02.08.10Lecture 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 microscopyFertilization 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 membraneSignaling pathways exhibit a high degree of interconnectednessSome signaling proteins act to integrate incoming signalsReceptor signaling may be inactivated via different
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