PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Cell Communication 1Chapter 16 Cell CommunicationThe major signalingpathways relevantto cancerYou will not be responsible for: Specific downstream signaling pathwaysQuestions in this chapter you should be able to answer:Chapter 16:1 - 10 11all but e, 12,13,16,17,18, 19, 20, 22, 24, 25Cell Communication 2How do cells communicate with each other?Signaling mechanismsSignaling responsesCell Communication 3What types of molecules carry signals to cells?1) Gases (really small)NO, H2S, CO2) ‘Smallish’ organic moleculessteroidsneurotransmitters[drugs/poisons (nicotine, phytohormones, etc)]3) Peptide hormones (much bigger)EGFCell Communication 4Where are the receptors?Intracellular receptorsvs Cell-surface receptorsCell Communication 5How do cell surface receptors function?Signal transductionPathwaysSignaling proteinsSecondary Signals -- cAMP, Ca++, DAG, IP3FSH & ReceptorCell Communication 6Signaling pathways can interactMultiple signalsProcessed simultaneously Activating or inhibitingSignal integrationCell Communication 7What are the three types of cell surface receptors?= Ligand-gated channelCell Communication 8How are G-proteins activated?“7-pass” receptors-- Hundreds of different types-- triggering enumerable different cytoplasmic processesExamplesGlucagon – activates glucose release by liverLutenizing Hormone (LH) – triggers progesteronerelease from ovaryAdrenalin (epinephrine) – increases heart rateAllergen – mast cell degranulationG-protein-linked receptorsCell Communication 9Acetylcholine acts at a G-protein-linked receptor on heart muscle to make the heart beat more slowly by the effect of the G protein on a K+ channel, as shown in this Figure. Which one or more of the following would enhance this effect of acetylcholine? Explain.(a) A high concentration of a non-hydrolyzable analog of GTP.(b) Mutations in the acetylcholine receptor that weaken the interaction between the receptor and acetylcholine.(c) Mutations in the G protein α-subunit that speed-up the hydrolysis of GTP.(d) Mutations in the K+ Channel that make the βγ-subunit bind tighterCell Communication 10How do activated G-proteins trigger release of ‘secondary messenger’ molecules?-- open channels-- activate enzymesSecondary messengers include:cAMP, Ca++, DAG, IP3Some toxins interfere with G-proteinsCholera toxin Inhibits GTPase activity of α-subunit-- causes Na+ efflux into intestine -- water flow into intestinePertussis toxinPrevents GDP/GTP exchange-- GTP locked in off state-- mucous secretion into lungscAMP SignalingCell Communication 11Downstream effects can be Downstream enzyme activation (can be very rapid)-- effect of adrenalineChanges in gene expression(slower)There can be many other types of responsesBlock gene expressionActivate exocytosis-- allergic responses-- insulin release or endocytosis-- phagocytic cellsCell Communication 12Retina contains G-protein coupled light receptorsRod cellsActivation ↓ Na+ flow Na channel gated by cGMPRhodopsinTransducin (G-protein)-- activates cGTP phosphodiesteraseΔ Membrane potentialQuestion 16-8P 556Cell Communication 13How do enzyme-linked receptors function?Receptor Tyrosine Kinases (RTK)DimerizationAutophosphorylationActivated signaling proteinsCell Communication 14RTK Signaling often occurs through RasA “monomeric” GTP-binding proteinRAS activates a kinase “cascade” (MAP Kinase module)Cell Communication 15Signaling Pathways and CancerOncogenes -- Deregulated cell proliferation-- mitogens and growth factorsConstitutive Activation/SignalingRAS mutations are common in cancersCell Communication 16How are complex signally pathways ‘dissected’?Genetically engineer cells to contain…-- Knockout mutations-- Constitutive expression mutationsHow do these 5 experiment establish signaling sequence of RAS, X and Y?Cell Communication 17When activated by the signal, the platelet-derived growth factor (PDGF) receptor phosphorylates itself on multiple tyrosines (as indicated below by the circled Ps; the numbers next to these Ps indicate the amino acid number of the tyrosine). These phosphorylated tyrosines serve as docking sites for proteins (A, B, C, and D) that interact with the activated PDGF-receptor. Binding of PDGF activates the PDGF-receptor leading to an increase in DNA synthesis. To determine whether protein A, B, C, and/or D are responsible for activation of DNA synthesis, you construct mutant versions of the PDGF-receptor that retain one or more tyrosine phosphorylation sites. In the cells, the various versions of the PDGF-receptor become phosphorylated on whichever tyrosines remain. You measure the level of DNA synthesis in cells that express the various mutant receptors and obtain the data shown below.A. From these data, which, if any, of these proteins A, B, C, and D are involved in the stimulation of DNA synthesis by PDGF? Why?B. Which, if any, of these proteins inhibit DNA synthesis? Why?C. Which, if any, of these proteins appear to play no detectable role in DNA synthesis? Why?D. What is the effect of the binding of A on the effect of