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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. Signal transduction • Cells respond to a ligand only if expressing the cognate receptor • 1st messenger binds to receptor • Outside cell • Binds to cell surface • Effectors generate 2nd messengers • Inside cell • Signal amplification • Some diffuse through cytosol • Some diffuse within plasma membrane • Exert allosteric effects on various enzymes & proteins

  4. Signal transduction • Cells respond to a ligand only if expressing the cognate receptor • 1st messenger binds to receptor • Outside cell • Binds to cell surface • Alters receptor conformation • Signaling pathway • Each protein alters the conformation of next protein • Conformation usually altered by phosphorylation • Target proteins ultimately alter cell activity • E.g. TXN, TLN, Enzymes, etc • Signal amplification

  5. 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

  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) domains • 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” GTP GDP G-GDP G-GTP N Active receptor 1 2 3 4 5 6 7   RGS G-GDP G-GTP  C Pi

  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. Signal transduction • 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. GPCRs • G-alpha-q • Increased Phospholipase C (PLC)-beta activity • Hydrolyzes specific phospholipids • Increased [diacylglycerol (DAG)] and [inositol triphosphate (IP3)]

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

  15. G-alpha-q • Increased [Ca2+] in cytoplasm • Ca2+ binds many cytoplasmic proteins • Calmodulin, regulator of many proteins

  16. G-alpha-q • 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. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • Extracellular ligand binding domain • Ligand binding triggers receptor dimerization

  18. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors

  19. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites for additional protein factors • SH2 domains in proteins such as Src and Grb2 bind to PY-receptor

  20. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites for additional protein factors • 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. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • The Ras - Mitogen Activated Protein Kinase (MAPK) pathway • Ras is a small G protein “switch” (single subunit, no beta or gamma) • Over 100 Ras family genes • Lipid anchor to plasma membrane • Disease: ~30% of cancers have activating Ras mutations (break the GTPase) “off ” “on” GTP GDP Ras-GDP Ras-GTP GEF GAP Ras-GDP Ras-GTP Pi

  22. Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes • The Ras - Mitogen Activated Protein Kinase (MAPK) pathway • Ras is a small G protein “switch” (single subunit, no beta or gamma) • GEF = Guanine Nucleotide Exchange Factor (e.g. Sos) • GAP = GTPase Activating Protein “off ” “on” GTP GDP Ras-GDP Ras-GTP GEF GAP Ras-GDP Ras-GTP Pi

  23. RTK: Insulin receptor

  24. Signal transduction • Convergence • ECM --> Integrin --> Ras • EGF --> EGFR --> Ras

  25. Signal transduction • Crosstalk • cAMP can block growth by inhibiting Raf

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