Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 2202.08.10Lecture 10:Cell Communication IIGPCR signaling is inactivated by arrestinsCalcium transients trigger many cellular processes•Many signals trigger Ca+2 release (not just GPCRs)•Skeletal muscle contracts in response to calcium release•Ca+2 triggers regulated secretion (I.e. in neurons)•Sperm entry triggers a calcium wave during fertilizationFertilization induces a rise in Ca+2 that starts embryogenesis•Starfish egg loaded with a calcium-sensitive fluorescent dye•Fertilized in vitro and monitored by fluorescence microscopyQuickTime™ and aAnimation decompressorare needed to see this picture.Fertilization induces a rise in Ca+2 that starts embryogenesisThe effects of calcium in the cytosol are mediated by calcium-binding proteins•Protein kinase C: activated by calcium & DAG•Calmodulin: activated by conformational change by calcium binding•Ca+2 /calmodulin-dependent kinase (Cam-kinase): activated by Ca+2 -calmodulinActivation of CaM-kinase3 classes of cell surface receptorsEnzyme-linked receptors fall into 3 categories1. Receptor tyrosine kinases2. Cytokine receptors3. TGF-β receptors1. Receptor tyrosine kinases•Ligands are soluble or membrane-bound peptide or protein hormones (I.e. insulin, growth factors)•Some RTKs have been identified in studies of human cancers - mutant forms send proliferative signals to cells in absence of signalReceptor tyrosine kinases autophosporylate themselves•Phosphorylate tyrosine residues on target proteins and on themselves•Activation of a receptor tyrosine kinase stimulates assembly of a signaling complexTyrosine receptor signaling complexes•As many as 10 or 20 downstream signaling molecules - differ between receptors•Components such as phospholipases, lipid kinases, other protein kinases, and Ras•Complexes are disassembled by protein tyrosine phosphatasesReceptor tyrosine kinases activate the G protein RasGTP binding to Ras induces a conformational changeRas activates a cascade of kinases called MAP-kinasesScaffoldingproteinRTKs can activate the PI-3-kinase-Akt pathwayActivated Akt serves as a survival signal for the cell and stimulates cell growth2. Cytokine receptors•Cytokines are small secreted proteins •Control growth and differentiation of many types of tissues (I.e. induce formation of different types of blood cells, interferons)Cytokine receptors signal to the nucleus in a direct pathway3. TGFβ receptor signaling•TGFβ - transforming growth factor β•A number of related extracellular signaling molecules important during development•Exert anti-proliferative signals to cells - loss of function can contribute to malignancy•Mutations in this pathway are often associated with pancreatic cancers but also implicated in colon, liver, and gastric tumorsTGF-β receptors activate gene regulatory proteins at the membraneReceptor signaling may be inactivated via different
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