymerase II to the DNA for transcription 2. Protein-protein interaction domains (bind to other transcription factors) 3. DNA