Signal Transduction Revised


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Signal Transduction Revised

  1. 1. SIGNAL TRANSDUCTION Marigold D.R. Majarucon-Ferrolino, M.D.
  2. 2. SIGNAL TRANSDUCTION <ul><li>The process of converting extracellular signals into cellular responses. </li></ul><ul><li>extracellular signaling molecules ( ligands ) - substances synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. </li></ul>
  4. 4. SIGNAL TRANSDUCTION <ul><li>Receptor – a specific protein that specifically binds a signaling molecule to initiate a response in a target cell </li></ul><ul><li>Cell responses : </li></ul><ul><li>changes in gene expression cell morphology </li></ul><ul><li>cell movements </li></ul>
  5. 5. SIGNAL TRANSDUCTION <ul><li>Communication by extracellular signals usually involves six steps: </li></ul><ul><li>synthesis and </li></ul><ul><li>2) release of the signaling molecule by the signaling cell </li></ul><ul><li>3) transport of the signal to the target cell </li></ul><ul><li>4) detection of the signal by a specific receptor protein </li></ul><ul><li>5) a change in cellular metabolism, function, or development triggered by the receptor-signal complex ;and </li></ul><ul><li>6) removal of the signal, which often terminates the cellular response. </li></ul>
  6. 6. TWO GENERAL KINDS OF CELL RECEPTORS <ul><li>CELL SURFACE RECEPTORS </li></ul><ul><li>LIGAND – hydrophilic signaling molecules </li></ul><ul><li>INTRACELLULAR RECEPTORS </li></ul><ul><li>LIGAND – hydrophobic signaling molecules </li></ul>
  7. 8. CHARACTERISTICS OF RECEPTOR PROTEINS <ul><li>LIGAND-BINDING SPECIFICITY </li></ul><ul><li>-a ligand binds to a specific receptor </li></ul><ul><li>EFFECTOR SPECIFICITY </li></ul><ul><li>receptor-ligand complex mediates a specific cellular response </li></ul>
  8. 9. TYPES OF SIGNALING <ul><li>ENDOCRINE SIGNALING - signaling molecules (hormones) act on target cells distant from their site of synthesis by cells of endocrine organs. </li></ul><ul><li>PARACRINE SIGNALING - the signaling molecules (neurotransmitters) released by a cell only affect target cells in close proximity to it. </li></ul><ul><li>AUTOCRINE SIGNALING - cells respond to substances (growth factors) which they themselves release. </li></ul>
  9. 11. CLASSIFICATION OF HORMONES BASED ON SOLUBILITY AND RECEPTOR LOCATION <ul><li>SMALL LIPOPHILIC MOLECULES that diffuse across the plasma membrane and interact with intracellular receptors. </li></ul><ul><li>Examples: steroids, thyroxine and retinoic acid </li></ul><ul><li>WATER-SOLUBLE HORMONES with cell-surface receptors </li></ul><ul><li>Examples: Peptide hormones (insulin, growth factors, glucagons) </li></ul>
  10. 12. CLASSIFICATION OF HORMONES <ul><li>-SMALL CHARGED MOLECULES ( epinephrine, histamine) </li></ul><ul><li>LIPOPHILIC HORMONES with cell surface receptors </li></ul><ul><li>Examples: Prostaglandins </li></ul><ul><li>( prostacyclins, thromboxanes, </li></ul><ul><li>leukotrienes ) </li></ul>
  11. 13. MAJOR CLASSES OF CELL SURFACE RECEPTORS <ul><li>1)      G-protein coupled receptors </li></ul><ul><li>Examples: epinephrine,serotonin, glucagon receptors </li></ul><ul><li>2)      Ion channel receptors </li></ul><ul><li>Example : Acetylcholine receptor </li></ul><ul><li>3)      Tyrosine kinase-linked receptors </li></ul><ul><li>Examples: receptors for cytokines, interferons, and growth factors </li></ul><ul><li>4)   Receptors with intrinsic enzymatic activity </li></ul><ul><li>Examples: receptors for insulin and growth factors </li></ul>
  12. 15. SECOND MESSENGERS <ul><li>- Intracellular signaling molecules </li></ul><ul><li>3’ ,5’ cyclic AMP (cAMP) </li></ul><ul><li>3’,5’ cyclic GMP (cGMP) </li></ul><ul><li>1,2 diacylglycerol (DAG) </li></ul><ul><li>inositol 1,4,5 triphosphate (IP3) inositol phospholipids (phosphoinositides) </li></ul><ul><li>Ca++. </li></ul>
  13. 16. OTHER INTRACELLULAR SIGNALING PROTEINS IN SIGNAL TRANSDUCTION <ul><li>1) GTPase Switch Proteins – GTP-binding proteins that act as molecular switches in signal transduction pathways </li></ul><ul><li>“ ON” when bound to GTP </li></ul><ul><li>“ OFF” when bound to GDP. </li></ul><ul><li>Two classes of GTPase switch proteins: </li></ul><ul><li>a)      Trimeric G protein – coupled directly to activated receptors </li></ul><ul><li>b)      Monomeric Ras and Ras-like proteins – linked indirectly via other proteins </li></ul>
  14. 17. INTRACELLULAR SIGNALING PROTEINS <ul><li>2) PROTEIN KINASES – carry out the process of phosphorylation </li></ul><ul><li>-opposed by the activity of protein phosphatases </li></ul><ul><li>3) ADAPTER PROTEINS – no catalytic activity </li></ul><ul><li>- contain domains as docking sites for other proteins </li></ul>
  16. 19. SIGNALING VIA G-PROTEIN-COUPLED RECEPTORS (GPCR) <ul><li>G-Proteins – GTP-binding proteins </li></ul><ul><li>Trimeric proteins ( α β γ ) </li></ul><ul><li>Coupled directly to activated receptors </li></ul><ul><li>GTPases – convert GTP to GDP + Pi </li></ul><ul><li>ACTIVE- when GTP is bound </li></ul><ul><li>INACTIVE – when GDP is bound </li></ul>
  18. 23. G-PROTEIN-COUPLED RECEPTORS <ul><li>Activate events altering concentrations of intracellular mediators (SECOND MESSENGERS) </li></ul><ul><li>Common second messengers: </li></ul><ul><li>cyclic AMP (cAMP) </li></ul><ul><li>Ca++ </li></ul>
  20. 25. CYCLIC AMP (cAMP) <ul><li>Second messenger produced from hydrolysis of pyrophosphate from ATP </li></ul><ul><li>Synthesized by Adenylyl Cyclase </li></ul><ul><li>Degraded by cAMP phosphodiesterase to form 5’AMP. </li></ul>
  21. 27. CARBOHYDRATE METABOLSIM REGULATION BY cAMP <ul><li>cAMP activates glycogen phosphorylase (glygenolysis) </li></ul><ul><li>cAMP inhibits glycogen synthase (Glycogenesis) </li></ul><ul><li>Insulin inhibits cAMP </li></ul><ul><li>Glucagon and Epinephrine activates cAMP </li></ul>
  22. 28. PHOSPHOINOSITIDES <ul><li>Second messengers derived from phosphorylation of inositol by PI kinase </li></ul><ul><li>Phosphatidyl inositol (PI) </li></ul><ul><li>PI 4-phosphate (PIP) </li></ul><ul><li>PI 4,5-Biphosphate (PIP2) </li></ul><ul><li>Inositol 1,4,5-triphosphate (PI3) </li></ul>
  23. 29. TWO BRANCHES OF INOSITOL PHOSPHOLIPID PATHWAY <ul><li>Activated Phospholipase C- ß cleaves PIP2 to generate IP3 and DAG(diacylglycerol) </li></ul><ul><li>IP3 releases Ca++ from ER </li></ul><ul><li>DAG together with bound Ca++ activates C-Kinase </li></ul><ul><li>C-Kinase phosphorylates cell proteins </li></ul>
  24. 32. SIGNALING BY RECEPTOR TYROSINE KINASES AND RAS <ul><li>LIGANDS- soluble or membrane-bound protein hormones </li></ul><ul><li>NGF, PDGF, FGF,EGF, insulin </li></ul><ul><li>Binding stimulates the receptor’s intrinsic protein kinase activity </li></ul><ul><li>Functions:cell proliferation,differentia- </li></ul><ul><li>tion,cell survival and metabolism </li></ul>
  25. 33. RECEPTOR TYROSINE KINASE (RTK) <ul><li>RAS – the GTPase monomeric protein that transduce signals from RTK </li></ul><ul><li>ACTIVE – when bound to GTP </li></ul><ul><li>INACTIVE – when bound to GDP </li></ul><ul><li>Not directly linked to RTK </li></ul>
  26. 34. KEY LINKS OF RAS TO RTK <ul><li>GRB2 – adapter protein for receptor </li></ul><ul><li>SH2 domain- binds to phosphotyrosine residue in activated receptor </li></ul><ul><li>SH3 domains- bind to and activate Sos </li></ul><ul><li>Sos – functions as GEF(guanine nucleotide exchange protein) </li></ul><ul><li>- converts GDP-Ras to GTP-Ras </li></ul>
  27. 35. CYCLING OF RAS BETWEEN ACTIVE AND INACTIVE FORMS <ul><li>Guanine Nucleotide Exchange Factor (GEF) facilitates dissociation of Ras from GDP </li></ul><ul><li>GTP binds while GEF dissociates yielding active Ras*GTP </li></ul><ul><li>Hydrolysis of bound GTP to regenerate inactive Ras*GDP. </li></ul>
  28. 37. ACTIVATION OF RAS FOLLOWING BINDING OF LIGAND TO RTK <ul><li>Binding of ligand causes dimerization and autophosphorylation of tyrosine residues </li></ul><ul><li>Binding GRB2 and Sos couples receptor to inactive Ras </li></ul><ul><li>Sos promotes dissociation of GDP from Ras </li></ul><ul><li>GTP binds and Sos dissociates from active Ras </li></ul>
  29. 39. SIGNALING BY MAP KINASE PATHWAY <ul><li>MAP KINASE – serine/threonine kinase </li></ul><ul><li>Translocates into nucleus to phosphorylate proteins involved in transcription </li></ul><ul><li>Induced by activated Ras </li></ul><ul><li>Other proteins involved: </li></ul><ul><li>Raf – serine/threonine kinase </li></ul><ul><li>MEK- a dual-specificity protein kinase </li></ul>
  30. 40. CASCADE OF PROTEIN KINASES <ul><li>Activated Ras binds to N-terminal of Raf </li></ul><ul><li>Raf binds to and phosphorylates MEK </li></ul><ul><li>MEK phosphorylates and activates MAP kinase </li></ul><ul><li>MAP kinase phosphorylates nuclear transcription factors mediating cellular responses </li></ul>
  31. 42. SIGNALING FROM PLASMA MEMBRANE TO NUCLEUS <ul><li>CRE ( cAmp-response element) – cis-acting DNA sequence in genes regulated by cAMP </li></ul><ul><li>CREB (CRE-binding protein)- a transcription factor to which CRE binds </li></ul><ul><li>CBP/300 – a co-activator allowing CREB to stimulate transcription </li></ul>
  32. 43. CREB links cAMP to Transcription <ul><li>cAMP activates cAmp-dependent protein kinase (cAPK) </li></ul><ul><li>cAPK translocates to nucleus and phosphorylates CREB </li></ul><ul><li>CREB interacts with CBP/300 </li></ul><ul><li>CREB-CBP/300 complex binds to and activates transcription of target genes </li></ul>
  33. 45. MAP KINASES REGULATE TRANSCRIPTION <ul><li>MAP kinase is activated via RTK-Ras pathway </li></ul><ul><li>translocates to the nucleus and phosphorylates activators and repressors of transcription </li></ul>
  34. 46. NF-kß TRANSCRIPTION FACTOR <ul><li>A heterodimer </li></ul><ul><li>In resting cells, found in cytoplasm </li></ul><ul><li>bound to an inhibitor I- kß </li></ul><ul><li>In response to extracellular signal, I- kß is phosphorylated and degraded </li></ul><ul><li>NF- kß translocates to nucleus and binds to DNA and regulates transcription </li></ul>
  35. 48. THANK YOU!