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CHAPTER 15

CHAPTER 15. Cell Signaling and Signal Transduction: Communication Between Cells. Signal transduction. Extracellular ligand: 1st messenger Autocrine: ligand binds to producing cell Paracrine: ligand binds to a neighbor cell

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CHAPTER 15

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  1. CHAPTER 15 Cell Signaling and Signal Transduction: Communication Between Cells

  2. Signal transduction • Extracellular ligand: 1st messenger • Autocrine: ligand binds to producing cell • Paracrine: ligand binds to a neighbor cell • Endocrine: ligand binds to a distant cell after traveling through the circulatory system

  3. A Survey of Extracellular Messengers • Extracellular messengers (the signal) include: • Small molecules such as amino acids, steroids, lipids and their derivatives • Gases such as NO and CO • Various peptides and proteins serotonin Edn1

  4. Signal transduction: theme 1 (GPCR) • Cells respond to a ligand only if expressing the cognate receptor • 1st messenger • binds to cell surface receptor • triggers conformation change in the intracellular domain(s) • Activates intracellular ‘Effector’ enzymes • Effector generates 2nd messengers molecules inside the cell • 2nd messengers alter the function of further downstream factors

  5. Signal transduction: theme 2 (RTK) • Cells respond to a ligand only if expressing the cognate receptor • 1st messenger • binds to cell surface receptor • triggers conformation change in the intracellular domain(s) • Intracellular enzyme domain becomes activated (kinase) • Triggers a cascade of kinases activating additional downstream kinases • Target proteins ultimately alter cell activity • E.g. TXN, TLN, Enzymes, etc

  6. G protein-coupled receptors (GPCRs) BINDING • GPCRs involved in vision, smell, emotion (1000s of genes) • Respond to a wide variety of ligands • Proteins, small chemical compounds, metabolites, photons

  7. G protein-coupled receptors (GPCRs) BINDING • GPCRs involved in vision, smell, emotion (1000s of genes) • Respond to a wide variety of ligands • Proteins, small chemical compounds, metabolites, photons • Ligands bind to extracellular side of receptor • Induces a conformational change in intracellular domains • 7 transmembrane (7TM) receptors • serpentine structure passed through membrane 7 times N 1 2 3 4 5 6 7 C

  8. GPCRs ACTIVATION / SIGNAL TRANSMISSION • Receptor is ‘coupled’ to a large heterotrimeric G protein “switch” • Alpha, beta and gamma subunits • Alpha subunit = GTP hydrolyzing enzyme (GTPase) • GTP bound form is switched ‘on’ • GDP bound form is switched ‘off’ • The ligand-bound receptor promotes exchange of GDP for GTP “off ” “on” Active receptor GTP GDP N G-GDP G-GTP 1 2 3 4 5 6 7 Pi RGS    C

  9. GPCRs ACTIVATION / SIGNAL TRANSMISSION • Four classes of G-alpha subunit • G-alpha-s increases activity of Adenylate Cyclase (AC) • An “Effector” • ATP --> cAMP + PPi • cAMP is a 2nd messenger generated within the cytoplasm • G-alpha-i decreases activity of AC

  10. ACTIVATION / SIGNAL TRANSMISSION • G-alpha-q increases activity of the effector Phospholipase C (PLC) • PI(4,5)P2 --> DAG + IP3 • DAG and IP3 are both 2nd messengers • G-alpha-12/13 is not well understood, but is linked to cancer

  11. GPCRs TERMINATION • Regulators of G protein Signaling (RGS) • Enhance GTPase activity • GPCR-kinases (GRKs) • Phosphorylate internal portions of active receptors • Arrestins • Compete with G-alpha for binding to phosphorylated GPCR • Desensitization: loss of response to a stimulus in spite of the continued presence of the stimulus

  12. GPCR: Gas • Epinephrine: glucose mobilization • G-alpha-s • Increased AC activity • Increased [cAMP] • cAMP allosterically activates Protein Kinase A (PKA) • PKA inhibits Glycogen Synthase • PKA activates Glycogen Phosphorylase • Leads to glycogen breakdown and release of glucose • PKA stimulates TXN factor activity • Phosphorylates cAMP Response Element Binding (CREB) protein • Drives TXN of various target genes

  13. GPCR: Gaq • Increased Phospholipase C (PLC)-beta activity • Hydrolyzes specific phospholipids • Increased [diacylglycerol (DAG)] and [inositoltriphosphate (IP3)]

  14. GPCR: Gaq • DAG allosterically activates Protein Kinase C (PKC) • IP3 allosterically opens a Calcium channel on the smooth Endoplasmic Retriculum • Increased [Ca2+] in cytoplasm

  15. GPCR: Gaq • Increased [Ca2+] in cytoplasm • Ca2+ binds many cytoplasmic proteins • Calmodulin, regulator of many proteins

  16. GPCR: Gaq • Increased [Ca2+] in cytoplasm • Ca2+ can pass through GAP junctions into neighboring cells • Ca2+ gated Ca2+ channels in neighboring cells open further increasing [Ca2+] • Propagation of Ca2+ effects through GAP junctions integrates tissue response (Ca2+ waves) Video

  17. Receptor Tyrosine Kinases (RTKs) • Over 90 different genes • Extracellular ligandbinding triggers receptor dimerization

  18. Receptor Tyrosine Kinases (RTKs) • Intracellular tyrosine (Y) kinasedomain • Dimerizationallows for trans-autophosphorylation of the receptors

  19. Receptor Tyrosine Kinases (RTKs) • Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites • SH2 domains in proteins such as Src and Grb2 bind to PY-receptor

  20. Receptor Tyrosine Kinases (RTKs) • Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites • SH2 domains in proteins such as Src and Grb2 bind to PY-receptor • Drag partner proteins along with them from the cytoplasm to the membrane

  21. The Ras-MAPK pathway • Ras is a small G protein “switch” (no beta or gamma) • Over 100 Ras family genes • Lipid anchor to plasma membrane • GEF = Guanine Nucleotide Exchange Factor (e.g. Sos) • GAP = GTPaseActivating Protein • MitogenActivated Protein Kinases(MAPKs) • A large family of kinases subject to regulation by phosphorylation “off ” “on” GEF GTP GDP Ras-GDP Ras-GTP Pi GAP

  22. Disease and the Ras-MAPK pathway • Ras G12V mutations • Insensitive to GAP activity • Ras stuck in “on” state • Neurofibromatosis type I • NF1 gene encodes a GAP gene for Ras • NF1 mutations leave Ras stuck in the “on” state X “off ” “on” GEF GTP GDP Ras-GTP Ras-GDP GAP

  23. RTK

  24. RTK: Insulin receptor

  25. Convergence in signal transduction • Examples: • Integrins: • ECM --> Integrin --> Ras • RTKs: • EGF --> EGFR --> Ras

  26. Crosstalk in signal transduction • Examples: • GPCR RTK • PKA-cAMPcan inhibit Raf but activate CREB

  27. Apoptosis (Programmed Cell Death) • ~10^10 cell deaths per day in the average human

  28. Extrinsic: Receptor-mediated Apoptosis • Ligand: Tumor Necrosis Factor (TNF) • TNF --> TNF-Receptor --> Procaspase recruitment • Procaspaseproteolytically activated to form “initiator” caspase • Initiator proteolytically activates “executioner” caspases • Caspase Activated DNase (CAD)

  29. Intrinsic pathway • Irreparable DNA damage, sustained high [Ca2+] • Activates proapoptoticfactor: BAD/Bax • Punches holes in mitochondria • Release of cytochromec from mitochondria • Activates initiator caspase complex • Activates executioner caspases • Activates CAD

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